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New Insights into Adipose Tissue Metabolic Function and Dysfunction

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (20 December 2022) | Viewed by 28161

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Dr. Federica Mannino

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Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy
Interests: pharmacology; natural products; oxidative stress; inflammatory disease; atherosclerosis; metabolic disease; neurodegenerative diseases; autophagy; proliferation and differentiation process
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Dr. Giovanni Pallio

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Department of Biomedical and Dental Sciences and Morphological and Functional Imaging, University of Messina, 98125 Messina, Italy
Interests: preclinical pharmacology; inflammation; oxidative stress; natural products; flavonoids; cannabinoids
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Dear Colleagues,

Adipose tissue is widely known as an endocrine organ able to modulate systemic metabolism thanks to its effects on energy storage, adipokine production, and adaptive thermogenesis; this endocrine function is carried out in various organs, such as liver, kidney, pancreas, and brain, and thus contributes to homeostatic regulation, energy balance, insulin sensitivity, and vascular–endothelial function.

Dysregulations of differentiation, metabolism, and the endocrine function of adipocytes lead to adipose tissue dysfunction that triggers the activation of molecular pathways involved in the physiopathology of overall metabolic diseases, such as obesity, inflammation, insulin resistance, and type 2 diabetes.

New therapeutic approaches targeting adipose tissue, its signaling molecules, and heterogeneity could provide hopeful benefits to understand the pathophysiology and treat several metabolic syndromes.

The purpose of this issue of the International Journal of Molecular Sciences entitled “New Insights into Adipose Tissue Metabolic Function and Dysfunction” is to include original research papers and/or relevant updates of literature data on new insights into the pathogenesis, molecular pathways, and beneficial effects of novel and safe treatments of metabolic diseases associated with adipose tissue disfunction.

Dr. Federica Mannino
Dr. Giovanni Pallio
Guest Editors

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Keywords

inflammation
browning
thermogenesis
adipogenesis
diabetes
adipokines
energy storage
insulin resistance
obesity
lipolysis

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New Insights into Adipose Tissue Metabolic Function and Dysfunction 3.0 in International Journal of Molecular Sciences

Published Papers (12 papers)

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Editorial

Jump to: Research, Review

4 pages, 193 KiB

Open AccessEditorial

New Insights into Adipose Tissue Metabolic Function and Dysfunction

by Giovanni Pallio

Int. J. Mol. Sci. 2023, 24(12), 9953; https://doi.org/10.3390/ijms24129953 - 09 Jun 2023

Cited by 1 | Viewed by 960

Abstract

Currently, one-third of people worldwide are overweight or obese, with a higher prevalence in women than in men and in the elderly than in the young [...] Full article

(This article belongs to the Special Issue New Insights into Adipose Tissue Metabolic Function and Dysfunction)

Research

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16 pages, 2135 KiB

Open AccessArticle

Changes in Lipid Metabolism Enzymes in Rat Epididymal Fat after Chronic Central Leptin Infusion Are Related to Alterations in Inflammation and Insulin Signaling

by María E. Casado, Sandra Canelles, Eduardo Arilla-Ferreiro, Laura M. Frago and Vicente Barrios

Int. J. Mol. Sci. 2023, 24(8), 7065; https://doi.org/10.3390/ijms24087065 - 11 Apr 2023

Cited by 2 | Viewed by 1274

Abstract

Leptin inhibits food intake and reduces the size of body fat depots, changing adipocyte sensitivity to insulin to restrain lipid accrual. This adipokine may modulate the production of cytokines that could diminish insulin sensitivity, particularly in visceral adipose tissue. To explore this possibility, we examined the effects of chronic central administration of leptin on the expression of key markers of lipid metabolism and its possible relationship with changes in inflammatory- and insulin-signaling pathways in epididymal adipose tissue. Circulating non-esterified fatty acids and pro- and anti-inflammatory cytokines were also measured. Fifteen male rats were divided into control (C), leptin (L, icv, 12 μg/day for 14 days), and pair-fed (PF) groups. We found a decrease in the activity of glucose-6-phosphate dehydrogenase and malic enzyme in the L group, with no changes in the expression of lipogenic enzymes. A reduction in the expression of lipoprotein lipase and carnitine palmitoyl-transferase-1A, together with a decrease in the phosphorylation of insulin-signaling targets and a low-grade inflammatory pattern, were detected in the epididymal fat of L rats. In conclusion, the decrease in insulin sensitivity and increased pro-inflammatory environment could regulate lipid metabolism, reducing epididymal fat stores in response to central leptin infusion. Full article

