TFEB drives PGC-1α expression in adipocytes to protect against diet-induced metabolic dysfunction

TFEB is a basic helix-loop-helix transcription factor that confers protection against metabolic diseases such as atherosclerosis by targeting a network of genes involved in autophagy-lysosomal biogenesis and lipid catabolism. In this study, we sought to characterize the role of TFEB in adipocyte and adipose tissue physiology and evaluate the therapeutic potential of adipocyte-specific TFEB overexpression in obesity. We demonstrated that mice with adipocyte-specific TFEB overexpression (Adipo-TFEB) were protected from diet-induced obesity, insulin resistance, and metabolic sequelae. Adipo-TFEB mice were lean primarily through increased metabolic rate, suggesting a role for adipose tissue browning and enhanced nonshivering thermogenesis in fat. Transcriptional characterization revealed that TFEB targeted genes involved in adipose tissue browning rather than those involved in autophagy. One such gene encoded PGC-1α, an established target of TFEB that promotes adipocyte browning. To dissect the role of PGC-1α in mediating the downstream effects of TFEB overexpression, we generated mice with adipocyte-specific PGC-1α deficiency and TFEB overexpression. Without PGC-1α, the ability of TFEB overexpression to brown adipose tissue and to elicit beneficial metabolic effects was blunted. Overall, these data implicate TFEB as a PGC-1α–dependent regulator of adipocyte browning and suggest its therapeutic potential in treating metabolic disease.

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DsbA-L deficiency in T cells promotes diet-induced thermogenesis through suppressing IFN-γ production

Nature Communications ◽

10.1038/s41467-020-20665-4 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Haiyan Zhou ◽

Xinyi Peng ◽

Jie Hu ◽

Liwen Wang ◽

Hairong Luo ◽

...

Keyword(s):

T Cells ◽

Adipose Tissue ◽

T Cell ◽

Energy Homeostasis ◽

Metabolic Diseases ◽

Therapeutic Potential ◽

Whole Body ◽

Brown Adipose ◽

Ifn Γ ◽

Diet Induced Thermogenesis

AbstractAdipose tissue-resident T cells have been recognized as a critical regulator of thermogenesis and energy expenditure, yet the underlying mechanisms remain unclear. Here, we show that high-fat diet (HFD) feeding greatly suppresses the expression of disulfide-bond A oxidoreductase-like protein (DsbA-L), a mitochondria-localized chaperone protein, in adipose-resident T cells, which correlates with reduced T cell mitochondrial function. T cell-specific knockout of DsbA-L enhances diet-induced thermogenesis in brown adipose tissue (BAT) and protects mice from HFD-induced obesity, hepatosteatosis, and insulin resistance. Mechanistically, DsbA-L deficiency in T cells reduces IFN-γ production and activates protein kinase A by reducing phosphodiesterase-4D expression, leading to increased BAT thermogenesis. Taken together, our study uncovers a mechanism by which T cells communicate with brown adipocytes to regulate BAT thermogenesis and whole-body energy homeostasis. Our findings highlight a therapeutic potential of targeting T cells for the treatment of over nutrition-induced obesity and its associated metabolic diseases.

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Effects of ERβ and ERα on OVX-induced changes in adiposity and insulin resistance

Journal of Endocrinology ◽

10.1530/joe-19-0321 ◽

2020 ◽

Vol 245 (1) ◽

pp. 165-178 ◽

Cited By ~ 2

Author(s):

Terese M Zidon ◽

Jaume Padilla ◽

Kevin L Fritsche ◽

Rebecca J Welly ◽

Leighton T McCabe ◽

...

