Next Article in Journal
Water-Tree Characteristics and Its Mechanical Mechanism of Crosslinked Polyethylene Grafted with Polar-Group Molecules
Next Article in Special Issue
Increased Secreted Frizzled-Related Protein 5 mRNA Expression in the Adipose Tissue of Women with Nonalcoholic Fatty Liver Disease Associated with Obesity
Previous Article in Journal
Mechanical Disturbance of Osteoclasts Induces ATP Release That Leads to Protein Synthesis in Skeletal Muscle through an Akt-mTOR Signaling Pathway
Previous Article in Special Issue
Lysine Deprivation Regulates Npy Expression via GCN2 Signaling Pathway in Mandarin Fish (Siniperca chuatsi)
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:

The Role and Regulatory Mechanism of Brown Adipose Tissue Activation in Diet-Induced Thermogenesis in Health and Diseases

Department of Physiology & Biophysics, National Defense Medical Center (NDMC), 161, Section 6 Min-Chuan East Road, Taipei 114, Taiwan
Graduate Institute of Medical Science, National Defense Medical Center (NDMC), 161, Section 6 Min-Chuan East Road, Taipei 114, Taiwan
Department of Medical Research, Tri-Service General Hospital, Taipei 114, Taiwan
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2022, 23(16), 9448;
Submission received: 28 July 2022 / Revised: 15 August 2022 / Accepted: 18 August 2022 / Published: 21 August 2022
(This article belongs to the Special Issue Nutrition and Metabolism in Health and Disease: From Gene to Organism)


Brown adipose tissue (BAT) has been considered a vital organ in response to non-shivering adaptive thermogenesis, which could be activated during cold exposure through the sympathetic nervous system (SNS) or under postprandial conditions contributing to diet-induced thermogenesis (DIT). Humans prefer to live within their thermal comfort or neutral zone with minimal energy expenditure created by wearing clothing, making shelters, or using an air conditioner to regulate their ambient temperature; thereby, DIT would become an important mechanism to counter-regulate energy intake and lipid accumulation. In addition, there has been a long interest in the intriguing possibility that a defect in DIT predisposes one to obesity and other metabolic diseases. Due to the recent advances in methodology to evaluate the functional activity of BAT and DIT, this updated review will focus on the role and regulatory mechanism of BAT biology in DIT in health and diseases and whether these mechanisms are applicable to humans.

1. Introduction

The thermogenic activity of BAT is stimulated by cold and also by a meal that induced a parallel increase in heat production, which has been well-documented to resist obesity through facilitating adaptive thermogenesis and energy expenditure (EE) both in rodents and humans [1]. BAT possesses a higher capacity to metabolize glucose and fatty acids, promotes heat production and EE, and is characterized by multilocular small lipid droplets, high mitochondrial density, and the expression of key thermogenic protein-uncoupling protein 1 (UCP1). There is evidence supporting that BAT could significantly affect whole-body energy metabolism in rodents and humans [2,3]. Therefore, BAT activation has been considered a potential therapeutic target in the treatment of obesity and related diseases [4].
In humans and rodents, the resting metabolic rate (RMR) accounts for 60–70% of whole-body EE, which is required for the performance of cellular and organ functions [5,6]. RMR is majorly determined by fat-free mass in the body. In general, gender difference and aging are the two main physiological factors to affect RMR [7,8,9], which may be due to differences in fat-free mass, especially skeletal muscle [10]. DIT is the increase in EE associated with food intake [11] and accounts for 5–15% of total EE [12]. The magnitude of the thermic effect of food depends on diet composition and caloric intake. DIT represents about 10% of daily total EE in healthy subjects [11]. DIT also could be affected by oral stimuli (i.e., the duration of tasting food and chewing in the mouth) [13], and environmental factors [14].

2. Translational Aspects of BAT-Mediated Adaptive Thermogenesis on the Maintenance of Whole-Body EE

Obesity caused by excess fat storage is a consequence of a long-term imbalance of energy intake and EE, which is detrimental to the health of people. Understanding the counter-regulatory mechanisms of energy metabolism is critical to the development of effective therapies to treat the epidemic of obesity. However, so far, therapeutic approaches aiming at increasing EE remain inconclusive. The currently developed drug targets have either low efficacy or severe cardiometabolic effects [15], which remain crucial for future drug development [4,16].
BAT has been speculated as a potential anti-obesity target due to its capacity for adaptive thermogenic activity and contribution to total daily EE. So far, the studies conducted with rodent models have provided a major understanding of the BAT contribution to whole-body energy metabolism [17]. Notwithstanding, the majority of fat depots are similar in rodents and humans. Mouse BAT is mainly distributed in the interscapular BAT and some small depots are found in the cervical, axillary, perivascular, and perirenal regions [18]. Metabolically active BAT is found in adult humans in the neck and supraclavicular regions [18,19].
A recent human study has demonstrated that subjects with BAT activity were independently correlated with a lower prevalence of type 2 diabetes, dyslipidemia, and cardiovascular diseases. In particular, the beneficial effects were more pronounced in overweight or obese individuals with BAT, indicating that BAT might play a role in mitigating obesity and its comorbidities [20].

3. The Dual Role of BAT Activation under the States of Energy Needed and Energy Excess Conditions

The balance of energy intake and EE is essential for the maintenance of energy homeostasis and body weight. Total EE is made up of the sum of energy (calories) used to maintain the cells and organ function on a daily basis, and is composed of five main components: (1) RMR, (2) activity-related EE (AEE), (3) thermic effect of food (TEF), (4) adaptive thermogenesis, and (5) growth [5,21]. BAT activation is involved in the mechanism underlying at least three major components of total EE (Item 2, 3, 4), indicating its importance in the regulation of energy homeostasis. In addition, adaptive thermogenesis including shivering and non-shivering thermogenesis is crucial to maintaining mammal body temperature [22,23]. In non-shivering thermogenesis, brown and brite/beige fat dissipates chemical energy as heat by UCP1-dependent thermogenesis [24], as well as by other “futile” enzymatic cycles UCP1 independent thermogenesis [24,25].
Cold exposure is the most effective physiological regimen to activate BAT. However, it would be hard to increase human exposure to cold temperatures under well-controlled ambient temperature with the presence of clothing and an air conditioner. On the other hand, it remains uncertain whether the regulatory signal pathways of cold-induced thermogenesis (CIT) could be the potential drug targets for anti-obesity treatment due to adverse effects of chronic cold exposure such as elevated blood pressure [15] and deterioration of the development of atherosclerosis [26].
On the other hand, the study of Rothwell and Stock [27] in 1979 conducted with male Sprague-Dawley rats demonstrated that rats with high-fat and cafeteria diet feeding exhibited less weight gain than expected based on energy intake with a simultaneous increase in BAT activity and EE. In addition, a previous study has shown that BAT’s thermogenic response to diet feeding is not observed in animals without UCP1 [28]. Thus, the role of UCP1-dependent thermogenesis and EE in BAT in the maintenance of energy balance after a meal seems to have been noted [29]. Moreover, DIT is the thermogenesis generated after meals and is another component of non-shivering thermogenesis. The involvement of BAT in DIT has been demonstrated in small rodents recently [30,31]. There was also some updated information available on humans [3,32].

4. Diet-Induced Activation of BAT

4.1. Definition of DIT

DIT is defined as an increase in EE after a meal above that of the fasting state and is related to digestion, intestinal absorption, and storage of these nutrients, contributing 5–15% to total daily EE. DIT is generally composed of two components: an obligatory part and a facultative part. Obligatory DIT is also called “the thermic effect of food”, which refers to the heat necessarily released during digestion and processing of the food. The values for the obligatory DIT are for carbohydrates 5–10%, lipids 0–3%, and protein 20–30% [33]. The current methods to obtain the above values cannot be excluded since the thermogenesis is parallelly generated from facultative DIT. For instance, DIT in humans is generally measured using ventilated hood systems [34,35,36] or respiratory chambers [37,38,39,40]. In mice, DIT has been estimated by measuring the postprandial increase in body temperature and the increase in oxygen consumption (VO2) [31,41,42,43]. Although the existence of facultative DIT and the role of BAT for DIT remains debated [29,32,44], previous studies showed that facultative DIT was mediated, at least partly, through BAT-mediated thermogenesis [27,45]. Several reports have also shown that DIT can increase EE in response to overfeeding and eventually, retard excessive energy intake and weight gain in rodents [27,46,47,48]. In adult humans, several studies have indicated that the activation of BAT is involved in the generation of DIT [49,50,51]. Thus, the involvement of BAT activation in DIT has been considered the potential target to retard the development of overweight and obesity [27,52].

4.2. The Role of BAT Activation in Facultative Adaptive DIT and Whole-Body EE

BAT is one of the main sites for the generation of DIT. Recent studies have reported that the activation state of BAT is increased in animals fed energy-rich diets [27,28,30,52,53,54,55,56] and significantly contributes to the control of energy metabolism. On the other hand, DIT is higher in BAT-positive male subjects measured by 18F-fluorodeoxyglucose (18F-FDG)-PET/CT which could explain the lower incidence of obesity, insulin resistance, and diabetes mellitus type 2 than BAT-negative subjects [51]. Moreover, it has been reported that activation of human BAT during DIT is correlated with body mass index (BMI), sex, and age [57,58]. In addition, the augmentation of oxygen consumption, respiratory enzyme activity, and UCP1 protein, in parallel with an increased BAT activity and EE were noted in rats fed high fat and cafeteria diets [27,42]. On the other hand, whole-body oxygen consumption after a meal in UCP1-deficient mice was lower than that in wild-type control. Accordingly, UCP1-deficient mice are prone to develop obesity and insulin resistance when mice are fed a high-fat diet (HFD) and maintained at a thermoneutral temperature (30 °C). It was suggested that DIT could be induced by adrenergic stimulation of BAT activity through activation of the BAT-specific UCP1 protein [28,52]. Accordingly, UCP1-mediated thermogenesis is important for DIT in humans, and the possible contribution of BAT thermogenesis to DIT and regulation of energy balance have been suggested by the study focusing on single nucleotide polymorphism in the UCP1 gene. To examine the effects of A-3826G mutation in the UCP1 gene on DIT, Nagai et al. demonstrated that this UCP1 gene mutation could reduce postprandial thermogenesis in response to a high-fat meal shown in healthy boys [59].
On the other hand, it has been reported that the inactivation of UCP1 did not potentiate diet-induced obesity in mice. Recent studies have demonstrated that multiple UCP1 independent thermogenic mechanisms such as Ca2+ futile cycling through the SERCA2b-RyR2 pathway in the endoplasmic reticulum, creatine cycling in the mitochondria, and lipolysis/re-esterification (to provide fuel for futile cycling based on ATP sinks centered on fatty acid-mediated leak pathways driven by the ADP/ATP carrier) [24,25]. UCP1-independent EE has begun to be therapeutic potential that lies in refining our understanding of the regulation of adaptive thermogenesis. Accordingly, Anunciado-Koza and colleagues have demonstrated that the increase in oxygen consumption in UCP1+/+ and UCP1−/− mice were comparable when the diet is switched from chow to high fat or sucrose [29], indicating that DIT might be generated through both UCP1 dependent and independent pathways. Taken together, the current observation implicates that the thermogenic activation of BAT is involved in the development of DIT both in human and animal studies.

5. Mechanisms of DIT

BAT thermogenic activation significantly contributes to the DIT in postprandial conditions [32]. To date, there are many potential factors and mechanisms have been reported to participate in DIT. As shown in Figure 1, we summarized the updated reports about the regulatory mechanisms involved in diet-induced BAT activation (DIT) and the role of BAT activation in DIT in health and diseases. However, the precise nature of their roles and regulatory mechanisms of BAT activation in DIT and whole-body EE remains largely unexplained.

5.1. Sympathetic Nervous System (SNS)–BAT Axis

CIT could be generated by activating SNS and inducing BAT thermogenesis through the β3-adrenergic receptor (ADRB3) in mice and β2-adrenergic receptor in humans [60]. Based on the principal role of the SNS-βAR axis for CIT, it is conceivable that this axis might also be a key mechanism in DIT. For instance, SNS activity in BAT calculated from tissue norepinephrine turnover rate is increased in mice with long-term cafeteria and high-calorie diet feeding [61,62]. In addition, studies [63] also showed that surgical denervation of BAT could significantly attenuate metabolic activation of BAT after intake of a liquid meal in rats. Accordingly, denervation of BAT also alleviates the increase in mitochondrial GDP binding, total UCP1 protein content, and mitochondrial content in rats on an energy-enriched diet [64]. These results support the content that BAT activation in DIT is, at least in part, mediated through SNS activation. Moreover, previous reports have further demonstrated that food palatability and oropharyngeal taste sensation are also substantially involved in diet-induced sympathetic activation and BAT thermogenesis [65,66,67].