(This article belongs to the Special Issue New Insights into Adipose Tissue Metabolic Function and Dysfunction)

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14 pages, 2309 KiB

Open AccessArticle

Circulating Adipokines and Hepatokines Serve as Diagnostic Markers during Obesity Therapy

by Andreas Schmid, Miriam Arians, Monika Burg-Roderfeld, Thomas Karrasch, Andreas Schäffler, Martin Roderfeld and Elke Roeb

Int. J. Mol. Sci. 2022, 23(22), 14020; https://doi.org/10.3390/ijms232214020 - 14 Nov 2022

Cited by 1 | Viewed by 1741

Abstract

Allocation of morbidly obese patients to either conservative therapy options—such as lifestyle intervention and/or low-calorie diet (LCD)—or to bariatric surgery—preferably sleeve gastrectomy or Roux-en-Y gastric bypass (RYGB)—represents a crucial decision in order to obtain sustainable metabolic improvement and weight loss. The present study encompasses 160 severely obese patients, 81 of whom participated in an LCD program, whereas 79 underwent RYGB surgery. The post-interventional dynamics of physiologically relevant adipokines and hepatokines (ANGPTL4, CCL5, GDF15, GPNMB, IGFBP6), as well as their correlation with fat mass reduction and improvement of liver fibrosis, were analyzed. Systemic GDF15 was characterized as an excellent predictive marker for hepatic fibrosis as well as type 2 diabetes mellitus. Of note, baseline GDF15 serum concentrations were positively correlated with NFS and HbA1c levels after correction for BMI, suggesting GDF15 as a BMI-independent marker of hepatic fibrosis and T2D in obese individuals. Specific GDF15 cut-off values for both diseases were calculated. Overall, the present data demonstrate that circulating levels of specific adipokines and hepatokines are regulated with therapy-induced fat loss and metabolic improvement and might, therefore, serve as biomarkers for the success of obesity therapy strategies. Full article

(This article belongs to the Special Issue New Insights into Adipose Tissue Metabolic Function and Dysfunction)

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18 pages, 2172 KiB

Open AccessArticle

Macrophage Phenotypes and Gene Expression Patterns Are Unique in Naturally Occurring Metabolically Healthy Obesity

by Alistaire D. Ruggiero, Ravichandra Vemuri, Masha Block, Darla DeStephanis, Matthew Davis, Jeff Chou, Abigail Williams, Ashlynn Brock, Swapan Kumar Das and Kylie Kavanagh

Int. J. Mol. Sci. 2022, 23(20), 12680; https://doi.org/10.3390/ijms232012680 - 21 Oct 2022

Cited by 5 | Viewed by 2064

Abstract

Obesity impacts 650 million individuals globally, often co-occurring with metabolic syndrome. Though many obese individuals experience metabolic abnormalities (metabolically unhealthy obese [MUO]), ~30% do not (metabolically healthy obese [MHO]). Conversely, >10% of lean individuals are metabolically unhealthy (MUL). To evaluate the physiologic drivers of these phenotypes, a 44-animal African green monkey cohort was selected using metabolic syndrome risk criteria to represent these four clinically defined health groups. Body composition imaging and subcutaneous adipose tissue (SQ AT) biopsies were collected. Differences in adipocyte size, macrophage subtype distribution, gene expression, vascularity and fibrosis were analyzed using digital immunohistopathology, unbiased RNA-seq, endothelial CD31, and Masson’s trichrome staining, respectively. MHO AT demonstrated significant increases in M2 macrophages (p = 0.02) and upregulation of fatty acid oxidation-related terms and transcripts, including FABP7 (p = 0.01). MUO AT demonstrated downregulation of these factors and co-occurring upregulation of immune responses. These changes occurred without differences in AT distributions, adipocyte size, AT endothelial cells, collagen I deposition, or circulating cytokine levels. Without unhealthy diet consumption, healthy obesity is defined by an increased SQ AT M2/M1 macrophage ratio and lipid handling gene expression. We highlight M2 macrophages and fatty acid oxidation as targets for improving metabolic health with obesity. Full article

(This article belongs to the Special Issue New Insights into Adipose Tissue Metabolic Function and Dysfunction)

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15 pages, 3454 KiB

Open AccessArticle

Molecular and Physiological Effects of Browning Agents on White Adipocytes from Bone Marrow Mesenchymal Stromal Cells

by Girolamo Di Maio, Nicola Alessio, Gianfranco Peluso, Silverio Perrotta, Marcellino Monda and Giovanni Di Bernardo

Int. J. Mol. Sci. 2022, 23(20), 12151; https://doi.org/10.3390/ijms232012151 - 12 Oct 2022