Keyword(s):

Insulin Resistance ◽

Estrogen Receptor ◽

Adipose Tissue ◽

Energy Expenditure ◽

Estrogen Receptor Alpha ◽

Metabolic Diseases ◽

Metabolic Effects ◽

Metabolic Dysfunction ◽

Gene And Protein Expression ◽

Induced Changes

Loss of ovarian hormones leads to increased adiposity and insulin resistance (IR), increasing the risk for cardiovascular and metabolic diseases. The purpose of this study was to investigate whether the molecular mechanism behind the adverse systemic and adipose tissue-specific metabolic effects of ovariectomy requires loss of signaling through estrogen receptor alpha (ERα) or estrogen receptor β (ERβ). We examined ovariectomized (OVX) and ovary-intactwild-type (WT), ERα-null (αKO), and ERβ-null (βKO) female mice (age ~49 weeks; n = 7–12/group). All mice were fed a phytoestrogen-free diet (<15 mg/kg) and either remained ovary-intact (INT) or were OVX and followed for 12 weeks. Body composition, energy expenditure, glucose tolerance, and adipose tissue gene and protein expression were analyzed. INT αKO were ~25% fatter with reduced energy expenditure compared to age-matched INT WT controls and βKO mice (all P < 0.001). Following OVX, αKO mice did not increase adiposity or experience a further increase in IR, unlike WT and βKO, suggesting that loss of signaling through ERα mediates OVX-induced metabolic dysfunction. In fact, OVX in αKO mice (i.e., signaling through ERβ in the absence of ERα) resulted in reduced adiposity, adipocyte size, and IR (P < 0.05 for all). βKO mice responded adversely to OVX in terms of increased adiposity and development of IR. Together, these findings challenge the paradigm that ERα mediates metabolic protection over ERβ in all settings. These findings lead us to suggest that, following ovarian hormone loss, ERβ may mediate protective metabolic benefits.

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The Role of Adipose Tissue Mitochondria: Regulation of Mitochondrial Function for the Treatment of Metabolic Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms20194924 ◽

2019 ◽

Vol 20 (19) ◽

pp. 4924 ◽

Cited By ~ 27

Author(s):

Lee ◽

Park ◽

Oh ◽

Lee ◽

Kim ◽

...

Keyword(s):

Adipose Tissue ◽

Mitochondrial Function ◽

Energy Homeostasis ◽

Metabolic Diseases ◽

Oxidative Capacity ◽

Adipose Tissues ◽

Adaptive Thermogenesis ◽

Brown Adipose

: Mitochondria play a key role in maintaining energy homeostasis in metabolic tissues, including adipose tissues. The two main types of adipose tissues are the white adipose tissue (WAT) and the brown adipose tissue (BAT). WAT primarily stores excess energy, whereas BAT is predominantly responsible for energy expenditure by non-shivering thermogenesis through the mitochondria. WAT in response to appropriate stimuli such as cold exposure and β-adrenergic agonist undergoes browning wherein it acts as BAT, which is characterized by the presence of a higher number of mitochondria. Mitochondrial dysfunction in adipocytes has been reported to have strong correlation with metabolic diseases, including obesity and type 2 diabetes. Dysfunction of mitochondria results in detrimental effects on adipocyte differentiation, lipid metabolism, insulin sensitivity, oxidative capacity, and thermogenesis, which consequently lead to metabolic diseases. Recent studies have shown that mitochondrial function can be improved by using thiazolidinedione, mitochondria-targeted antioxidants, and dietary natural compounds; by performing exercise; and by controlling caloric restriction, thereby maintaining the metabolic homeostasis by inducing adaptive thermogenesis of BAT and browning of WAT. In this review, we focus on and summarize the molecular regulation involved in the improvement of mitochondrial function in adipose tissues so that strategies can be developed to treat metabolic diseases.

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Does Adipose Tissue Thermogenesis Play a Role in Metabolic Health?