5.2. Gut-Secreted Peptides and Hormones and Bile Acids

Since the release of gastrointestinal peptides is one of the acute physiological responses to eating, some of these peptides have been reported to act as mediators to regulate DIT. For instance, gut hormones could activate BAT through their effects on the efferent SNS tone, such as cholecystokinin (CCK) [68,69] and glucagon-like peptide (GLP-1) [70]. In addition, the study of Li et al. [71] revealed a novel endocrine gut–BAT–brain axis triggered by secretin that initiates the canonical secretin receptor (SCTR)–cAMP–PKA–lipolysis–UCP1 pathway in brown adipocytes from the intestine during a meal. Their observation supported that a postprandial increase in circulating secretin activates BAT thermogenesis by binding to SCTR in brown adipocytes. On the other hand, bile acids have been documented to activate BAT directly through Takeda G-protein receptor 5 (TGR5) in brown adipocytes [72]. Watanabe et al., [73] further demonstrated that bile acids activate TGR5 in mouse brown adipocytes and then, facilitate thermogenic activity through type 2 deiodinase (D2) activation. Accordingly, direct stimulatory effects of bile acids (chenodeoxycholic acid) on BAT activity have been evidenced in humans using brown adipocytes in vitro and using FDG-PET/CT scan in vivo [73,74]. TGR5 has also been demonstrated to participate in browning of white adipose tissue under cold exposure and prolonged HFD feeding [75]. Thereby, targeting TGR5–BAT axis with bile acids or drugs could be a promising target for combating obesity and related metabolic disorders in humans.

5.3. Insulin

It is well recognized that the role of insulin as a key hormone in the storage of ingested nutrients, and also possesses the capacity to modulate energy balance after a meal. A recent study has indicated that insulin is a crucial protein involved in the mitochondrial bioenergetic and thermogenic capacity of brown adipocytes [76]. In fact, BAT appears to be differently activated by insulin and cold. When activated by cold, it dissipates energy in a perfusion-dependent manner. Nevertheless, in response to insulin, BAT glucose uptake could have a 5-fold increase independently of its perfusion [77,78]. In addition, it is suggested that insulin may play an important role in the dietary induction of facilitative adaptive thermogenesis. For instance, the study conducted with ten healthy lean volunteers and a euglycemic clamp method in conjunction with respiratory exchange measurements, has shown the progressive increase in RMR along with the increase in the glucose infusion rate without changes in insulin and norepinephrine concentrations. It is implicated that insulin-stimulated glucose uptake is crucial for the thermogenic response of insulin [79]. On the other hand, Lee et al. have demonstrated that the recruitment of human BAT is accompanied by augmented DIT and postprandial insulin sensitivity [80]. Thus, it appears that the interactions between insulin and thermogenesis seen in rats could also exist in humans after meals.
Insulin resistance is a well-characterized consequence of obesity. Cafeteria diet feeding was conducted with normal and diabetic animals to assess changes in insulin-mediated glucose metabolism and to investigate the effects of insulin resistance on the development of DIT [81]. The attenuated DIT shown in cafeteria-fed diabetic rats was restored by an intensive program of insulin administration [81]. In addition, insulin resistance could result in a defect in insulin-mediated thermogenic response which contributes to the pathogenesis of obesity in humans [80]. The study of Aherne and Hull [82] conducted with human autopsy demonstrated that for obese infants of diabetic mothers exhibited impaired BAT function, further suggesting that maternal insulin deficiency may affect the thermogenic function of BAT in the offspring. Nevertheless, a recent report from Loeliger, R.C. has shown that DIT was not associated with BAT activity. DIT after an oral glucose load was not associated with stimulated 18F-FDG uptake into BAT, suggesting that DIT is independent of BAT activity caused by facilitating glucose uptake in humans [32]. The underlying mechanism of insulin on DIT is needed to be further clarified.

5.4. Liver-Derived Factors

Hepatic tissue has been documented to be involved to a significant extent in the thermogenesis process. The study was conducted with rats fed chow or a cafeteria diet of highly palatable human foods and measured the RMRs (VO2) before and shortly after two-thirds hepatectomy or sham operation at thermoneutrality (28 °C), and again after administration of propranolol (5 mg/kg). The difference in RMR between the resting period and propranolol treated period was used to represent the DIT. Their result suggests that liver is the major (70–100%) effector of the DIT [83,84]. In addition, Wallace et al. have demonstrated for the first time that the enhancement of specific calorigenic metabolic processes such as mitochondrial glycerophosphate oxidase within the liver contributes significantly to the heat production of DIT in cafeteria-fed rats [85]. These observations implicate that hepatic tissue might substantially take part in DIT under postprandial conditions.

5.5. Leptin

The adipocyte-derived leptin is a key factor in the regulation of energy balance [86], which is significantly increased in the obese state [87]. In fact, leptin has been reported to activate BAT sympathetic activity [88] and heat production [89,90,91]. In addition, a recent report has shown that refeeding increased plasma leptin concentrations in 48-h-fasted lean rats and leptin could mediate the increases in body temperature through hypothalamus-adrenal medulla-adipose tissue crosstalk after a meal [92]. Accordingly, chronic leptin treatment could stimulate BAT-mediated thermogenesis in leptin-deficient ob/ob mice by enhancing sympathetic innervation and activation [93]. Furthermore, BAT-ectomized rats reduced the thermogenic effect of food by 60% [92], suggesting that BAT appears to be a crucial mediator of leptin-induced thermogenesis. However, some earlier studies have found that female leptin-deficient ob/ob mice fed a palatable cafeteria diet still result in increased leptin-independent SNS activity and thermogenesis in BAT [94]. Some other reports also pointed out that leptin do not possess thermogenic function [95,96] and act as the mediator of DIT. These controversial observations might attribute to the differences in gender, methods, and experimental condition, which are needed to be further elucidated.
In contrast to leptin, adiponectin exhibits several characteristics of inhibiting energy expenditure. For instance, adiponectin inhibits UCP1 expression by reducing ADRB3 expression in brown adipocytes, along with reducing BAT thermogenesis in mice [97]. Previous report showed that neither fasting nor refeeding changed adiponectin serum levels in both young and old male rats [98]. The involvement of adiponectin in DIT process remains ambiguous.

5.6. Muscle

Sarcolipin (SLN) is a regulator of the Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) pump in muscle has been proposed to play an important role in DIT [55,99,100,101] and EE [102]. For instance, SLN regulates muscle-based non-shivering thermogenesis and is up-regulated with HFD. In addition, SLN KO mice are prone to develop diet-induced obesity and glucose intolerance. On the other hand, mice with SLN gene deletion gained comparable weight as UCP1-deficient mice on HFD, implicating that loss of muscle-based thermogenesis has similar consequences on weight gain as loss of UCP1-mediated thermogenesis [100]. Moreover, the body weight of mice with SLN overexpression is significantly lower than that of littermate control and they were resistant to HFD-induced obesity [101]. These mechanistic experiments indicated that SLN as an uncoupler of SERCA pump might create both energy demand and increase energy expenditure and are essential for counter-regulation of diet-induced energy intake.

5.7. Thyroid Hormones

Thyroid hormones, thyroxine (T4) and triiodothyronine (T3), have been well-documented to be a crucial determinant of energy expenditure and basal metabolic rate and also involved in the regulation of thermogenic responses to cold and diet [103]. Both cold-challenged and cafeteria-fed rats exhibited increases in circulating thyroid hormone levels [104]. In rats, overnutrition induced by a cafeteria diet is accompanied by a large increase in EE along with plasma T3 concentration [105]. T3 also acts as the main regulator of producing DIT in birds [106]. Accordingly, long-term over-feeding in men also exhibited accelerated metabolic rate and an increase in circulating T3 level [107]. Taken together, these observations implicate that thyroid hormone, especially T3, might substantially contribute to the generation of DIT under postprandial condition.

6. Food-Derived Stimulants and Diet-Induced BAT Thermogenesis

Dietary molecules are important factors in potentiating BAT thermogenic functions and affecting energy metabolism. Nutritional modulation of adaptive thermogenesis is a newly developing research field and of clinical importance to evaluate its potential as a therapeutic target to prevent the development of obesity and promote human health. There are several signaling pathways that have been reported to be involved in stimulating BAT activation by dietary molecules.

6.1. Caloric Intake and Circadian Rhythmicity

An increase in calorie intake or meal size has been demonstrated to facilitate DIT [6,108,109]. In contrast, caloric restriction leads to reduce hormonal responses for insulin and incretin (GIP and GLP-1) and lower DIT in healthy adults [109]. On the other hand, the extremely hypocaloric diet (200 kcal) could induce similar DIT to the moderately hypocaloric diet (400 kcal), which led to a negative energy balance and greater thermogenic efficiency in healthy male adults [109]. In addition, a study regarding circadian rhythmicity in the human DIT showed that after a hypocaloric diet (1046 kcal/day) subjects displayed more efficient energetic value in the morning than in the evening, implicating that the timing of food intake is also important for successful weight loss under conditions of caloric restriction [110]. Thus, these studies suggest that caloric intake and circadian rhythmicity are substantially involved in the regulation of postprandial energy metabolism.

6.2. Phytochemicals (e.g., Capsaicin, Resveratrol, Curcumin, and Green Tea)

The effects of capsaicin, the major pungent component of chili peppers, and its analogs capsinoids on BAT-mediated thermogenesis and EE have been intensively studied. On the other hand, previous studies have demonstrated that chemical activation of TRP channels by food ingredients can recruit and activate BAT in humans and animal models [111,112,113]. The transient receptor potential vanilloid (TRPV)1 located on primary afferent neurons has been speculated to be a primary target for capsinoids [114]. Both capsaicin and capsinoids are potent in activating TRPV1 expression in sensory nerves within the gastrointestinal tract and increasing SNS activity in BAT. Thereafter, they would induce a rapid increase in BAT temperature and subsequently facilitate whole-body EE and fat oxidation in small rodents [115] and humans [116,117,118].
Resveratrol (3,5,4-trihydroxystilbene), a natural polyphenolic compound found in the skin of grapes and other plants, has been demonstrated to prevent obesity and related complications [119,120]. Resveratrol has also been suggested to facilitate thermogenesis in BAT [121]. Resveratrol could induce UCP1 gene expression and oxygen consumption in BAT of mice fed either normal chow or HFD [122]. Accordingly, in animal models of obesity, the addition of resveratrol could reverse HFD-induced suppression of UCP1 expression and oxygen consumption in BAT, resulting in an increased basic metabolic rate [123,124]. Furthermore, there is compelling evidence that resveratrol promotes BAT activation through distinct molecular pathways via synergistic mechanisms of mitochondrial biogenesis, AMP-kinase signaling, SIRT1 activity, and cAMP signaling [121,123,125,126].
Curcumin is the principal curcuminoid of Indian spice turmeric, which is a member of the ginger family. Curcumin has been shown to have a protective effect on obesity and metabolic diseases [127,128,129]. The anti-obesity effects of curcumin were not exhibited in UCP1-deficient mice [130], implicating the involvement of UCP1-dependent thermogenesis. A recent report further suggests that gut microbiota mediates the effects of curcumin on enhancing UCP1-dependent thermogenesis and improving high-fat diet-induced obesity in mice [130]. Curcumin has been reported to enhance EE through stimulating thermogenesis by enhancing the expression of AMPK, SIRT1, proliferator-activated-receptor-gamma-coactivator1-α (PGC-1α), catechol-O-methyltransferase (COMT) and SNS activity in BAT [131,132,133]. In addition, curcumin also increased the expression of critical mitochondrial proteins such as carnitine palmitoyltransferase I (CPT1, responsible for the oxidation of fatty acids) and cytochrome C (responsible for mitochondrial oxidative phosphorylation) as well as the number of mitochondria in brown adipocytes [134].
The consumption of green tea or its components, green tea catechins, have been reported to be able to increase fat oxidation and energy expenditure along with upregulated UCP1 expression in rat BAT, suggesting that suppressive effect of catechins on body fat accumulation is associated with increased BAT activity [135]. Catechins in green tea could facilitate noradrenaline and ADRB3 signaling activation and subsequently stimulate thermogenesis and fat oxidation in mice [136,137]. However, thermogenic activation by green tea catechins remains controversial in humans. In obese men, consuming tea catechins, such as EGCG increased postprandial fat oxidation, but failed to change energy expenditure [138]. In addition, green tea supplementation has been reported to upregulate uncoupling protein 3 expression in adipose tissue of severely obese women without promoting weight loss [139]. On the other hand, a meta-analysis of placebo-controlled studies showed that intake of catechin-caffeine mixtures facilitated energy expenditure and fat oxidation in humans [140]. Notedly, catechin treatment might cause adverse side effects, especially in cardiovascular systems through stimulation of the SNS activity in long-term usage.