Cited by 4 | Viewed by 1900

Abstract

Two different types of adipose depots can be observed in mammals: white adipose tissue (WAT) and brown adipose tissue (BAT). The primary role of WAT is to deposit surplus energy in the form of triglycerides, along with many metabolic and hormonal activities; as thermogenic tissue, BAT has the distinct characteristic of using energy and glucose consumption as a strategy to maintain the core body temperature. Under specific stimuli—such as exercise, cold exposure, and drug treatment—white adipocytes can utilize their extraordinary flexibility to transdifferentiate into brown-like cells, called beige adipocytes, thereby acquiring new morphological and physiological characteristics. For this reason, the process is identified as the ‘browning of WAT’. We evaluated the ability of some drugs, including GW501516, sildenafil, and rosiglitazone, to induce the browning process of adult white adipocytes obtained from differentiated mesenchymal stromal cells (MSCs). In addition, we broadened our investigation by evaluating the potential browning capacity of IRISIN, a myokine that is stimulated by muscular exercises. Our data indicate that IRISIN was effective in promoting the browning of white adipocytes, which acquire increased expression of UCP1, increased mitochondrial mass, and modification in metabolism, as suggested by an increase of mitochondrial oxygen consumption, primarily in presence of glucose as a nutrient. These promising browning agents represent an appealing focus in the therapeutic approaches to counteracting metabolic diseases and their associated obesity. Full article

(This article belongs to the Special Issue New Insights into Adipose Tissue Metabolic Function and Dysfunction)

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29 pages, 4964 KiB

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Brown Adipose Tissue Sheds Extracellular Vesicles That Carry Potential Biomarkers of Metabolic and Thermogenesis Activity Which Are Affected by High Fat Diet Intervention

by Tamara Camino, Nerea Lago-Baameiro, Aurelio Sueiro, Susana Belén Bravo, Iván Couto, Francisco Fernando Santos, Javier Baltar, Felipe F. Casanueva and María Pardo

Int. J. Mol. Sci. 2022, 23(18), 10826; https://doi.org/10.3390/ijms231810826 - 16 Sep 2022

Cited by 14 | Viewed by 2915

Abstract

Brown adipose tissue (BAT) is a key target for the development of new therapies against obesity due to its role in promoting energy expenditure; BAT secretory capacity is emerging as an important contributor to systemic effects, in which BAT extracellular vesicles (EVs) (i.e., batosomes) might be protagonists. EVs have emerged as a relevant cellular communication system and carriers of disease biomarkers. Therefore, characterization of the protein cargo of batosomes might reveal their potential as biomarkers of the metabolic activity of BAT. In this study, we are the first to isolate batosomes from lean and obese Sprague–Dawley rats, and to establish reference proteome maps. An LC-SWATH/MS analysis was also performed for comparisons with EVs secreted by white adipose tissue (subcutaneous and visceral WAT), and it showed that 60% of proteins were exclusive to BAT EVs. Precisely, batosomes of lean animals contain proteins associated with mitochondria, lipid metabolism, the electron transport chain, and the beta-oxidation pathway, and their protein cargo profile is dramatically affected by high fat diet (HFD) intervention. Thus, in obesity, batosomes are enriched with proteins involved in signal transduction, cell communication, the immune response, inflammation, thermogenesis, and potential obesity biomarkers including UCP1, Glut1, MIF, and ceruloplasmin. In conclusion, the protein cargo of BAT EVs is affected by the metabolic status and contains potential biomarkers of thermogenesis activity. Full article

(This article belongs to the Special Issue New Insights into Adipose Tissue Metabolic Function and Dysfunction)

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23 pages, 27182 KiB

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Toll-like Receptor 7 (TLR7) Is Expressed in Adipocytes and the Pharmacological TLR7 Agonist Imiquimod and Adipocyte-Derived Cell-Free Nucleic Acids (cfDNA) Regulate Adipocyte Function

by Miriam Thomalla, Andreas Schmid, Julia Hehner, Sebastian Koehler, Elena Neumann, Ulf Müller-Ladner, Andreas Schäffler and Thomas Karrasch

Int. J. Mol. Sci. 2022, 23(15), 8475; https://doi.org/10.3390/ijms23158475 - 30 Jul 2022

