Research

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15 pages, 3242 KiB

Open AccessArticle

PPARγ Acetylation in Adipocytes Exacerbates BAT Whitening and Worsens Age-Associated Metabolic Dysfunction

by Ying He, Ruotong Zhang, Lexiang Yu, Tarik Zahr, Xueming Li, Tae-Wan Kim and Li Qiang

Cells 2023, 12(10), 1424; https://doi.org/10.3390/cells12101424 - 18 May 2023

Cited by 3 | Viewed by 1903

Aging and obesity are the two prominent driving forces of metabolic dysfunction, yet the common underlying mechanisms remain elusive. PPARγ, a central metabolic regulator and primary drug target combatting insulin resistance, is hyperacetylated in both aging and obesity. By employing a unique adipocyte-specific [...] Read more.

Aging and obesity are the two prominent driving forces of metabolic dysfunction, yet the common underlying mechanisms remain elusive. PPARγ, a central metabolic regulator and primary drug target combatting insulin resistance, is hyperacetylated in both aging and obesity. By employing a unique adipocyte-specific PPARγ acetylation-mimetic mutant knock-in mouse model, namely aKQ, we demonstrate that these mice develop worsened obesity, insulin resistance, dyslipidemia, and glucose intolerance as they age, and these metabolic deregulations are resistant to intervention by intermittent fasting. Interestingly, aKQ mice show a whitening phenotype of brown adipose tissue (BAT) manifested in lipid filling and suppressed BAT markers. Diet-induced obese aKQ mice retain an expected response to thiazolidinedione (TZD) treatment, while BAT function remains impaired. This BAT whitening phenotype persists even with the activation of SirT1 through resveratrol treatment. Moreover, the adverse effect of TZDs on bone loss is exacerbated in aKQ mice and is potentially mediated by their increased Adipsin levels. Our results collectively suggest pathogenic implications of adipocyte PPARγ acetylation, contributing to metabolic dysfunction in aging and thus posing as a potential therapeutic target. Full article

(This article belongs to the Special Issue Advances in Adipose Tissue Biology: From Biological Characteristics to Therapeutic Targets)

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19 pages, 2607 KiB

Open AccessArticle

Adipose Tissue Caveolin-1 Upregulation in Obesity Involves TNF-α/NF-κB Mediated Signaling

by Ashraf Al Madhoun, Shihab Kochumon, Dania Haddad, Reeby Thomas, Rasheeba Nizam, Lavina Miranda, Sardar Sindhu, Milad S. Bitar, Rasheed Ahmad and Fahd Al-Mulla

Cells 2023, 12(7), 1019; https://doi.org/10.3390/cells12071019 - 27 Mar 2023

Cited by 3 | Viewed by 1870

Abstract

Obesity is characterized by chronic low-grade inflammation. Obese people have higher levels of caveolin-1 (CAV1), a structural and functional protein present in adipose tissues (ATs). We aimed to define the inflammatory mediators that influence CAV1 gene regulation and the associated mechanisms in obesity. [...] Read more.

Obesity is characterized by chronic low-grade inflammation. Obese people have higher levels of caveolin-1 (CAV1), a structural and functional protein present in adipose tissues (ATs). We aimed to define the inflammatory mediators that influence CAV1 gene regulation and the associated mechanisms in obesity. Using subcutaneous AT from 27 (7 lean and 20 obese) normoglycemic individuals, in vitro human adipocyte models, and in vivo mice models, we found elevated CAV1 expression in obese AT and a positive correlation between the gene expression of CAV1, tumor necrosis factor-alpha (TNF-α), and the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). CAV1 gene expression was associated with proinflammatory cytokines and chemokines and their cognate receptors (r ≥ 0.447, p ≤ 0.030), but not with anti-inflammatory markers. CAV1 expression was correlated with CD163, indicating a prospective role for CAV1 in the adipose inflammatory microenvironment. Unlike wild-type animals, mice lacking TNF-α exhibited reduced levels of CAV1 mRNA/proteins, which were elevated by administering exogenous TNF-α. Mechanistically, TNF-α induces CAV1 gene transcription by mediating NF-κB binding to its two regulatory elements located in the CAV1 proximal regulatory region. The interplay between CAV1 and the TNF-α signaling pathway is intriguing and has potential as a target for therapeutic interventions in obesity and metabolic syndromes. Full article

(This article belongs to the Special Issue Advances in Adipose Tissue Biology: From Biological Characteristics to Therapeutic Targets)

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15 pages, 2324 KiB

Open AccessArticle

Sex-Dependent Role of Adipose Tissue HDAC9 in Diet-Induced Obesity and Metabolic Dysfunction

by Brandee Goo, Samah Ahmadieh, Abdalrahman Zarzour, Nicole K. H. Yiew, David Kim, Hong Shi, Jacob Greenway, Stephen Cave, Jenny Nguyen, Swetha Aribindi, Mark Wendolowski, Praneet Veerapaneni, Mourad Ogbi, Weiqin Chen, Yun Lei, Xin-Yun Lu, Ha Won Kim and Neal L. Weintraub

Cells 2022, 11(17), 2698; https://doi.org/10.3390/cells11172698 - 30 Aug 2022

Cited by 5 | Viewed by 2135

Abstract

Obesity is a major risk factor for both metabolic and cardiovascular disease. We reported that, in obese male mice, histone deacetylase 9 (HDAC9) is upregulated in adipose tissues, and global deletion of HDAC9 protected against high fat diet (HFD)-induced obesity and metabolic disease. [...] Read more.