6.3. Dietary Fatty Acids

Fish oil enriched with n-3 polyunsaturated fatty acids, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), has an anti-obesity effect in humans and rodents [141,142,143,144]. Fish oil could also promote thermogenesis and energy expenditure accompanied by augmented UCP1 expression in brown/beige adipocytes [145]. The effect of fish oil was likely mediated by the SNS and TRPV1, leading to ADRB3 stimulation and BAT thermogenesis in mice. EPA-mediated browning effects were abolished in Trpv1 knockout mice [146]. Moreover, dietary fish oil has been reported to increase DIT in mice via the increased UCP1 activation in BAT and induced beige biogenesis in subcutaneous WAT. In addition, these fish oil-induced mechanisms in BAT contribute to activate PPARα via the binding to peroxisome proliferator-activated receptor (PPAR) α [147]. Peroxisome proliferator-activated receptors (PPARs) are members of a nuclear receptor superfamily involved in the regulation of nutrient-dependent transcription. Peroxisome-derived lipids has been reported to regulate adipose thermogenesis by mediating cold-induced mitochondrial fission [148]. On the other hand, pemafibrate, a selective PPARα agonist, activates thermogenesis in subcutaneous (inguinal) white and brown adipose tissues by increasing plasma levels of fibroblast growth factor 21 and protecting again diet-induced obesity in mice [149]. These observations suggest that fish oil might be a promising thermogenic dietary fat to against obesity [150].

6.4. All-Trans Retinoic Acid and a Vitamin A Metabolite

Retinoic acid is an active metabolite of vitamin A and has been reported to substantially contribute to BAT thermogenesis via nuclear retinoic acid receptors (RARs). In vitro experiment, retinoic acid has been reported to induce expression of UCP1 in mouse beige and brown adipocytes [151] and facilitate BAT activation via unique transcriptional regulation, instead of ADRB3-mediated signaling. Retinoic acid-treated animals have shown increases in UCP1 expression and improved RAR and PPARδ activation, leading to augmented BAT activation and fatty acid oxidation [152]. Conversely, a vitamin A–deficient diet feeding increased body weight, whole body fat mass, and reduced BAT thermogenic potential in mice [153]. Accordingly, a study in healthy adults showed the inverse relationship between vitamin A intake and adiposity [154]. Additionally, in morbidly obese subjects, it exhibited the inverse correlation between serum retinol and BMI [155]. It is implicated that dietary supplement of retinoic acid possesses anti-obesity potential via promoting DIT-associated thermogenesis and whole-body EE.

7. BAT Dysfunction in Metabolic Diseases

7.1. Obesity

Obesity is characterized by excessive fat storage due to long-term energy intake over EE [156]. DIT can be an important component in regulating whole-body EE and there has been speculated that a defect in DIT predisposes to obesity [14,157,158]. The thermogenic response to food has been proposed to act as a causative factor for obesity by de Jonge and Bray [159]. They reported in their review that 29 of 49 relevant studies found the thermic effects of food to be lower in obese than in lean subjects. Animal studies for DIT also provided evidence that obesity phenotypes in ob/ob mice were associated with defective BAT adaptive thermogenesis [160]. Thus, it is implicated that obesity might be causally linked to a defective BAT in an obese animal model. Nevertheless, it has been reported that energy expenditure positively correlates with the increase in body mass in humans. Accordingly, severe obesity is associated with an increase in EE [161]. These observations indicate that the regulatory mechanism of EE in obese mice and obese subjects might be different. Nevertheless, the association between lower DIT and obesity also remains controversial. Some reports have demonstrated that no difference exists in DIT between obese and nonobese individuals [108,162,163,164,165]. For instance, Tentolouris et al. [163] have shown that there are no differences in DIT or macronutrient oxidation between nonobese and obese subjects after a carbohydrate-rich meal and a fat-rich meal. D’Alessio et al. [108] tested the effect of four mixed diets containing different amounts of fat-free calories (kcal/kg) intake. Their result showed the increase in EE in the obese and nonobese groups were not different. However, the other report has shown a greater increase in EE in obese European men than in their nonobese counterparts after consuming an isocaloric test meal [164]. Since DIT is influenced by the amount of caloric intake and diet macronutrient composition [110], it would be crucial to be standardized for both the caloric and composition content of the meal, while comparing DIT between obese and nonobese individuals. Therefore, more studies are needed to elucidate the role and the mechanism underlying DIT in obese and nonobese subjects, which is of clinical importance for developing potential anti-obesity diet supplements.

7.2. Diabetes

The obesity-associated insulin resistance is a crucial risk factor in the development of type 2 diabetes. On the other hand, the development of type 2 diabetes exhibits not only the derangement in glucose disposal (e.g., insulin resistance) but also a defect in thermogenic function, which would result in an increase in weight gain [166]. Rothwell and Stock [64] have reported that streptozotocin-induced diabetes (defect of insulin secretion) abolishes the increase in metabolic rate associated with cafeteria feeding. Impaired DIT in cafeteria-fed diabetic rats could be recovered by insulin administration [81]. Furthermore, the study conducted with type 2 diabetic patients showed that there is a diminution in thermogenic response to intravenous insulin infusion along with diminished insulin-mediated glucose uptake [79]. Accordingly, glucose-induced postprandial thermogenesis is decreased in the presence of insulin resistance and/or reduced insulin response to the glucose load in nondiabetic and diabetic obese subjects [167].

7.3. Hyperlipidemia

Hyperlipidemic patients with obesity and type 2 diabetes characterized by high plasma TG and low plasma HDL-cholesterol concentrations have been reported to exhibit lower thermogenic adipocyte activity than that in healthy subjects [4,168]. In addition, it has been demonstrated that the expression of UCP1 in human epicardial fat is positively correlated with lower plasma TG and higher plasma HDL-cholesterol levels [169]. BAT activity is not only attenuated in hyperlipidemia with obesity but also inversely correlated with BMI and body fat mass. On the other hand, since thermogenesis of BAT consumes large amounts of fatty acids, BAT has been considered to play a key role in TG clearance [170]. Brown adipocytes take up fatty acids via CD36 and oxidize them to fuel thermogenesis, while the liver clears plasma LDL remnants [170]. Ablation of BAT could result in hyperlipidemia in mice [171], indicating that BAT plays a critical role in maintaining TG homeostasis in circulation. Moreover, BAT activation has been documented to lead to the decomposition of triglycerides in cells through increasing oxidative metabolism and UCP1-dependent thermogenesis [3]. Thereby, BAT activity might be causally involved in the pathogenesis of hyperlipidemia in human subjects.
Nevertheless, it has been discovered that decreased activity of BAT is associated with insulin resistance, which can alter systemic lipid metabolism, consequently leading to the development of hyperlipidemia [172]. Thereby, insulin resistance could also be an important confounding factor to affect DIT in hyperlipidemic subjects.

7.4. NAFLD

NAFLD is highly associated with obesity and related metabolic disorders. Several environmental factors are known to affect NAFLD including a Western diet, high fat and cholesterol-enriched diet, and a high fructose-enriched diet [173]. Insulin resistance is also a key factor in the pathogenesis of NAFLD. In a clinical study, individuals with NAFLD have lower BAT activity than counterpart control and BAT activity is inversely related to insulin resistance and hepatic fat accumulation [174]. On the other hand, BAT has been reported to possess the capability to protect against NAFLD by facilitating the utilization of FFAs to fuel its thermogenesis and activation of BAT and subsequently, decreasing both circulating FFA levels and uptake of FFAs into the liver [174]. In preclinical studies, enhancing the metabolic activity of BAT potently reduces liver lipid accumulation in rodents [175]. BAT activity in humans is also associated with reduced risk for NAFLD [176], suggesting that BAT activation might play a protective role in human NAFLD. Croci et al., conducted with 20 patients with NAFLD showed that the low EE in NAFLD subjects was mainly due to lower fat-oxidation in basal conditions than in healthy control [177]. These observations have demonstrated that the anti-liver steatosis function of BAT is likely to be conserved both in rodents and humans.

7.5. Cancer-Associated Cachexia (CAC)

BAT is not only involved in the regulation of adaptive thermogenesis and energy balance but also contributes to the physiologic perturbations associated with cachexia [178]. The activation of BAT and augmented UCP1 expression were noted in the development of cancer cachexia. Moreover, inflammatory signaling as an energetically wasteful and maladaptive response to anorexia during the development of cachexia has been considered to play an important role in the modification of BAT biology [178]. CAC could cause profound metabolic disturbance and is characterized by progressing muscle wasting and adipose loss and asthenia. CAC is not solely attributable to inadequate nutritional intake cause severely increases the morbidity and mortality risk in cancer patients [179]. Weight loss has been ascribed to a mechanism of altered DIT which leads to a reduction in the efficiency with which ingested substrate is stored [180]. However, it has been demonstrated that the reduction of DIT in cancer patients is another element of starvation adaptation contributing to their weight loss. It is implicated that altered thermogenesis does not contribute to the weight loss seen in cancer cachexia.

8. Conclusions and Future Perspectives

BAT has been speculated as a promising target for combating obesity and metabolic diseases. Apart from CIT, BAT has been suggested to play a facilitative role in the generation of DIT. Diet-induced BAT activation may contribute more significantly to the regulation of whole-body energy metabolism and weight control in our usual daily life. Benefit from recent advances in technologies to evaluate the diet-induced BAT activation, many exogenous and endogenous regulatory factors such as diet nutrient components, thermogenic food ingredients, various postprandially secreted humoral factors and SNS activity have been reported to modulate BAT thermogenesis and EE through multiple thermogenesis-related signal pathways as shown in Table 1. This review provides updated information regarding the role of BAT activation in DIT and the possible regulatory mechanisms. It would help to facilitate the translation development of potential dietary factors/food ingredients that can trigger diet-induced BAT activation and possess anti-obesity potential. On the other hand, it would help to understand the pathological link between BAT activation in DIT and the development of metabolic diseases.

Author Contributions

P.-C.C. developed the first manuscript draft; P.-S.H. reviewed, revised, and approved the final version of the manuscript. All authors have read and agreed to the published version of the manuscript.


This study was supported by the Ministry of Science and Technology of the R.O.C. under MOST 111-2320-B-016-003 -MY3, MOST 110-2320-B-016-003, MOST 111-2320-B-016-016 and the Chi-Mei Medical Center, Tainan, Taiwan under CMNDMC 108-03.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

All the data are presented in the manuscript.

Conflicts of Interest

The authors declare no conflict of interest.