Journal of Obesity ◽

10.1155/2013/204094 ◽

2013 ◽

Vol 2013 ◽

pp. 1-4

Author(s):

Craig Porter ◽

Elisabet Børsheim ◽

Labros S. Sidossis

Keyword(s):

Adipose Tissue ◽

Energy Metabolism ◽

Brown Adipose Tissue ◽

Metabolic Diseases ◽

Oxidative Capacity ◽

Whole Body ◽

Research Strategies ◽

Brown Adipocytes ◽

Brown Adipose

The function ascribed to brown adipose tissue in humans has long been confined to thermoregulation in neonates, where this thermogenic capacity was thought lost with maturation. Recently, brown adipose tissue depots have been identified in adult humans. The significant oxidative capacity of brown adipocytes and the ability of their mitochondria to respire independently of ATP production, has led to renewed interest in the role that these adipocytes play in human energy metabolism. In our view, there is a need for robust physiological studies determining the relationship between molecular signatures of brown adipose tissue, adipose tissue mitochondrial function, and whole body energy metabolism, in order to elucidate the significance of thermogenic adipose tissue in humans. Until such information is available, the role of thermogenic adipose tissue in human metabolism and the potential that these adipocytes may prevent or treat obesity and metabolic diseases in humans will remain unknown. In this article, we summarize the recent literature pertaining to brown adipose tissue function with the aims of drawing the readers’ attention to the lack of data concerning the role of brown adipocytes in human physiology, and to the potential limitations of current research strategies.

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Impact of pesticide exposure on adipose tissue development and function

Biochemical Journal ◽

10.1042/bcj20200324 ◽

2020 ◽

Vol 477 (14) ◽

pp. 2639-2653 ◽

Cited By ~ 1

Author(s):

Robert M. Gutgesell ◽

Evangelia E. Tsakiridis ◽

Shanza Jamshed ◽

Gregory R. Steinberg ◽

Alison C. Holloway

Keyword(s):

Adipose Tissue ◽

Metabolic Diseases ◽

Pesticide Exposure ◽

Health Care Expenditure ◽

Metabolic Dysfunction ◽

Obesity Epidemic ◽

Synthetic Chemicals ◽

Brown Adipose ◽

Adipose Tissue Development ◽

And Function

Obesity is a leading cause of morbidity, mortality and health care expenditure whose incidence is rapidly rising across the globe. Although the cause of the obesity epidemic is typically viewed as a product of an increased availability of high calorie foods and/or a reduction in physical activity, there is mounting evidence that exposure to synthetic chemicals in our environment may play an important role. Pesticides, are a class of chemicals whose widespread use has coincided with the global rise of obesity over the past two decades. Importantly, given their lipophilic nature many pesticides have been shown to accumulate with adipose tissue depots, suggesting they may be disrupting the function of white adipose tissue (WAT), brown adipose tissue (BAT) and beige adipose tissue to promote obesity and metabolic diseases such as type 2 diabetes. In this review, we discuss epidemiological evidence linking pesticide exposure with body mass index (BMI) and the incidence of diabetes. We then review preclinical studies in rodent models which have directly evaluated the effects of different classes of insecticides and herbicides on obesity and metabolic dysfunction. Lastly, we review studies conducted in adipose tissue cells lines and the purported mechanisms by which pesticides may induce alterations in adipose tissue function. The review of the literature reveals major gaps in our knowledge regarding human exposure to pesticides and our understanding of whether physiologically relevant concentrations promote obesity and elicit alterations in key signaling pathways vital for maintaining adipose tissue metabolism.

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Elucidating the Regulatory Role of Melatonin in Brown, White, and Beige Adipocytes

Advances in Nutrition ◽

10.1093/advances/nmz070 ◽

2019 ◽

Cited By ~ 1

Author(s):

Ziye Xu ◽

Wenjing You ◽

Jiaqi Liu ◽

Yizhen Wang ◽

Tizhong Shan

Keyword(s):