Obesity is a major risk factor for both metabolic and cardiovascular disease. We reported that, in obese male mice, histone deacetylase 9 (HDAC9) is upregulated in adipose tissues, and global deletion of HDAC9 protected against high fat diet (HFD)-induced obesity and metabolic disease. Here, we investigated the impact of adipocyte-specific HDAC9 gene deletion on diet-induced obesity in male and female mice. The HDAC9 gene expression was increased in adipose tissues of obese male and female mice and HDAC9 expression correlated positively with body mass index in humans. Interestingly, female, but not male, adipocyte-specific HDAC9 KO mice on HFD exhibited reduced body weight and visceral adipose tissue mass, adipocyte hypertrophy, and improved insulin sensitivity, glucose tolerance and adipogenic differentiation gene expression. Furthermore, adipocyte-specific HDAC9 gene deletion in female mice improved metabolic health as assessed by whole body energy expenditure, oxygen consumption, and adaptive thermogenesis. Mechanistically, compared to female mice, HFD-fed male mice exhibited preferential HDAC9 expression in the stromovascular fraction, which may have offset the impact of adipocyte-specific HDAC9 gene deletion in male mice. These results suggest that HDAC9 expressed in adipocytes is detrimental to obesity in female mice and provides novel evidence of sex-related differences in HDAC9 cellular expression and contribution to obesity-related metabolic disease. Full article

(This article belongs to the Special Issue Advances in Adipose Tissue Biology: From Biological Characteristics to Therapeutic Targets)

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16 pages, 6225 KiB

Open AccessArticle

COX-2 Deficiency Promotes White Adipogenesis via PGE2-Mediated Paracrine Mechanism and Exacerbates Diet-Induced Obesity

by Chunqing Wang, Xing Zhang, Liping Luo, Yan Luo, Dandan Wu, Dianna Spilca, Que Le, Xin Yang, Katelyn Alvarez, William Curtis Hines, Xuexian O. Yang and Meilian Liu

Cells 2022, 11(11), 1819; https://doi.org/10.3390/cells11111819 - 02 Jun 2022

Cited by 7 | Viewed by 2897

Abstract

Cyclooxygenase-2 (COX-2) plays a critical role in regulating innate immunity and metabolism by producing prostaglandins (PGs) and other lipid mediators. However, the implication of adipose COX-2 in obesity remains largely unknown. Using adipocyte-specific COX-2 knockout (KO) mice, we showed that depleting COX-2 in [...] Read more.

Cyclooxygenase-2 (COX-2) plays a critical role in regulating innate immunity and metabolism by producing prostaglandins (PGs) and other lipid mediators. However, the implication of adipose COX-2 in obesity remains largely unknown. Using adipocyte-specific COX-2 knockout (KO) mice, we showed that depleting COX-2 in adipocytes promoted white adipose tissue development accompanied with increased size and number of adipocytes and predisposed diet-induced adiposity, obesity, and insulin resistance. The increased size and number of adipocytes by COX-2 KO were reversed by the treatment of prostaglandin E2 (PGE2) but not PGI2 and PGD2 during adipocyte differentiation. PGE2 suppresses PPARγ expression through the PKA pathway at the early phase of adipogenesis, and treatment of PGE2 or PKA activator isoproterenol diminished the increased lipid droplets in size and number in COX-2 KO primary adipocytes. Administration of PGE2 attenuated increased fat mass and fat percentage in COX-2 deficient mice. Taken together, our study demonstrated the suppressing effect of adipocyte COX-2 on adipogenesis and reveals that COX-2 restrains adipose tissue expansion via the PGE2-mediated paracrine mechanism and prevents the development of obesity and related metabolic disorders. Full article

(This article belongs to the Special Issue Advances in Adipose Tissue Biology: From Biological Characteristics to Therapeutic Targets)

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13 pages, 3164 KiB

Open AccessArticle

Lipocalin 2 Deficiency Alters Prostaglandin Biosynthesis and mTOR Signaling Regulation of Thermogenesis and Lipid Metabolism in Adipocytes

by Jessica Deis, Te-Yueh Lin, Theresa Bushman and Xiaoli Chen

Cells 2022, 11(9), 1535; https://doi.org/10.3390/cells11091535 - 03 May 2022

Cited by 5 | Viewed by 1991

Abstract

Apart from a well-known role in the innate immune system, lipocalin 2 (Lcn2) has been recently characterized as a critical regulator of thermogenesis and lipid metabolism. However, the physiological mechanism through which Lcn2 regulates cellular metabolism and thermogenesis in adipocytes remains unknown. We [...] Read more.