  1. Okamatsu-Ogura, Y.; Kuroda, M.; Tsutsumi, R.; Tsubota, A.; Saito, M.; Kimura, K.; Sakaue, H. UCP1-dependent and UCP1-independent metabolic changes induced by acute cold exposure in brown adipose tissue of mice. Metabolism 2020, 113, 154396. [Google Scholar] [CrossRef]
  2. Yang, L.; Zhao, D.; Yin, R.; Ma, Y.; Zhang, N. Combined effects of voluntary running and liraglutide on glucose homeostasis, fatty acid composition of brown adipose tissue phospholipids, and white adipose tissue browning in db/db mice. Chin. J. Physiol. 2022, 65, 117. [Google Scholar] [CrossRef] [PubMed]
  3. Saito, M.; Matsushita, M.; Yoneshiro, T.; Okamatsu-Ogura, Y. Brown Adipose Tissue, Diet-Induced Thermogenesis, and Thermogenic Food Ingredients: From Mice to Men. Front. Endocrinol. 2020, 11, 222. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Cheng, L.; Wang, J.; Dai, H.; Duan, Y.; An, Y.; Shi, L.; Lv, Y.; Li, H.; Wang, C.; Ma, Q.; et al. Brown and beige adipose tissue: A novel therapeutic strategy for obesity and type 2 diabetes mellitus. Adipocyte 2021, 10, 48–65. [Google Scholar] [CrossRef] [PubMed]
  5. Speakman, J.R. Measuring energy metabolism in the mouse-theoretical, practical, and analytical considerations. Front. Physiol. 2013, 4, 34. [Google Scholar] [CrossRef] [Green Version]
  6. Reed, G.W.; Hill, J.O. Measuring the thermic effect of food. Am. J. Clin. Nutr. 1996, 63, 164–169. [Google Scholar] [CrossRef] [Green Version]
  7. Byrne, N.M.; Hills, A.P.; Hunter, G.R.; Weinsier, R.L.; Schutz, Y. Metabolic equivalent: One size does not fit all. J. Appl. Physiol. 2005, 99, 1112–1119. [Google Scholar] [CrossRef] [Green Version]
  8. Dionne, I.; Després, J.; Bouchard, C.; Tremblay, A. Gender difference in the effect of body composition on energy metabolism. Int. J. Obes. 1999, 23, 312–319. [Google Scholar] [CrossRef] [Green Version]
  9. Bosy-Westphal, A.; Wolf, A.; Bührens, F.; Hitze, B.; Czech, N.; Mönig, H.; Selberg, O.; Settler, U.; Pfeuffer, M.; Schrezenmeir, J.; et al. Familial influences and obesity-associated metabolic risk factors contribute to the variation in resting energy expenditure: The Kiel Obesity Prevention Study. Am. J. Clin. Nutr. 2008, 87, 1695–1701. [Google Scholar] [CrossRef] [Green Version]
  10. Muller, M.J.; Bosy-Westphal, A.; Kutzner, D.; Heller, M. Metabolically active components of fat-free mass and resting energy expenditure in humans: Recent lessons from imaging technologies. Obes. Rev. 2002, 3, 113–122. [Google Scholar] [CrossRef]
  11. Rothwell, N.J.; Stock, M.J.; Stribling, D. Diet-induced thermogenesis. Pharmacol. Ther. 1982, 17, 251–268. [Google Scholar] [CrossRef]
  12. Okla, M.; Kim, J.; Koehler, K.; Chung, S. Dietary Factors Promoting Brown and Beige Fat Development and Thermogenesis. Adv. Nutr. Int. Rev. J. 2017, 8, 473–483. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Hamada, Y.; Hayashi, N. Chewing increases postprandial diet-induced thermogenesis. Sci. Rep. 2021, 11, 23714. [Google Scholar] [CrossRef]
  14. Wang, B.; Tsakiridis, E.E.; Zhang, S.; Llanos, A.; Desjardins, E.M.; Yabut, J.M.; Green, A.E.; Day, E.A.; Smith, B.K.; Lally, J.S.V.; et al. The pesticide chlorpyrifos promotes obesity by inhibiting diet-induced thermogenesis in brown adipose tissue. Nat. Commun. 2021, 12, 1–12. [Google Scholar] [CrossRef] [PubMed]
  15. Marlatt, K.L.; Ravussin, E. Brown Adipose Tissue: An Update on Recent Findings. Curr. Obes. Rep. 2017, 6, 389–396. [Google Scholar] [CrossRef]
  16. Rui, L. Brown and Beige Adipose Tissues in Health and Disease. Compr. Physiol. 2017, 7, 1281–1306. [Google Scholar] [CrossRef]
  17. Bastías-Pérez, M.; Zagmutt, S.; Soler-Vázquez, M.C.; Serra, D.; Mera, P.; Herrero, L. Impact of Adaptive Thermogenesis in Mice on the Treatment of Obesity. Cells 2020, 9, 316. [Google Scholar] [CrossRef] [Green Version]
  18. Sakers, A.; De Siqueira, M.K.; Seale, P.; Villanueva, C.J. Adipose-tissue plasticity in health and disease. Cell 2022, 185, 419–446. [Google Scholar] [CrossRef]
  19. Frontini, A.; Cinti, S. Distribution and Development of Brown Adipocytes in the Murine and Human Adipose Organ. Cell Metab. 2010, 11, 253–256. [Google Scholar] [CrossRef] [Green Version]
  20. Becher, T.; Palanisamy, S.; Kramer, D.J.; Eljalby, M.; Marx, S.J.; Wibmer, A.G.; Butler, S.D.; Jiang, C.S.; Vaughan, R.; Schöder, H.; et al. Brown adipose tissue is associated with cardiometabolic health. Nat. Med. 2021, 27, 58–65. [Google Scholar] [CrossRef]
  21. Ndahimana, D.; Kim, E.-K. Measurement Methods for Physical Activity and Energy Expenditure: A Review. Clin. Nutr. Res. 2017, 6, 68–80. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Cannon, B.; Nedergaard, J. Brown Adipose Tissue: Function and Physiological Significance. Physiol. Rev. 2004, 84, 277–359. [Google Scholar] [CrossRef] [PubMed]
  23. Lowell, B.B.; Spiegelman, B.M. Towards a molecular understanding of adaptive thermogenesis. Nature 2000, 404, 652–660. [Google Scholar] [CrossRef] [PubMed]
  24. Roesler, A.; Kazak, L. UCP1-independent thermogenesis. Biochem. J. 2020, 477, 709–725. [Google Scholar] [CrossRef] [PubMed]
  25. Oeckl, J.; Janovska, P.; Adamcova, K.; Bardova, K.; Brunner, S.; Dieckmann, S.; Ecker, J.; Fromme, T.; Funda, J.; Gantert, T.; et al. Loss of UCP1 function augments recruitment of futile lipid cycling for thermogenesis in murine brown fat. Mol. Metab. 2022, 61, 101499. [Google Scholar] [CrossRef]
  26. Dong, M.; Yang, X.; Lim, S.; Cao, Z.; Honek, J.; Lu, H.; Zhang, C.; Seki, T.; Hosaka, K.; Wahlberg, E.; et al. Cold Exposure Promotes Atherosclerotic Plaque Growth and Instability via UCP1-Dependent Lipolysis. Cell Metab. 2013, 18, 118–129. [Google Scholar] [CrossRef] [Green Version]
  27. Rothwell, N.J.; Stock, M.J. A role for brown adipose tissue in diet-induced thermogenesis. Nature 1979, 281, 31–35. [Google Scholar] [CrossRef]
  28. von Essen, G.; Lindsund, E.; Cannon, B.; Nedergaard, J. Adaptive facultative diet-induced thermogenesis in wild-type but not in UCP1-ablated mice. Am. J. Physiol. Endocrinol. Metab. 2017, 313, E515–E527. [Google Scholar] [CrossRef] [Green Version]
  29. Kozak, L.P. Brown Fat and the Myth of Diet-Induced Thermogenesis. Cell Metab. 2010, 11, 263–267. [Google Scholar] [CrossRef] [Green Version]
  30. Bargut, T.C.L.; Silva-E-Silva, A.C.A.G.; Souza-Mello, V.; Mandarim-De-Lacerda, C.A.; Aguila, M.B. Mice fed fish oil diet and upregulation of brown adipose tissue thermogenic markers. Eur. J. Nutr. 2015, 55, 159–169. [Google Scholar] [CrossRef]
  31. Ezoe, M.; Wakamatsu, J.-I.; Takahata, Y.; Hasegawa, T.; Morimatsu, F.; Nishimura, T. Diet-Induced Thermogenesis and Expression Levels of Thyroid Hormone Target Genes and Their Products in Rats Differ between Meat Proteins. J. Nutr. Sci. Vitaminol. 2016, 62, 93–100. [Google Scholar] [CrossRef] [Green Version]
  32. Loeliger, R.C.; Maushart, C.I.; Gashi, G.; Senn, J.R.; Felder, M.; Becker, A.S.; Müller, J.; Balaz, M.; Wolfrum, C.; Burger, I.A.; et al. Relation of diet-induced thermogenesis to brown adipose tissue activity in healthy men. Am. J. Physiol. Metab. 2021, 320, E93–E101. [Google Scholar] [CrossRef] [PubMed]
  33. Tappy, L. Thermic effect of food and sympathetic nervous system activity in humans. Reprod. Nutr. Dev. 1996, 36, 391–397. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Segal, K.R.; Chun, A.; Coronel, P.; Cruz-Noori, A.; Santos, R. Reliability of the measurement of postprandial thermogenesis in men of three levels of body fatness. Metabolism 1992, 41, 754–762. [Google Scholar] [CrossRef]
  35. Weststrate, J.A. Resting metabolic rate and diet-induced thermogenesis: A methodological reappraisal. Am. J. Clin. Nutr. 1993, 58, 592–601. [Google Scholar] [CrossRef] [PubMed]
  36. Weststrate, J.A.; Weys, P.J.; Poortvliet, E.J.; Deurenberg, P.; Hautvast, J.G. Diurnal variation in postabsorptive resting metabolic rate and diet-induced thermogenesis. Am. J. Clin. Nutr. 1989, 50, 908–914. [Google Scholar] [CrossRef] [PubMed]
  37. Ravussin, E.; Lillioja, S.; Anderson, T.E.; Christin, L.; Bogardus, C. Determinants of 24-hour energy expenditure in man. Methods and results using a respiratory chamber. J. Clin. Investig. 1986, 78, 1568–1578. [Google Scholar] [CrossRef] [Green Version]
  38. Schutz, Y.; Bessard, T.; Jéquier, E. Diet-induced thermogenesis measured over a whole day in obese and nonobese women. Am. J. Clin. Nutr. 1984, 40, 542–552. [Google Scholar] [CrossRef]
  39. Tataranni, P.A.; Larson, D.E.; Snitker, S.; Ravussin, E. Thermic effect of food in humans: Methods and results from use of a respiratory chamber. Am. J. Clin. Nutr. 1995, 61, 1013–1019. [Google Scholar] [CrossRef]
  40. Usui, C.; Ando, T.; Ohkawara, K.; Miyake, R.; Oshima, Y.; Hibi, M.; Oishi, S.; Tokuyama, K.; Tanaka, S. Validity and reproducibility of a novel method for time-course evaluation of diet-induced thermogenesis in a respiratory chamber. Physiol. Rep. 2015, 3, e12410. [Google Scholar] [CrossRef] [Green Version]
  41. Huang, X.; Hancock, D.P.; Gosby, A.K.; McMahon, A.C.; Solon, S.M.; Le Couteur, D.G.; Conigrave, A.D.; Raubenheimer, D.; Simpson, S.J. Effects of dietary protein to carbohydrate balance on energy intake, fat storage, and heat production in mice. Obesity 2012, 21, 85–92. [Google Scholar] [CrossRef] [PubMed]
  42. Rothwell, N.J.; Stock, M.J.; Warwick, B.P. The effect of high fat and high carbohydrate cafeteria diets on diet-induced thermogenesis in the rat. Int. J. Obes. 1983, 7, 263–270. [Google Scholar] [PubMed]