Adipose Tissue ◽

Energy Metabolism ◽

Metabolic Disorders ◽

Metabolic Diseases ◽

Body Weight Gain ◽

Tissue Mass ◽

Brown Adipocytes ◽

Brown Adipose ◽

Beige Adipocytes

AbstractThe high prevalence of obesity and its associated metabolic diseases has heightened the importance of understanding control of adipose tissue development and energy metabolism. In mammals, 3 types of adipocytes with different characteristics and origins have been identified: white, brown, and beige. Beige and brown adipocytes contain numerous mitochondria and have the capability to burn energy and counteract obesity, while white adipocytes store energy and are closely associated with metabolic disorders and obesity. Thus, regulation of the development and function of different adipocytes is important for controlling energy balance and combating obesity and related metabolic disorders. Melatonin is a neurohormone, which plays multiple roles in regulating inflammation, blood pressure, insulin actions, and energy metabolism. This article summarizes and discusses the role of melatonin in white, beige, and brown adipocytes, especially in affecting adipogenesis, inducing beige formation or white adipose tissue browning, enhancing brown adipose tissue mass and activities, improving anti-inflammatory and antioxidative effects, regulating adipokine secretion, and preventing body weight gain. Based on the current findings, melatonin is a potential therapeutic agent to control energy metabolism, adipogenesis, fat deposition, adiposity, and related metabolic diseases.

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Allicin regulates energy homeostasis through brown adipose tissue

10.1101/713305 ◽

2019 ◽

Author(s):

Chuanhai Zhang ◽

Xiaoyun He ◽

Yao Sheng ◽

Jia Xu ◽

Cui Yang ◽

...

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Energy Homeostasis ◽

Metabolic Diseases ◽

Whole Body ◽

Brown Adipocyte ◽

Brown Adipose ◽

Promising Therapeutic Approach ◽

Treatment Of Obesity

AbstractBackground/objectives:Disorder of energy homeostasis can lead to a variety of metabolic diseases, especially obesity. Brown adipose tissue (BAT) is a promising potential therapeutic target for the treatment of obesity and related metabolic diseases. Allicin, a main bioactive ingredient in garlic, has multiple biology and pharmacological function. However, the role of Allicin, in the regulation of metabolic organ, especially the role of activation of BAT, has not been well studied. Here, we analyzed the role of Allicin in whole-body metabolism and the activation of BAT.Results:Allicin had a significant effect in inhibiting body weight gain, decreasing adiposity, maintaining glucose homeostasis, improving insulin resistance, and ameliorating hepatic steatosis in diet-introduced obesity (DIO) mice. Then we find that Allicin can strongly activate brown adipose tissue (BAT). The activation of brown adipocyte treated with Allicin was also confirmed in mouse primary brown adipocytes.Conclusion:Allicin can ameliorate obesity through activating brown adipose tissue. Our findings provide a promising therapeutic approach for the treatment of obesity and metabolic disorders.

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Proteostasis in thermogenesis and obesity

Biological Chemistry ◽

10.1515/hsz-2019-0427 ◽

2020 ◽

Vol 401 (9) ◽

pp. 1019-1030

Author(s):

Alexander Bartelt ◽

Scott B. Widenmaier

Keyword(s):

Adipose Tissue ◽

Metabolic Diseases ◽

Modern Society ◽

Metabolic Dysfunction ◽

Unfolded Protein ◽

Metabolic Systems ◽

Brown Adipose ◽

Beige Adipocytes ◽

Working Together ◽

The Unfolded Protein Response

AbstractThe proper production, degradation, folding and activity of proteins, proteostasis, is essential for any cellular function. From single cell organisms to humans, selective pressures have led to the evolution of adaptive programs that ensure proteins are properly produced and disposed of when necessary. Environmental factors such as temperature, nutrient availability, pathogens as well as predators have greatly influenced the development of mechanisms such as the unfolded protein response, endoplasmic reticulum-associated protein degradation and autophagy, working together in concert to secure cellular proteostasis. In our modern society, the metabolic systems of the human body face the distinct challenge of changed diets, chronic overnutrition and sedentary lifestyles. Obesity and excess white adipose tissue accumulation are linked to a cluster of metabolic diseases and disturbed proteostasis is a common feature. Conversely, processes that promote energy expenditure such as exercise, shivering as well as non-shivering thermogenesis by brown adipose tissue (BAT) and beige adipocytes counteract metabolic dysfunction. Here we review the basic concepts of proteostasis in obesity-linked metabolic diseases and focus on adipocytes, which are critical regulators of mammalian energy metabolism.