Apart from a well-known role in the innate immune system, lipocalin 2 (Lcn2) has been recently characterized as a critical regulator of thermogenesis and lipid metabolism. However, the physiological mechanism through which Lcn2 regulates cellular metabolism and thermogenesis in adipocytes remains unknown. We found that Lcn2 expression and secretion are significantly upregulated by arachidonic acid (AA) and mTORC1 inhibition in differentiated inguinal adipocytes. AA-induced Lcn2 expression and secretion correlate with the inflammatory NFkB activation. Lcn2 deficiency leads to the upregulation of cyclooxygenase-2 (COX2) expression, as well as increased biosynthesis and secretion of prostaglandins (PGs), particularly PGE2 and PGD2, induced by AA in adipocytes. Furthermore, Lcn2 deficiency affects the mTOR signaling regulation of thermogenic gene expression, lipogenesis, and lipolysis. The loss of Lcn2 dismisses the effect of mTORC1 inhibition by rapamycin on COX2, thermogenesis genes, lipogenesis, and lipolysis, but has no impact on p70 S6Kinase-ULK1 activation in Lcn2-deficient adipocytes. We conclude that Lcn2 converges the COX2-PGE2 and mTOR signaling pathways in the regulation of thermogenesis and lipid metabolism in adipocytes. Full article

(This article belongs to the Special Issue Advances in Adipose Tissue Biology: From Biological Characteristics to Therapeutic Targets)

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Review

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28 pages, 2079 KiB

Open AccessReview

Perivascular Adipose Tissue and Vascular Smooth Muscle Tone: Friends or Foes?

by Amer Ahmed, Aasia Bibi, Massimo Valoti and Fabio Fusi

Cells 2023, 12(8), 1196; https://doi.org/10.3390/cells12081196 - 20 Apr 2023

Cited by 9 | Viewed by 2296

Abstract

Perivascular adipose tissue (PVAT) is a specialized type of adipose tissue that surrounds most mammalian blood vessels. PVAT is a metabolically active, endocrine organ capable of regulating blood vessel tone, endothelium function, vascular smooth muscle cell growth and proliferation, and contributing critically to [...] Read more.

Perivascular adipose tissue (PVAT) is a specialized type of adipose tissue that surrounds most mammalian blood vessels. PVAT is a metabolically active, endocrine organ capable of regulating blood vessel tone, endothelium function, vascular smooth muscle cell growth and proliferation, and contributing critically to cardiovascular disease onset and progression. In the context of vascular tone regulation, under physiological conditions, PVAT exerts a potent anticontractile effect by releasing a plethora of vasoactive substances, including NO, H₂S, H₂O₂, prostacyclin, palmitic acid methyl ester, angiotensin 1-7, adiponectin, leptin, and omentin. However, under certain pathophysiological conditions, PVAT exerts pro-contractile effects by decreasing the production of anticontractile and increasing that of pro-contractile factors, including superoxide anion, angiotensin II, catecholamines, prostaglandins, chemerin, resistin, and visfatin. The present review discusses the regulatory effect of PVAT on vascular tone and the factors involved. In this scenario, dissecting the precise role of PVAT is a prerequisite to the development of PVAT-targeted therapies. Full article

(This article belongs to the Special Issue Advances in Adipose Tissue Biology: From Biological Characteristics to Therapeutic Targets)

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18 pages, 1481 KiB

Open AccessReview

The Influence of Ambient Temperature on Adipose Tissue Homeostasis, Metabolic Diseases and Cancers

by Rehna Paula Ginting, Ji-Min Lee and Min-Woo Lee

Cells 2023, 12(6), 881; https://doi.org/10.3390/cells12060881 - 12 Mar 2023

Cited by 3 | Viewed by 2218

Abstract

Adipose tissue is a recognized energy storage organ during excessive energy intake and an endocrine and thermoregulator, which interacts with other tissues to regulate systemic metabolism. Adipose tissue dysfunction is observed in most obese mouse models and humans. However, most studies using mouse [...] Read more.