  43. Wakamatsu, J.-I.; Takabayashi, N.; Ezoe, M.; Hasegawa, T.; Fujimura, T.; Takahata, Y.; Morimatsu, F.; Nishimura, T. Postprandial Thermic Effect of Chicken Involves Thyroid Hormones and Hepatic Energy Metabolism in Rats. J. Nutr. Sci. Vitaminol. 2013, 59, 516–525. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Maxwell, G.M.; Nobbs, S.; Bates, D.J. Diet-induced thermogenesis in cafeteria-fed rats: A myth? Am. J. Physiol. 1987, 253 Pt 1, E264–E270. [Google Scholar] [CrossRef]
  45. Glick, Z.; Teague, R.J.; Bray, G.A. Brown Adipose Tissue: Thermic Response Increased by a Single Low Protein, High Carbohydrate Meal. Science 1981, 213, 1125–1127. [Google Scholar] [CrossRef]
  46. Tseng, Y.-H.; Cypess, A.M.; Kahn, C.R. Cellular bioenergetics as a target for obesity therapy. Nat. Rev. Drug Discov. 2010, 9, 465–482. [Google Scholar] [CrossRef] [Green Version]
  47. Tremblay, A.; Royer, M.-M.; Chaput, J.-P.; Doucet, É. Adaptive thermogenesis can make a difference in the ability of obese individuals to lose body weight. Int. J. Obes. 2013, 37, 759–764. [Google Scholar] [CrossRef] [Green Version]
  48. Bachman, E.S.; Dhillon, H.; Zhang, C.Y.; Cinti, S.; Bianco, A.C.; Kobilka, B.K.; Lowell, B.B. βAR signaling required for diet-induced thermogenesis and obesity resistance. Science 2002, 297, 843–845. [Google Scholar] [CrossRef] [Green Version]
  49. Vosselman, M.J.; Brans, B.; van der Lans, A.A.; Wierts, R.; van Baak, M.A.; Mottaghy, F.M.; Schrauwen, P.; Lichtenbelt, W.D.V.M. Brown adipose tissue activity after a high-calorie meal in humans. Am. J. Clin. Nutr. 2013, 98, 57–64. [Google Scholar] [CrossRef] [Green Version]
  50. Din, M.U.; Saari, T.; Raiko, J.; Kudomi, N.; Maurer, S.F.; Lahesmaa, M.; Fromme, T.; Amri, E.Z.; Klingenspor, M.; Solin, O.; et al. Postprandial Oxidative Metabolism of Human Brown Fat Indicates Thermogenesis. Cell Metab. 2018, 28, 207–216.e3. [Google Scholar] [CrossRef]
  51. Hibi, M.; Oishi, S.; Matsushita, M.; Yoneshiro, T.; Yamaguchi, T.; Usui, C.; Yasunaga, K.; Katsuragi, Y.; Kubota, K.; Tanaka, S.; et al. Brown adipose tissue is involved in diet-induced thermogenesis and whole-body fat utilization in healthy humans. Int. J. Obes. 2016, 40, 1655–1661. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  52. Feldmann, H.M.; Golozoubova, V.; Cannon, B.; Nedergaard, J. UCP1 Ablation Induces Obesity and Abolishes Diet-Induced Thermogenesis in Mice Exempt from Thermal Stress by Living at Thermoneutrality. Cell Metab. 2009, 9, 203–209. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. García-Ruiz, E.; Reynés, B.; Díaz-Rúa, R.; Ceresi, E.; Oliver, P.; Palou, A. The intake of high-fat diets induces the acquisition of brown adipocyte gene expression features in white adipose tissue. Int. J. Obes. 2015, 39, 1619–1629. [Google Scholar] [CrossRef] [PubMed]
  54. Kontani, Y.; Wang, Y.; Kimura, K.; Inokuma, K.-I.; Saito, M.; Suzuki-Miura, T.; Wang, Z.; Sato, Y.; Mori, N.; Yamashita, H. UCP1 deficiency increases susceptibility to diet-induced obesity with age. Aging Cell 2005, 4, 147–155. [Google Scholar] [CrossRef]
  55. Rowland, L.A.; Maurya, S.K.; Bal, N.C.; Kozak, L.; Periasamy, M. Sarcolipin and uncoupling protein 1 play distinct roles in diet-induced thermogenesis and do not compensate for one another. Obesity 2016, 24, 1430–1433. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  56. Ueta, C.B.; Fernandes, G.W.; Capelo, L.P.; Fonseca, T.L.; Maculan, F.D.; Gouveia, C.H.A.; Brum, P.C.; Christoffolete, M.A.; Aoki, M.S.; Lancellotti, C.L.; et al. β1 Adrenergic receptor is key to cold- and diet-induced thermogenesis in mice. J. Endocrinol. 2012, 214, 359–365. [Google Scholar] [CrossRef] [Green Version]
  57. Ouellet, V.; Routhier-Labadie, A.; Bellemare, W.; Lakhal-Chaieb, L.; Turcotte, E.; Carpentier, A.C.; Richard, D. Outdoor Temperature, Age, Sex, Body Mass Index, and Diabetic Status Determine the Prevalence, Mass, and Glucose-Uptake Activity of 18F-FDG-Detected BAT in Humans. J. Clin. Endocrinol. Metab. 2011, 96, 192–199. [Google Scholar] [CrossRef]
  58. Habek, N.; Kordić, M.; Jurenec, F.; Dugandžić, A. Infrared thermography, a new method for detection of brown adipose tissue activity after a meal in humans. Infrared Phys. Technol. 2018, 89, 271–276. [Google Scholar] [CrossRef]
  59. Nagai, N.; Sakane, N.; Ueno, L.M.; Hamada, T.; Moritani, T. The −3826 A→G Variant of the Uncoupling Protein-1 Gene Diminishes Postprandial Thermogenesis after a High Fat Meal in Healthy Boys. J. Clin. Endocrinol. Metab. 2003, 88, 5661–5667. [Google Scholar] [CrossRef] [Green Version]
  60. Blondin, D.P.; Nielsen, S.; Kuipers, E.N.; Severinsen, M.C.; Jensen, V.H.; Miard, S.; Jespersen, N.Z.; Kooijman, S.; Boon, M.R.; Fortin, M.; et al. Human Brown Adipocyte Thermogenesis Is Driven by β2-AR Stimulation. Cell Metab. 2020, 32, 287–300.e7. [Google Scholar] [CrossRef]
  61. Young, J.B.; Saville, E.; Rothwell, N.J.; Stock, M.J.; Landsberg, L. Effect of Diet and Cold Exposure on Norepinephrine Turnover in Brown Adipose Tissue of the Rat. J. Clin. Investig. 1982, 69, 1061–1071. [Google Scholar] [CrossRef] [PubMed]
  62. Yoshida, T.; Fisler, J.S.; Fukushima, M.; Bray, G.A.; Schemmel, R.A. Diet, lighting, and food intake affect norepinephrine turnover in dietary obesity. Am. J. Physiol. Content 1987, 252, R402–R408. [Google Scholar] [CrossRef] [PubMed]
  63. Saito, M.; Minokoshi, Y.; Shimazu, T. Metabolic and sympathetic nerve activities of brown adipose tissue in tube-fed rats. Am. J. Physiol. Metab. 1989, 257, E374–E378. [Google Scholar] [CrossRef] [PubMed]
  64. Rothwell, N.J.; Stock, M.J. Effects of denervating brown adipose tissue on the responses to cold, hyperphagia and noradrenaline treatment in the rat. J. Physiol. 1984, 355, 457–463. [Google Scholar] [CrossRef]
  65. Leblanc, J.; Cabanac, M.; Samson, P. Reduced postprandial heat production with gavage as compared with meal feeding in human subjects. Am. J. Physiol. Metab. 1984, 246, E95–E101. [Google Scholar] [CrossRef]
  66. Leblanc, J.; Brondel, L. Role of palatability on meal-induced thermogenesis in human subjects. Am. J. Physiol. Metab. 1985, 248, E333–E336. [Google Scholar] [CrossRef]
  67. Diamond, P.; Brondel, L.; Leblanc, J. Palatability and postprandial thermogenesis in dogs. Am. J. Physiol. Metab. 1985, 248, E75–E79. [Google Scholar] [CrossRef]
  68. Blouet, C.; Schwartz, G.J. Duodenal Lipid Sensing Activates Vagal Afferents to Regulate Non-Shivering Brown Fat Thermogenesis in Rats. PLoS ONE 2012, 7, e51898. [Google Scholar] [CrossRef]
  69. Yamazaki, T.; Morimoto-Kobayashi, Y.; Koizumi, K.; Takahashi, C.; Nakajima, S.; Kitao, S.; Taniguchi, Y.; Katayama, M.; Ogawa, Y. Secretion of a gastrointestinal hormone, cholecystokinin, by hop-derived bitter components activates sympathetic nerves in brown adipose tissue. J. Nutr. Biochem. 2018, 64, 80–87. [Google Scholar] [CrossRef]
  70. Beiroa, D.; Imbernon, M.; Gallego, R.; Senra, A.; Herranz, D.; Villarroya, F.; Serrano, M.; Fernø, J.; Salvador, J.; Escalada, J.; et al. GLP-1 Agonism Stimulates Brown Adipose Tissue Thermogenesis and Browning Through Hypothalamic AMPK. Diabetes 2014, 63, 3346–3358. [Google Scholar] [CrossRef] [Green Version]
  71. Li, Y.; Schnabl, K.; Gabler, S.-M.; Willershäuser, M.; Reber, J.; Karlas, A.; Laurila, S.; Lahesmaa, M.; Din, M.U.; Bast-Habersbrunner, A.; et al. Secretin-Activated Brown Fat Mediates Prandial Thermogenesis to Induce Satiation. Cell 2018, 175, 1561–1574.e12. [Google Scholar] [CrossRef] [Green Version]
  72. Vítek, L.; Haluzik, M. The role of bile acids in metabolic regulation. J. Endocrinol. 2016, 228, R85–R96. [Google Scholar] [CrossRef] [PubMed]
  73. Watanabe, M.; Houten, S.; Mataki, C.; Christoffolete, M.; Kim, B.W.; Sato, H.; Messaddeq, N.; Harney, J.W.; Ezaki, O.; Kodama, T.; et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 2006, 439, 484–489. [Google Scholar] [CrossRef] [PubMed]
  74. Broeders, E.P.; Nascimento, E.B.; Havekes, B.; Brans, B.; Roumans, K.H.; Tailleux, A.; Schaart, G.; Kouach, M.; Charton, J.; Deprez, B.; et al. The Bile Acid Chenodeoxycholic Acid Increases Human Brown Adipose Tissue Activity. Cell Metab. 2015, 22, 418–426. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  75. Velazquez-Villegas, L.A.; Perino, A.; Lemos, V.; Zietak, M.; Nomura, M.; Pols, T.W.H.; Schoonjans, K. TGR5 signalling promotes mitochondrial fission and beige remodelling of white adipose tissue. Nat. Commun. 2018, 9, 245. [Google Scholar] [CrossRef] [Green Version]
  76. Golic, I.; Kalezic, A.; Jankovic, A.; Jonic, S.; Korac, B.; Korac, A. Insulin Modulates the Bioenergetic and Thermogenic Capacity of Rat Brown Adipocytes In Vivo by Modulating Mitochondrial Mosaicism. Int. J. Mol. Sci. 2020, 21, 9204. [Google Scholar] [CrossRef] [PubMed]
  77. Orava, J.; Nuutila, P.; Lidell, M.E.; Oikonen, V.; Noponen, T.; Viljanen, T.; Scheinin, M.; Taittonen, M.; Niemi, T.; Enerbäck, S.; et al. Different Metabolic Responses of Human Brown Adipose Tissue to Activation by Cold and Insulin. Cell Metab. 2011, 14, 272–279. [Google Scholar] [CrossRef] [Green Version]
  78. Stanford, K.I.; Middelbeek, R.J.; Townsend, K.L.; An, D.; Nygaard, E.B.; Hitchcox, K.M.; Markan, K.R.; Nakano, K.; Hirshman, M.F.; Tseng, Y.-H.; et al. Brown adipose tissue regulates glucose homeostasis and insulin sensitivity. J. Clin. Investig. 2013, 123, 215–223. [Google Scholar] [CrossRef] [Green Version]
  79. Ravussin, E.; Bogardus, C. Thermogenic response to insulin and glucose infusions in man: A model to evaluate the different components of the thermic effect of carbohydrate. Life Sci. 1982, 31, 2011–2018. [Google Scholar] [CrossRef]
  80. Lee, P.; Smith, S.; Linderman, J.; Courville, A.B.; Brychta, R.J.; Dieckmann, W.; Werner, C.D.; Chen, K.Y.; Celi, F.S. Temperature-Acclimated Brown Adipose Tissue Modulates Insulin Sensitivity in Humans. Diabetes 2014, 63, 3686–3698. [Google Scholar] [CrossRef] [Green Version]