Cited by 4 | Viewed by 1658

Abstract

Endosome-localized Toll-like receptors (TLRs) 3 and 9 are expressed and functionally active in adipocytes. The functionality and role of TLR7 in adipocyte biology and innate immunity of adipose tissue (AT) is poorly characterized. We analyzed TLR7 mRNA and protein expression in murine 3T3-L1 and primary adipocytes, in co-cultures of 3T3-L1 adipocytes with murine J774A.1 monocytes and in human AT. The effects of TLR7 agonists imiquimod (IMQ) and cell-free nucleic acids (cfDNA) on adipokine concentration in cell-culture supernatants and gene expression profile were investigated. We found that TLR7 expression is strongly induced during adipocyte differentiation. TLR7 gene expression in adipocytes and AT stroma-vascular cells (SVC) seems to be independent of TLR9. IMQ downregulates resistin concentration in adipocyte cell-culture supernatants and modulates gene expression of glucose transporter Glut4. Adipocyte-derived cfDNA reduces adiponectin and resistin in cell-culture supernatants and potentially inhibits Glut4 gene expression. The responsiveness of 3T3-L1 adipocytes to imiquimod is preserved in co-culture with J774A.1 monocytes. Obesity-related, adipocyte-derived cfDNA engages adipocytic pattern recognition receptors (PRRs), modulating AT immune and metabolic homeostasis during adipose inflammation. Full article

(This article belongs to the Special Issue New Insights into Adipose Tissue Metabolic Function and Dysfunction)

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10 pages, 2541 KiB

Open AccessArticle

Taste 2 Receptor Is Involved in Differentiation of 3T3-L1 Preadipocytes

by Shunsuke Kimura, Ai Tsuruma and Eisuke Kato

Int. J. Mol. Sci. 2022, 23(15), 8120; https://doi.org/10.3390/ijms23158120 - 23 Jul 2022

Cited by 3 | Viewed by 1936

Abstract

Expression of taste 2 receptor (T2R) genes, also known as bitter taste receptor genes, has been reported in a variety of tissues. The white adipose tissue of mice has been shown to express Tas2r108, Tas2r126, Tas2r135, Tas2r137, and Tas2r143, but the function of T2Rs in adipocytes remains unclear. Here, we show that fasting and stimulation by bitter compounds both increased Tas2r expression in mouse white adipose tissue, and serum starvation and stimulation by bitter compounds both increased the expression of Tas2r genes in 3T3-L1 adipocytes, suggesting that T2Rs have functional roles in adipocytes. RNA sequencing analysis of 3T3-L1 adipocytes stimulated by epicatechin, the ligand of Tas2r126, suggested that this receptor may play a role in the differentiation of adipocytes. Overexpression of Tas2r126 in 3T3-L1 preadipocytes decreases fat accumulation after induction of differentiation and reduces the expression of adipogenic genes. Together, these results indicate that Tas2r126 may be involved in adipocyte differentiation. Full article

(This article belongs to the Special Issue New Insights into Adipose Tissue Metabolic Function and Dysfunction)

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15 pages, 3779 KiB

Open AccessArticle

An Iron Refractory Phenotype in Obese Adipose Tissue Macrophages Leads to Adipocyte Iron Overload

by Magdalene K. Ameka, William N. Beavers, Ciara M. Shaver, Lorraine B. Ware, Vern Eric Kerchberger, Kelly Q. Schoenfelt, Lili Sun, Tatsuki Koyama, Eric P. Skaar, Lev Becker and Alyssa H. Hasty

Int. J. Mol. Sci. 2022, 23(13), 7417; https://doi.org/10.3390/ijms23137417 - 03 Jul 2022

Cited by 8 | Viewed by 2830

Abstract

Adipocyte iron overload is a maladaptation associated with obesity and insulin resistance. The objective of the current study was to determine whether and how adipose tissue macrophages (ATMs) regulate adipocyte iron concentrations and whether this is impacted by obesity. Using bone marrow-derived macrophages (BMDMs) polarized to M0, M1, M2, or metabolically activated (MMe) phenotypes, we showed that MMe BMDMs and ATMs from obese mice have reduced expression of several iron-related proteins. Furthermore, the bioenergetic response to iron in obese ATMs was hampered. ATMs from iron-injected lean mice increased their glycolytic and respiratory capacities, thus maintaining metabolic flexibility, while ATMs from obese mice did not. Using an isotope-based system, we found that iron exchange between BMDMs and adipocytes was regulated by macrophage phenotype. At the end of the co-culture, MMe macrophages transferred and received more iron from adipocytes than M0, M1, and M2 macrophages. This culminated in a decrease in total iron in MMe macrophages and an increase in total iron in adipocytes compared with M2 macrophages. Taken together, in the MMe condition, the redistribution of iron is biased toward macrophage iron deficiency and simultaneous adipocyte iron overload. These data suggest that obesity changes the communication of iron between adipocytes and macrophages and that rectifying this iron communication channel may be a novel therapeutic target to alleviate insulin resistance. Full article