Adipose tissue is a recognized energy storage organ during excessive energy intake and an endocrine and thermoregulator, which interacts with other tissues to regulate systemic metabolism. Adipose tissue dysfunction is observed in most obese mouse models and humans. However, most studies using mouse models were conducted at room temperature (RT), where mice were chronically exposed to mild cold. In this condition, energy use is prioritized for thermogenesis to maintain body temperature in mice. It also leads to the activation of the sympathetic nervous system, followed by the activation of β-adrenergic signaling. As humans live primarily in their thermoneutral (TN) zone, RT housing for mice limits the interpretation of disease studies from mouse models to humans. Therefore, housing mice in their TN zone (~28–30 °C) can be considered to mimic humans physiologically. However, factors such as temperature ranges and TN pre-acclimatization periods should be examined to obtain reliable results. In this review, we discuss how adipose tissue responds to housing temperature and the outcomes of the TN zone in metabolic disease studies. This review highlights the critical role of TN housing in mouse models for studying adipose tissue function and human metabolic diseases. Full article

(This article belongs to the Special Issue Advances in Adipose Tissue Biology: From Biological Characteristics to Therapeutic Targets)

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21 pages, 1714 KiB

Open AccessReview

Adipose Tissue Paracrine-, Autocrine-, and Matrix-Dependent Signaling during the Development and Progression of Obesity

by Elizabeth K. Johnston and Rosalyn D. Abbott

Cells 2023, 12(3), 407; https://doi.org/10.3390/cells12030407 - 25 Jan 2023

Cited by 14 | Viewed by 2932

Abstract

Obesity is an ever-increasing phenomenon, with 42% of Americans being considered obese (BMI ≥ 30) and 9.2% being considered morbidly obese (BMI ≥ 40) as of 2016. With obesity being characterized by an abundance of adipose tissue expansion, abnormal tissue remodeling is a [...] Read more.

Obesity is an ever-increasing phenomenon, with 42% of Americans being considered obese (BMI ≥ 30) and 9.2% being considered morbidly obese (BMI ≥ 40) as of 2016. With obesity being characterized by an abundance of adipose tissue expansion, abnormal tissue remodeling is a typical consequence. Importantly, this pathological tissue expansion is associated with many alterations in the cellular populations and phenotypes within the tissue, lending to cellular, paracrine, mechanical, and metabolic alterations that have local and systemic effects, including diabetes and cardiovascular disease. In particular, vascular dynamics shift during the progression of obesity, providing signaling cues that drive metabolic dysfunction. In this review, paracrine-, autocrine-, and matrix-dependent signaling between adipocytes and endothelial cells is discussed in the context of the development and progression of obesity and its consequential diseases, including adipose fibrosis, diabetes, and cardiovascular disease. Full article

(This article belongs to the Special Issue Advances in Adipose Tissue Biology: From Biological Characteristics to Therapeutic Targets)

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28 pages, 1202 KiB

Open AccessReview

Hypoxia as a Double-Edged Sword to Combat Obesity and Comorbidities

by Ruwen Wang, Qin Sun, Xianmin Wu, Yiyin Zhang, Xiaorui Xing, Kaiqing Lin, Yue Feng, Mingqi Wang, Yibing Wang and Ru Wang

Cells 2022, 11(23), 3735; https://doi.org/10.3390/cells11233735 - 23 Nov 2022

Cited by 9 | Viewed by 2963

Abstract

The global epidemic of obesity is tightly associated with numerous comorbidities, such as type II diabetes, cardiovascular diseases and the metabolic syndrome. Among the key features of obesity, some studies have suggested the abnormal expansion of adipose-tissue-induced local endogenous hypoxic, while other studies [...] Read more.

The global epidemic of obesity is tightly associated with numerous comorbidities, such as type II diabetes, cardiovascular diseases and the metabolic syndrome. Among the key features of obesity, some studies have suggested the abnormal expansion of adipose-tissue-induced local endogenous hypoxic, while other studies indicated endogenous hyperoxia as the opposite trend. Endogenous hypoxic aggravates dysfunction in adipose tissue and stimulates secretion of inflammatory molecules, which contribute to obesity. In contrast, hypoxic exposure combined with training effectively generate exogenous hypoxic to reduce body weight and downregulate metabolic risks. The (patho)physiological effects in adipose tissue are distinct from those of endogenous hypoxic. We critically assess the latest advances on the molecular mediators of endogenous hypoxic that regulate the dysfunction in adipose tissue. Subsequently we propose potential therapeutic targets in adipose tissues and the small molecules that may reverse the detrimental effect of local endogenous hypoxic. More importantly, we discuss alterations of metabolic pathways in adipose tissue and the metabolic benefits brought by hypoxic exercise. In terms of therapeutic intervention, numerous approaches have been developed to treat obesity, nevertheless durability and safety remain the major concern. Thus, a combination of the therapies that suppress endogenous hypoxic with exercise plans that augment exogenous hypoxic may accelerate the development of more effective and durable medications to treat obesity and comorbidities. Full article

(This article belongs to the Special Issue Advances in Adipose Tissue Biology: From Biological Characteristics to Therapeutic Targets)

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