  81. Rothwell, N.J.; Stock, M.J. A role for insulin in the diet-induced thermogenesis of cafeteria-fed rats. Metab.-Clin. Exp. 1981, 30, 673–678. [Google Scholar] [CrossRef]
  82. Aherne, W.; Hull, D. Brown adipose tissue and heat production in the newborn infant. J. Pathol. Bacteriol. 1966, 91, 223–234. [Google Scholar] [CrossRef]
  83. Ma, S.W.; Nadeau, B.E.; Foster, D.O. Evidence for liver as the major site of the diet-induced thermogenesis of rats fed a “cafeteria” diet. Can. J. Physiol. Pharmacol. 1987, 65, 1802–1804. [Google Scholar] [CrossRef]
  84. Ma, S.W.; Foster, D.O. Brown adipose tissue, liver, and diet-induced thermogenesis in cafeteria diet-fed rats. Can. J. Physiol. Pharmacol. 1989, 67, 376–381. [Google Scholar] [CrossRef]
  85. Berry, M.; Clark, D.; Grivell, A.; Wallace, P. The contribution of hepatic metabolism to diet-induced thermogenesis. Metabolism 1985, 34, 141–147. [Google Scholar] [CrossRef]
  86. Schnabl, K.; Li, Y.; Klingenspor, M. The gut hormone secretin triggers a gut–brown fat–brain axis in the control of food intake. Exp. Physiol. 2020, 105, 1206–1213. [Google Scholar] [CrossRef]
  87. Friedman, J. The long road to leptin. J. Clin. Investig. 2016, 126, 4727–4734. [Google Scholar] [CrossRef] [Green Version]
  88. Collins, S.; Kuhn, C.M.; Petro, A.E.; Swick, A.G.; Chrunyk, B.A.; Surwit, R.S. Role of leptin in fat regulation. Nature 1996, 380, 677. [Google Scholar] [CrossRef]
  89. Commins, S.P.; Marsh, D.J.; Thomas, S.A.; Watson, P.M.; Padgett, M.A.; Palmiter, R.; Gettys, T.W. Norepinephrine is required for leptin effects on gene expression in brown and white adipose tissue. Endocrinology 1999, 140, 4772–4778. [Google Scholar] [CrossRef]
  90. Commins, S.P.; Watson, P.M.; Padgett, M.A.; Dudley, A.; Argyropoulos, G.; Gettys, T.W. Induction of uncoupling protein expression in brown and white adipose tissue by leptin. Endocrinology 1999, 140, 292–300. [Google Scholar] [CrossRef]
  91. Scarpace, P.J.; Matheny, M.; Pollock, B.H.; Tumer, N. Leptin increases uncoupling protein expression and energy expenditure. Am. J. Physiol. Metab. 1997, 273, E226–E230. [Google Scholar] [CrossRef]
  92. Perry, R.J.; Lyu, K.; Rabin-Court, A.; Dong, J.; Li, X.; Yang, Y.; Qing, H.; Wang, A.; Yang, X.; Shulman, G.I. Leptin mediates postprandial increases in body temperature through hypothalamus–adrenal medulla–adipose tissue crosstalk. J. Clin. Investig. 2020, 130, 2001–2016. [Google Scholar] [CrossRef] [Green Version]
  93. Wang, P.; Loh, K.H.; Wu, M.; Morgan, D.A.; Schneeberger, M.; Yu, X.; Chi, J.; Kosse, C.; Kim, D.; Rahmouni, K.; et al. A leptin–BDNF pathway regulating sympathetic innervation of adipose tissue. Nature 2020, 583, 839–844. [Google Scholar] [CrossRef] [PubMed]
  94. Himms-Hagen, J.; Hogan, S.; Zaror-Behrens, G. Increased brown adipose tissue thermogenesis in obese (ob/ob) mice fed a palatable diet. Am. J. Physiol. Metab. 1986, 250, E274–E281. [Google Scholar] [CrossRef] [PubMed]
  95. Fischer, A.W.; Cannon, B.; Nedergaard, J. Leptin-deficient mice are not hypothermic, they are anapyrexic. Mol. Metab. 2016, 6, 173. [Google Scholar] [CrossRef] [PubMed]
  96. Fischer, A.W.; Hoefig, C.S.; Abreu-Vieira, G.; de Jong, J.M.; Petrovic, N.; Mittag, J.; Cannon, B.; Nedergaard, J. Leptin Raises Defended Body Temperature without Activating Thermogenesis. Cell Rep. 2016, 14, 1621–1631. [Google Scholar] [CrossRef] [Green Version]
  97. Qiao, L.; Yoo, H.S.; Bosco, C.; Lee, B.; Feng, G.-S.; Schaack, J.; Chi, N.-W.; Shao, J. Adiponectin reduces thermogenesis by inhibiting brown adipose tissue activation in mice. Diabetologia 2014, 57, 1027–1036. [Google Scholar] [CrossRef] [Green Version]
  98. Kmiec, Z.; Pokrywka, L.; Kotlarz, G.; Kubasik, J.; Szutowicz, A.; Mysliwski, A. Effects of Fasting and Refeeding on Serum Leptin, Adiponectin and Free Fatty Acid Concentrations in Young and Old Male Rats. Gerontology 2005, 51, 357–362. [Google Scholar] [CrossRef]
  99. van den Berg, S.A.A.; Lichtenbelt, W.V.M.; van Dijk, K.W.; Schrauwen, P. Skeletal muscle mitochondrial uncoupling, adaptive thermogenesis and energy expenditure. Curr. Opin. Clin. Nutr. Metab. Care 2011, 14, 243–249. [Google Scholar] [CrossRef] [Green Version]
  100. Bal, N.C.; Maurya, S.K.; Sopariwala, D.H.; Sahoo, S.K.; Gupta, S.C.; Shaikh, S.A.; Pant, M.; Rowland, L.A.; Bombardier, E.; Goonasekera, S.A.; et al. Sarcolipin is a newly identified regulator of muscle-based thermogenesis in mammals. Nat. Med. 2012, 18, 1575–1579. [Google Scholar] [CrossRef] [Green Version]
  101. Maurya, S.; Bal, N.C.; Sopariwala, D.H.; Pant, M.; Rowland, L.A.; Shaikh, S.; Periasamy, M. Sarcolipin Is a Key Determinant of the Basal Metabolic Rate, and Its Overexpression Enhances Energy Expenditure and Resistance against Diet-induced Obesity. J. Biol. Chem. 2015, 290, 10840–10849. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  102. Reis, M.; Farage, M.; De Meis, L. Thermogenesis and energy expenditure: Control of heat production by the Ca2+-ATPase of fast and slow muscle. Mol. Membr. Biol. 2002, 19, 301–310. [Google Scholar] [CrossRef] [PubMed]
  103. Yau, W.W.; Yen, P.M. Thermogenesis in Adipose Tissue Activated by Thyroid Hormone. Int. J. Mol. Sci. 2020, 21, 3020. [Google Scholar] [CrossRef] [PubMed]
  104. Obregon, M.-J. Adipose tissues and thyroid hormones. Front. Physiol. 2014, 5, 479. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  105. Tulp, O.L.A.A.; Einstein, G.P. Treatment with α-Methylparatyrosine Inhibits Sympathetic but Not Thyroidal Responses to Diet-Induced Thermogenesis in Lean Cafeteria-Overfed Rats. Curr. Trends. Toxi Pharma. Res. 2022, 2, 1–6. [Google Scholar] [CrossRef]
  106. Gabarrou, J.-F.; Duchamp, C.; Williams, J.; Géraert, P.-A. A role for thyroid hormones in the regulation of diet-induced thermogenesis in birds. Br. J. Nutr. 1997, 78, 963–973. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  107. Danforth, E.; Horton, E.S.; O’Connell, M.; Sims, E.A.; Burger, A.G.; Ingbar, S.H.; Braverman, L.; Vagenakis, A.G. Dietary-induced alterations in thyroid hormone metabolism during overnutrition. J. Clin. Investig. 1979, 64, 1336–1347. [Google Scholar] [CrossRef] [Green Version]
  108. D’Alessio, D.A.; Kavle, E.C.; Mozzoli, M.A.; Smalley, K.J.; Polansky, M.; Kendrick, Z.V.; Owen, L.R.; Bushman, M.C.; Boden, G.; Owen, O.E. Thermic effect of food in lean and obese men. J. Clin. Investig. 1988, 81, 1781–1789. [Google Scholar] [CrossRef] [Green Version]
  109. Ishii, S.; Osaki, N.; Shimotoyodome, A. The Effects of a Hypocaloric Diet on Diet-Induced Thermogenesis and Blood Hormone Response in Healthy Male Adults: A Pilot Study. J. Nutr. Sci. Vitaminol. 2016, 62, 40–46. [Google Scholar] [CrossRef] [Green Version]
  110. Richter, J.; Herzog, N.; Janka, S.; Baumann, T.; Kistenmacher, A.; Oltmanns, K.M. Twice as High Diet-Induced Thermogenesis After Breakfast vs Dinner On High-Calorie as Well as Low-Calorie Meals. J. Clin. Endocrinol. Metab. 2020, 105, e211. [Google Scholar] [CrossRef]
  111. Yoneshiro, T.; Matsushita, M.; Saito, M. Translational aspects of brown fat activation by food-derived stimulants. In Brown Adipose Tissue; Springer: Cham, Switzerland, 2019; Volume 251, pp. 359–379. [Google Scholar] [CrossRef]
  112. Kaur, J.; Kumar, V.; Kumar, V.; Shafi, S.; Khare, P.; Mahajan, N.; Bhadada, S.K.; Kondepudi, K.K.; Bhunia, R.K.; Kuhad, A.; et al. Combination of TRP channel dietary agonists induces energy expending and glucose utilizing phenotype in HFD-fed mice. Int. J. Obes. 2021, 46, 153–161. [Google Scholar] [CrossRef] [PubMed]
  113. Thapa, D.; Barrett, B.; Argunhan, F.; Brain, S.D. Influence of Cold-TRP Receptors on Cold-Influenced Behaviour. Pharmaceuticals 2021, 15, 42. [Google Scholar] [CrossRef] [PubMed]
  114. Gupta, R.; Kapoor, B.; Gulati, M.; Kumar, B.; Gupta, M.; Singh, S.K.; Awasthi, A. Sweet pepper and its principle constituent capsiate: Functional properties and health benefits. Crit. Rev. Food Sci. Nutr. 2021, 6, 1–25. [Google Scholar] [CrossRef] [PubMed]
  115. Panchal, S.K.; Bliss, E.; Brown, L. Capsaicin in Metabolic Syndrome. Nutrients 2018, 10, 630. [Google Scholar] [CrossRef] [Green Version]
  116. Liao, S.-F.; Korivi, M.; Tsao, J.-P.; Huang, C.-C.; Chang, C.-C.; Cheng, I.-S. Effect of Capsinoids Supplementation on Fat Oxidation and Muscle Glycogen Restoration during Post-exercise Recovery in Humans. Curr. Pharm. Des. 2021, 27, 981–988. [Google Scholar] [CrossRef]
  117. Irandoost, P.; Yagin, N.L.; Namazi, N.; Keshtkar, A.; Farsi, F.; Alamdari, N.M.; Vafa, M. The effect of Capsaicinoids or Capsinoids in red pepper on thermogenesis in healthy adults: A systematic review and meta-analysis. Phytotherapy Res. 2020, 35, 1358–1377. [Google Scholar] [CrossRef]
  118. Yoneshiro, T.; Aita, S.; Kawai, Y.; Iwanaga, T.; Saito, M. Nonpungent capsaicin analogs (capsinoids) increase energy expenditure through the activation of brown adipose tissue in humans. Am. J. Clin. Nutr. 2012, 95, 845–850. [Google Scholar] [CrossRef] [Green Version]
  119. Mongioì, L.; La Vignera, S.; Cannarella, R.; Cimino, L.; Compagnone, M.; Condorelli, R.; Calogero, A. The Role of Resveratrol Administration in Human Obesity. Int. J. Mol. Sci. 2021, 22, 4362. [Google Scholar] [CrossRef]
  120. Hoca, M.; Becer, E.; Vatansever, H.S. The role of resveratrol in diabetes and obesity associated with insulin resistance. Arch. Physiol. Biochem. 2021, 15, 1–7. [Google Scholar] [CrossRef]
  121. Osuna-Prieto, F.J.; Martinez-Tellez, B.; Segura-Carretero, A.; Ruiz, J.R. Activation of Brown Adipose Tissue and Promotion of White Adipose Tissue Browning by Plant-based Dietary Components in Rodents: A Systematic Review. Adv. Nutr. Int. Rev. J. 2021, 12, 2147–2156. [Google Scholar] [CrossRef]