(This article belongs to the Special Issue New Insights into Adipose Tissue Metabolic Function and Dysfunction)

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Review

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21 pages, 773 KiB

Open AccessReview

Sex Differences in Adiposity and Cardiovascular Diseases

by Haoyun Li, Daniels Konja, Luyao Wang and Yu Wang

Int. J. Mol. Sci. 2022, 23(16), 9338; https://doi.org/10.3390/ijms23169338 - 19 Aug 2022

Cited by 13 | Viewed by 3246

Abstract

Body fat distribution is a well-established predictor of adverse medical outcomes, independent of overall adiposity. Studying body fat distribution sheds insights into the causes of obesity and provides valuable information about the development of various comorbidities. Compared to total adiposity, body fat distribution is more closely associated with risks of cardiovascular diseases. The present review specifically focuses on the sexual dimorphism in body fat distribution, the biological clues, as well as the genetic traits that are distinct from overall obesity. Understanding the sex determinations on body fat distribution and adiposity will aid in the improvement of the prevention and treatment of cardiovascular diseases (CVD). Full article

(This article belongs to the Special Issue New Insights into Adipose Tissue Metabolic Function and Dysfunction)

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23 pages, 1053 KiB

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Sexual Dimorphism in Brown Adipose Tissue Activation and White Adipose Tissue Browning

by Iker Gómez-García, Jenifer Trepiana, Alfredo Fernández-Quintela, Marta Giralt and María P. Portillo

Int. J. Mol. Sci. 2022, 23(15), 8250; https://doi.org/10.3390/ijms23158250 - 26 Jul 2022

Cited by 9 | Viewed by 2589

Abstract

The present narrative review gathers the studies reported so far, addressing sex differences in the effects of cold exposure, feeding pattern and age on brown adipose tissue (BAT) thermogenesis and white adipose tissue (WAT) browning. In rodents, when exposed to decreasing temperatures, females activate thermogenesis earlier. Results obtained in humans go in the same line, although they do not provide results as solid as those obtained in rodents. Regarding the effects of overfeeding, interesting sex differences on BAT thermogenic capacity have been reported, and the greater or lower sensitivity of each sex to this dietary situation seems to be dependent on the type of feeding. In the case of energy restriction, females are more sensitive than males. In addition, sex differences have also been observed in thermogenesis changes induced by phenolic compound administration. During sexual development, an increase in BAT mass and BAT activity takes place. This phenomenon is greater in boys than in girls, probably due to its relation to muscle-mass growth. The opposite situation takes place during ageing, a lifespan period where thermogenic capacity declines, this being more acute in men than in women. Finally, the vast majority of the studies have reported a higher susceptibility to developing WAT browning amongst females. The scarcity of results highlights the need for further studies devoted to analysing this issue, in order to provide valuable information for a more personalised approach. Full article

(This article belongs to the Special Issue New Insights into Adipose Tissue Metabolic Function and Dysfunction)

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22 pages, 1156 KiB

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Diabesity in Elderly Cardiovascular Disease Patients: Mechanisms and Regulators

by David García-Vega, José Ramón González-Juanatey and Sonia Eiras

Int. J. Mol. Sci. 2022, 23(14), 7886; https://doi.org/10.3390/ijms23147886 - 17 Jul 2022

Cited by 6 | Viewed by 3780

Abstract

Cardiovascular disease (CVD) is the leading cause of death in the world. In 2019, 550 million people were suffering from CVD and 18 million of them died as a result. Most of them had associated risk factors such as high fasting glucose, which caused 134 million deaths, and obesity, which accounted for 5.02 million deaths. Diabesity, a combination of type 2 diabetes and obesity, contributes to cardiac, metabolic, inflammation and neurohumoral changes that determine cardiac dysfunction (diabesity-related cardiomyopathy). Epicardial adipose tissue (EAT) is distributed around the myocardium, promoting myocardial inflammation and fibrosis, and is associated with an increased risk of heart failure, particularly with preserved systolic function, atrial fibrillation and coronary atherosclerosis. In fact, several hypoglycaemic drugs have demonstrated a volume reduction of EAT and effects on its metabolic and inflammation profile. However, it is necessary to improve knowledge of the diabesity pathophysiologic mechanisms involved in the development and progression of cardiovascular diseases for comprehensive patient management including drugs to optimize glucometabolic control. This review presents the mechanisms of diabesity associated with cardiovascular disease and their therapeutic implications. Full article

(This article belongs to the Special Issue New Insights into Adipose Tissue Metabolic Function and Dysfunction)

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