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Adipocyte-Specific ACKR3 Regulates Lipid Levels in Adipose Tissue

Biomedicines ◽

10.3390/biomedicines9040394 ◽

2021 ◽

Vol 9 (4) ◽

pp. 394

Author(s):

Selin Gencer ◽

Yvonne Döring ◽

Yvonne Jansen ◽

Soyolmaa Bayasgalan ◽

Olga Schengel ◽

...

Keyword(s):

Adipose Tissue ◽

Metabolic Diseases ◽

Cholesterol Content ◽

Metabolic Effects ◽

Peroxisome Proliferator ◽

Lipid Levels ◽

Peroxisome Proliferator Activated Receptor ◽

Ppar Γ ◽

Deficient Mice

Dysfunctional adipose tissue (AT) may contribute to the pathology of several metabolic diseases through altered lipid metabolism, insulin resistance, and inflammation. Atypical chemokine receptor 3 (ACKR3) expression was shown to increase in AT during obesity, and its ubiquitous elimination caused hyperlipidemia in mice. Although these findings point towards a role of ACKR3 in the regulation of lipid levels, the role of adipocyte-specific ACKR3 has not yet been studied exclusively in this context. In this study, we established adipocyte- and hepatocyte-specific knockouts of Ackr3 in ApoE-deficient mice in order to determine its impact on lipid levels under hyperlipidemic conditions. We show for the first time that adipocyte-specific deletion of Ackr3 results in reduced AT triglyceride and cholesterol content in ApoE-deficient mice, which coincides with increased peroxisome proliferator-activated receptor-γ (PPAR-γ) and increased Angptl4 expression. The role of adipocyte ACKR3 in lipid handling seems to be tissue-specific as hepatocyte ACKR3 deficiency did not demonstrate comparable effects. In summary, adipocyte-specific ACKR3 seems to regulate AT lipid levels in hyperlipidemic Apoe−/− mice, which may therefore be a significant determinant of AT health. Further studies are needed to explore the potential systemic or metabolic effects that adipocyte ACKR3 might have in associated disease models.

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Potential of Nutraceutical Supplementation in the Modulation of White and Brown Fat Tissues in Obesity-Associated Disorders: Role of Inflammatory Signalling

International Journal of Molecular Sciences ◽

10.3390/ijms22073351 ◽

2021 ◽

Vol 22 (7) ◽

pp. 3351

Author(s):

Federica Scarano ◽

Micaela Gliozzi ◽

Maria Caterina Zito ◽

Lorenza Guarnieri ◽

Cristina Carresi ◽

...

Keyword(s):

Adipose Tissue ◽

Inflammatory Mediators ◽

Metabolic Diseases ◽

Potential Effect ◽

Alcoholic Fatty Liver ◽

Adipose Tissue Dysfunction ◽

Brown Adipose ◽

Inflammatory State ◽

Inflammatory Signalling

The high incidence of obesity is associated with an increasing risk of several chronic diseases such as cardiovascular disease, type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). Sustained obesity is characterized by a chronic and unsolved inflammation of adipose tissue, which leads to a greater expression of proinflammatory adipokines, excessive lipid storage and adipogenesis. The purpose of this review is to clarify how inflammatory mediators act during adipose tissue dysfunction in the development of insulin resistance and all obesity-associated diseases. In particular, we focused our attention on the role of inflammatory signaling in brown adipose tissue (BAT) thermogenic activity and the browning of white adipose tissue (WAT), which represent a relevant component of adipose alterations during obesity. Furthermore, we reported the most recent evidence in the literature on nutraceutical supplementation in the management of the adipose inflammatory state, and in particular on their potential effect on common inflammatory mediators and pathways, responsible for WAT and BAT dysfunction. Although further research is needed to demonstrate that targeting pro-inflammatory mediators improves adipose tissue dysfunction and activates thermogenesis in BAT and WAT browning during obesity, polyphenols supplementation could represent an innovative therapeutic strategy to prevent progression of obesity and obesity-related metabolic diseases.

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