  122. Andrade, J.M.O.; Frade, A.C.M.; Guimarães, J.B.; Freitas, K.M.; Lopes, M.T.P.; Guimaraes, A.; De Paula, A.M.B.; Coimbra, C.C.; Santos, S.H.S. Resveratrol increases brown adipose tissue thermogenesis markers by increasing SIRT1 and energy expenditure and decreasing fat accumulation in adipose tissue of mice fed a standard diet. Eur. J. Nutr. 2014, 53, 1503–1510. [Google Scholar] [CrossRef]
  123. Horvath, C.; Wolfrum, C. Feeding brown fat: Dietary phytochemicals targeting non-shivering thermogenesis to control body weight. Proc. Nutr. Soc. 2020, 79, 338–356. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  124. Baur, J.A.; Pearson, K.J.; Price, N.L.; Jamieson, H.A.; Lerin, C.; Kalra, A.; Prabhu, V.V.; Allard, J.S.; Lopez-Lluch, G.; Lewis, K.; et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 2006, 444, 337–342. [Google Scholar] [CrossRef]
  125. Um, J.-H.; Park, S.-J.; Kang, H.; Yang, S.; Foretz, M.; McBurney, M.W.; Kim, M.K.; Viollet, B.; Chung, J.H. AMP-Activated Protein Kinase–Deficient Mice Are Resistant to the Metabolic Effects of Resveratrol. Diabetes 2010, 59, 554–563. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  126. Andrade, J.M.O.; Barcala-Jorge, A.S.; Batista-Jorge, G.C.; Paraíso, A.F.; de Freitas, K.M.; Lelis, D.D.F.; Guimarães, A.L.S.; de Paula, A.M.B.; Santos, S.H.S. Effect of resveratrol on expression of genes involved thermogenesis in mice and humans. Biomed. Pharmacother. 2019, 112, 108634. [Google Scholar] [CrossRef] [PubMed]
  127. Shao, W.; Yu, Z.; Chiang, Y.; Yang, Y.; Chai, T.; Foltz, W.; Lu, H.; Fantus, I.G.; Jin, T. Curcumin Prevents High Fat Diet Induced Insulin Resistance and Obesity via Attenuating Lipogenesis in Liver and Inflammatory Pathway in Adipocytes. PLoS ONE 2012, 7, e28784. [Google Scholar] [CrossRef]
  128. Vafaeipour, Z.; Razavi, B.M.; Hosseinzadeh, H. Effects of turmeric (Curcuma longa) and its constituent (curcumin) on the metabolic syndrome: An updated review. J. Integr. Med. 2022, 20, 193–203. [Google Scholar] [CrossRef]
  129. Zhu, X.; Du, S.; Yan, Q.; Min, C.; Zhou, N.; Zhou, W.; Li, X. Dietary curcumin supplementation promotes browning and energy expenditure in postnatal overfed rats. Nutr. Metab. 2021, 18, 1–14. [Google Scholar] [CrossRef]
  130. Han, Z.; Yao, L.; Zhong, Y.; Xiao, Y.; Gao, J.; Zheng, Z.; Fan, S.; Zhang, Z.; Gong, S.; Chang, S.; et al. Gut microbiota mediates the effects of curcumin on enhancing Ucp1-dependent thermogenesis and improving high-fat diet-induced obesity. Food Funct. 2021, 12, 6558–6575. [Google Scholar] [CrossRef]
  131. Lone, J.; Choi, J.H.; Kim, S.W.; Yun, J.W. Curcumin induces brown fat-like phenotype in 3T3-L1 and primary white adipocytes. J. Nutr. Biochem. 2015, 27, 193–202. [Google Scholar] [CrossRef]
  132. Kasprzak-Drozd, K.; Oniszczuk, T.; Gancarz, M.; Kondracka, A.; Rusinek, R.; Oniszczuk, A. Curcumin and Weight Loss: Does It Work? Int. J. Mol. Sci. 2022, 23, 639. [Google Scholar] [CrossRef] [PubMed]
  133. Mele, L.; Bidault, G.; Mena, P.; Crozier, A.; Brighenti, F.; Vidal-Puig, A.; Del Rio, D. Dietary (Poly)phenols, Brown Adipose Tissue Activation, and Energy Expenditure: A Narrative Review. Adv. Nutr. 2017, 8, 694–704. [Google Scholar] [CrossRef] [Green Version]
  134. Rupasinghe, H.V.; Sekhon-Loodu, S.; Mantso, T.; Panayiotidis, M.I. Phytochemicals in regulating fatty acid β-oxidation: Potential underlying mechanisms and their involvement in obesity and weight loss. Pharmacol. Ther. 2016, 165, 153–163. [Google Scholar] [CrossRef] [PubMed]
  135. Nomura, S.; Ichinose, T.; Jinde, M.; Kawashima, Y.; Tachiyashiki, K.; Imaizumi, K. Tea catechins enhance the mRNA expression of uncoupling protein 1 in rat brown adipose tissue. J. Nutr. Biochem. 2008, 19, 840–847. [Google Scholar] [CrossRef]
  136. Bolin, A.P.; Sousa-Filho, C.P.B.; Marinovic, M.P.; Rodrigues, A.C.; Otton, R. Polyphenol-rich green tea extract induces thermogenesis in mice by a mechanism dependent on adiponectin signaling. J. Nutr. Biochem. 2019, 78, 108322. [Google Scholar] [CrossRef]
  137. Bolin, A.P.; Sousa-Filho, C.P.B.; dos Santos, G.T.N.; Ferreira, L.T.; de Andrade, P.B.M.; Figueira, A.C.M.; Batista, F.A.H.; Otton, R. Adipogenic commitment induced by green tea polyphenols remodel adipocytes to a thermogenic phenotype. J. Nutr. Biochem. 2020, 83, 108429. [Google Scholar] [CrossRef] [PubMed]
  138. Thielecke, F.; Rahn, G.; Böhnke, J.; Adams, F.; Birkenfeld, A.L.; Jordan, J.; Boschmann, M. Epigallocatechin-3-gallate and postprandial fat oxidation in overweight/obese male volunteers: A pilot study. Eur. J. Clin. Nutr. 2010, 64, 704–713. [Google Scholar] [CrossRef]
  139. Quinhoneiro, D.C.G.; Nicoletti, C.F.; Pinhel, M.A.S.; Noronha, N.Y.; Braga, C.B.M.; Oliveira, B.A.P.; Cortes-Oliveira, C.; Oliveira, W.P.; Junior, W.S.; Marchini, J.S.; et al. Green tea supplementation upregulates uncoupling protein 3 expression in severe obese women adipose tissue but does not promote weight loss. Int. J. Food Sci. Nutr. 2018, 69, 995–1002. [Google Scholar] [CrossRef]
  140. Hursel, R.; Viechtbauer, W.; Dulloo, A.; Tremblay, A.; Tappy, L.; Rumpler, W.; Westerterp-Plantenga, M.S. The effects of catechin rich teas and caffeine on energy expenditure and fat oxidation: A meta-analysis. Obes. Rev. 2011, 12, e573–e581. [Google Scholar] [CrossRef] [Green Version]
  141. Pradhan, S.; Panchali, T.; Paul, B.; Khatun, A.; Rao Jarapala, S.; Mondal, K.C.; Ghosh, K.; Chakrabarti, S. Anti-obesity potentiality of Tapra fish (Opisthopterus tardoore) oil. J. Food Biochem. 2020, 44, e13448. [Google Scholar] [CrossRef]
  142. Yang, X.; Yi, X.; Zhang, F.; Li, F.; Lang, L.; Ling, M.; Lai, X.; Chen, L.; Quan, L.; Fu, Y.; et al. Cytochrome P450 epoxygenase-derived EPA and DHA oxylipins 17,18-epoxyeicosatetraenoic acid and 19,20-epoxydocosapentaenoic acid promote BAT thermogenesis and WAT browning through the GPR120-AMPKα signaling pathway. Food Funct. 2022, 13, 1232–1245. [Google Scholar] [CrossRef] [PubMed]
  143. Adeyemi, W.J.; Olayaki, L.A. Additive and nonadditive effects of salmon calcitonin and omega-3 fatty acids on antioxidant, hematological and bone and cartilage markers in experimental diabetic-osteoarthritic rats. Chin. J. Physiol. 2019, 62, 108–116. [Google Scholar] [CrossRef]
  144. Younan, S.M.; Rashed, L.A.; El Aziz, O.M.A. Cardioprotective Modulation of Cardiac Adiponectin and Adiponectin Receptors by Omega-3 in the High-Fat Fed Rats. Chin. J. Physiol. 2013, 56, 65–76. [Google Scholar] [CrossRef] [PubMed]
  145. Fernández-Galilea, M.; Félix-Soriano, E.; Colón-Mesa, I.; Escoté, X.; Moreno-Aliaga, M.J. Omega-3 fatty acids as regulators of brown/beige adipose tissue: From mechanisms to therapeutic potential. J. Physiol. Biochem. 2019, 76, 251–267. [Google Scholar] [CrossRef]
  146. Kim, M.; Goto, T.; Yu, R.; Uchida, K.; Tominaga, M.; Kano, Y.; Takahashi, N.; Kawada, T. Fish oil intake induces UCP1 upregulation in brown and white adipose tissue via the sympathetic nervous system. Sci. Rep. 2015, 5, 18013. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  147. Escher, P.; Braissant, O.; Basu-Modak, S.; Michalik, L.; Wahli, W.; Desvergne, B. Rat PPARs: Quantitative analysis in adult rat tissues and regulation in fasting and refeeding. Endocrinology 2001, 142, 4195–4202. [Google Scholar] [CrossRef] [PubMed]
  148. Park, H.; He, A.; Tan, M.; Johnson, J.; Dean, J.M.; Pietka, T.A.; Chen, Y.; Zhang, X.; Hsu, F.-F.; Razani, B.; et al. Peroxisome-derived lipids regulate adipose thermogenesis by mediating cold-induced mitochondrial fission. J. Clin. Investig. 2019, 129, 694–711. [Google Scholar] [CrossRef] [Green Version]
  149. Araki, M.; Nakagawa, Y.; Oishi, A.; Han, S.-I.; Wang, Y.; Kumagai, K.; Ohno, H.; Mizunoe, Y.; Iwasaki, H.; Sekiya, M.; et al. The Peroxisome Proliferator-Activated Receptor α (PPARα) Agonist Pemafibrate Protects against Diet-Induced Obesity in Mice. Int. J. Mol. Sci. 2018, 19, 2148. [Google Scholar] [CrossRef] [Green Version]
  150. Yamazaki, T.; Li, D.; Ikaga, R. Fish Oil Increases Diet-Induced Thermogenesis in Mice. Mar. Drugs 2021, 19, 278. [Google Scholar] [CrossRef]
  151. Murholm, M.; Isidor, M.S.; Basse, A.L.; Winther, S.; Sørensen, C.; Skovgaard-Petersen, J.; Nielsen, M.M.; Hansen, A.S.; Quistorff, B.; Hansen, J.B. Retinoic acid has different effects on UCP1 expression in mouse and human adipocytes. BMC Cell Biol. 2013, 14, 41. [Google Scholar] [CrossRef] [Green Version]
  152. Berry, D.C.; Noy, N. All-trans-retinoic acid represses obesity and insulin resistance by activating both peroxisome proliferation-activated receptor beta/delta and retinoic acid receptor. Mol. Cell Biol. 2009, 29, 3286–3296. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  153. Bonet, M.; Oliver, J.; Pico, C.; Felipe, F.; Ribot, J.; Cinti, S.; Palou, A. Opposite effects of feeding a vitamin A-deficient diet and retinoic acid treatment on brown adipose tissue uncoupling protein 1 (UCP1), UCP2 and leptin expression. J. Endocrinol. 2000, 166, 511–517. [Google Scholar] [CrossRef] [Green Version]
  154. Zulet, M.; Puchau, B.; Hermsdorff, H.H.M.; Navarro, C.; Martínez, J.A. Vitamin A Intake Is Inversely Related with Adiposity in Healthy Young Adults. J. Nutr. Sci. Vitaminol. 2008, 54, 347–352. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  155. Pereira, S.E.; Saboya, C.J.; Saunders, C.; Ramalho, A. Serum Levels and Liver Store of Retinol and Their Association with Night Blindness in Individuals with Class III Obesity. Obes. Surg. 2011, 22, 602–608. [Google Scholar] [CrossRef] [PubMed]
  156. Candi, E.; Campanelli, M.; Sica, G.; Schinzari, F.; Rovella, V.; Di Daniele, N.; Melino, J.; Tesauro, M. Differences in the vascular and metabolic profiles between metabolically healthy and unhealthy obesity. Endocr. Metab. Sci. 2021, 2, 100077. [Google Scholar] [CrossRef]
  157. Blaak, E.E.; Hul, G.; Verdich, C.; Stich, V.; Martinez, J.A.; Petersen, M.; Feskens, E.F.M.; Patel, K.; Oppert, J.M.; Barbe, P.; et al. Impaired Fat-induced Thermogenesis in Obese Subjects: The NUGENOB Study*. Obesity 2007, 15, 653–663. [Google Scholar] [CrossRef] [PubMed]
  158. Moon, J.; Koh, G. Clinical Evidence and Mechanisms of High-Protein Diet-Induced Weight Loss. J. Obes. Metab. Syndr. 2020, 29, 166–173. [Google Scholar] [CrossRef]
  159. de Jonge, L.; Bray, G.A. The thermic effect of food and obesity: A critical review. Obes. Res. 1997, 5, 622–631. [Google Scholar] [CrossRef]
  160. Trayhurn, P.; Thurlby, P.L.; James, W.P.T. Thermogenic defect in pre-obese ob/ob mice. Nat. 1977, 266, 60–62. [Google Scholar] [CrossRef]
  161. Leibel, R.L.; Rosenbaum, M.; Hirsch, J. Changes in Energy Expenditure Resulting from Altered Body Weight. N. Engl. J. Med. 1995, 332, 621–628. [Google Scholar] [CrossRef]
  162. Tentolouris, N.; Pavlatos, S.; Kokkinos, A.; Perrea, D.; Pagoni, S.; Katsilambros, N. Diet-induced thermogenesis and substrate oxidation are not different between lean and obese women after two different isocaloric meals, one rich in protein and one rich in fat. Metabolism 2008, 57, 313–320. [Google Scholar] [CrossRef] [PubMed]
  163. Tentolouris, N.; Alexiadou, K.; Kokkinos, A.; Koukou, E.; Perrea, D.; Kyriaki, D.; Katsilambros, N. Meal-induced thermogenesis and macronutrient oxidation in lean and obese women after consumption of carbohydrate-rich and fat-rich meals. Nutrition 2011, 27, 310–315. [Google Scholar] [CrossRef] [PubMed]
  164. Stiegler, P.; Sparks, S.A.; Cunliffe, A. Moderate exercise, postprandial energy expenditure, and substrate use in varying meals in lean and obese men. Int. J. Sport Nutr. Exerc. Metab. 2008, 18, 66–78. [Google Scholar] [CrossRef] [PubMed]
  165. Wen, J.; Bo, T.; Zhang, X.; Wang, Z.; Wang, D. Thermo-TRPs and gut microbiota are involved in thermogenesis and energy metabolism during low temperature exposure of obese mice. J. Exp. Biol. 2020, 223, jeb218974. [Google Scholar] [CrossRef]
  166. Felig, P. Insulin is the mediator of feecling-related thermogenesis: Insulin resistance and/or deficiency results in a thermogenic defect which contributes to the pathogenesis of obesity. Clin. Physiol. 1984, 4, 267–273. [Google Scholar] [CrossRef]
  167. Golay, A.; Schutz, Y.; Meyer, H.U.; Thiébaud, D.; Curchod, B.; Maeder, E.; Felber, J.-P.; Jéquier, E. Glucose-induced Thermogenesis in Nondiabetic and Diabetic Obese Subjects. Diabetes 1982, 31, 1023–1028. [Google Scholar] [CrossRef]
  168. Remie, C.M.E.; Moonen, M.P.B.; Roumans, K.H.M.; Nascimento, E.B.M.; Gemmink, A.; Havekes, B.; Schaart, G.; Kornips, E.; Joris, P.J.; Schrauwen-Hinderling, V.B.; et al. Metabolic responses to mild cold acclimation in type 2 diabetes patients. Nat. Commun. 2021, 12, 1–10. [Google Scholar] [CrossRef]
  169. Bartelt, A.; John, C.; Schaltenberg, N.; Berbée, J.F.P.; Worthmann, A.; Cherradi, M.L.; Schlein, C.; Piepenburg, J.; Boon, M.R.; Rinninger, F.; et al. Thermogenic adipocytes promote HDL turnover and reverse cholesterol transport. Nat. Commun. 2017, 8, 15010. [Google Scholar] [CrossRef]
  170. Bartelt, A.; Bruns, O.T.; Reimer, R.; Hohenberg, H.; Ittrich, H.; Peldschus, K.; Kaul, M.G.; Tromsdorf, U.I.; Weller, H.; Waurisch, C.; et al. Brown adipose tissue activity controls triglyceride clearance. Nat. Med. 2011, 17, 200–205. [Google Scholar] [CrossRef]
  171. Lowell, B.B.; Hamann, A.; Lawitts, J.A.; Himms-Hagen, J.; Boyer, B.B.; Kozak, L.P.; Flier, J.S. Development of obesity in transgenic mice after genetic ablation of brown adipose tissue. Nature 1993, 366, 740–742. [Google Scholar] [CrossRef]
  172. Turchi, R.; Tortolici, F.; Guidobaldi, G.; Iacovelli, F.; Falconi, M.; Rufini, S.; Faraonio, R.; Casagrande, V.; Federici, M.; De Angelis, L.; et al. Frataxin deficiency induces lipid accumulation and affects thermogenesis in brown adipose tissue. Cell Death Dis. 2020, 11, 51. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  173. Lian, C.-Y.; Zhai, Z.-Z.; Li, Z.-F.; Wang, L. High fat diet-triggered non-alcoholic fatty liver disease: A review of proposed mechanisms. Chem. Interact. 2020, 330, 109199. [Google Scholar] [CrossRef]
  174. Ahmed, B.A.; Ong, F.J.; Barra, N.G.; Blondin, D.P.; Gunn, E.; Oreskovich, S.M.; Szamosi, J.C.; Syed, S.A.; Hutchings, E.K.; Konyer, N.B.; et al. Lower brown adipose tissue activity is associated with non-alcoholic fatty liver disease but not changes in the gut microbiota. Cell Rep. Med. 2021, 2, 100397. [Google Scholar] [CrossRef] [PubMed]
  175. Gavaldà-Navarro, A.; Villarroya, J.; Cereijo, R.; Giralt, M.; Villarroya, F. The endocrine role of brown adipose tissue: An update on actors and actions. Rev. Endocr. Metab. Disord. 2021, 23, 31–41. [Google Scholar] [CrossRef] [PubMed]
  176. Ozguven, S.; Ones, T.; Yilmaz, Y.; Turoğlu, H.T.; Imeryuz, N.; İmeryüz, N. The role of active brown adipose tissue in human metabolism. Eur. J. Pediatr. 2015, 43, 355–361. [Google Scholar] [CrossRef]
  177. Croci, I.; Byrne, N.M.; Choquette, S.; Hills, A.P.; Chachay, V.S.; Clouston, A.D.; O’Moore-Sullivan, T.M.; Macdonald, G.A.; Prins, J.B.; Hickman, I.J. Whole-body substrate metabolism is associated with disease severity in patients with non-alcoholic fatty liver disease. Gut 2012, 62, 1625–1633. [Google Scholar] [CrossRef] [Green Version]
  178. Tsoli, M.; Moore, M.; Burg, D.; Painter, A.; Taylor, R.; Lockie, S.H.; Turner, N.; Warren, A.; Cooney, G.; Oldfield, B.; et al. Activation of Thermogenesis in Brown Adipose Tissue and Dysregulated Lipid Metabolism Associated with Cancer Cachexia in Mice. Cancer Res. 2012, 72, 4372–4382. [Google Scholar] [CrossRef] [Green Version]
  179. Luan, Y.; Zhang, Y.; Yu, S.; You, M.; Xu, P.C.; Chung, S.; Kurita, T.; Zhu, J.; Kim, S. Development of ovarian tumour causes significant loss of muscle and adipose tissue: A novel mouse model for cancer cachexia study. J. Cachex. Sarcopenia Muscle 2022, 13, 1289–1301. [Google Scholar] [CrossRef]
  180. Hansell, D.T.; Davies, J.W.L.; Burns, H.J.G. The Relationship between Resting Energy Expenditure and Weight Loss in Benign and Malignant Disease. Ann. Surg. 1986, 203, 240–245. [Google Scholar] [CrossRef]
Figure 1. The role and regulatory mechanism of BAT activation in DIT in health and diseases. (A) Under healthy condition, dietary intake could promote BAT activation (facultative DIT) and total DIT to facilitate whole-body energy metabolism. (B) Under disease conditions: (1) Metabolic abnormalities such as obesity, diabetes, hyperlipidemia and NAFLD, dietary intake-induced BAT activation, and total DIT will be attenuated and might subsequently, affect whole-body energy balance and weight control. (2) Cancer-associated Cachexia (CAC) is characterized by systemic inflammation, which could enhance thermogenesis in BAT and increase systemic energy expenditure. However, low DIT were noted in the development of cancer cachexia.
Figure 1. The role and regulatory mechanism of BAT activation in DIT in health and diseases. (A) Under healthy condition, dietary intake could promote BAT activation (facultative DIT) and total DIT to facilitate whole-body energy metabolism. (B) Under disease conditions: (1) Metabolic abnormalities such as obesity, diabetes, hyperlipidemia and NAFLD, dietary intake-induced BAT activation, and total DIT will be attenuated and might subsequently, affect whole-body energy balance and weight control. (2) Cancer-associated Cachexia (CAC) is characterized by systemic inflammation, which could enhance thermogenesis in BAT and increase systemic energy expenditure. However, low DIT were noted in the development of cancer cachexia.
Ijms 23 09448 g001
Table 1. The summary of the animal and human studies about BAT activity and DIT in health and diseases.
Table 1. The summary of the animal and human studies about BAT activity and DIT in health and diseases.
DIT in health
InterventionBATDITTotal EEEnergy
Experimental ModelReference
Mechanism of ActionActivity
Caloric intake
low humans[108,109]
high ↑↑↑↑ humans[107,108]
Circadian rhythmicity
day ↑↑↑↑ humans[109]
night humans[109]
Capsaicin↑ ADRB3↑↑↑↑↑↑mice[115]
↑ TRPVhumans[116,117,118]
Resveratrol↑ AMPK↑↑↑↑↑↑mice[122,124,125]
↑ SIRT1humans[126]
Curcumin↑ ADRB3↑↑↑↑↑↑rats[129]
↑ cAMP/PKAmice[130]
↑ AMPK cells[131]
Green tea↑ ADRB3↑↑↑↑ ±humans[138,139,140]
Fish oil ↑↑↑↑↑↑±humans[145]
↑ TRPVmice[146]
all-trans retinoic acid↑ PPARγ↑↑↑↑↑↑ cells[140]
DIT in diseases
InterventionBATDITTotal EEEnergy
Experimental ModelReference
Mechanism of ActionActivity
Metabolic abnormalities
Obesity humans[159]
T2DM rats[64,81]
Hyperlipidemia humans[170]
NAFLD mice[174]
Cancer-associated cachexia (CAC) ↑↑ mice[178,179]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Chan, P.-C.; Hsieh, P.-S. The Role and Regulatory Mechanism of Brown Adipose Tissue Activation in Diet-Induced Thermogenesis in Health and Diseases. Int. J. Mol. Sci. 2022, 23, 9448.

AMA Style

Chan P-C, Hsieh P-S. The Role and Regulatory Mechanism of Brown Adipose Tissue Activation in Diet-Induced Thermogenesis in Health and Diseases. International Journal of Molecular Sciences. 2022; 23(16):9448.

Chicago/Turabian Style

Chan, Pei-Chi, and Po-Shiuan Hsieh. 2022. "The Role and Regulatory Mechanism of Brown Adipose Tissue Activation in Diet-Induced Thermogenesis in Health and Diseases" International Journal of Molecular Sciences 23, no. 16: 9448.

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop