Epigenetic Regulators of White Adipocyte Browning

Adipocytes play an essential role in maintaining energy homeostasis in mammals. The primary function of white adipose tissue (WAT) is to store energy; for brown adipose tissue (BAT), primary function is to release fats in the form of heat. Dysfunctional or excess WAT can induce metabolic disorders such as dyslipidemia, obesity, and diabetes. Preadipocytes or adipocytes from WAT possess sufficient plasticity as they can transdifferentiate into brown-like beige adipocytes. Studies in both humans and rodents showed that brown and beige adipocytes could improve metabolic health and protect from metabolic disorders. Brown fat requires activation via exposure to cold or β-adrenergic receptor (β-AR) agonists to protect from hypothermia. Considering the fact that the usage of β-AR agonists is still in question with their associated side effects, selective induction of WAT browning is therapeutically important instead of activating of BAT. Hence, a better understanding of the molecular mechanisms governing white adipocyte browning is vital. At the same time, it is also essential to understand the factors that define white adipocyte identity and inhibit white adipocyte browning. This literature review is a comprehensive and focused update on the epigenetic regulators crucial for differentiation and browning of white adipocytes.

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ACE2 Pathway Regulates Thermogenesis and Energy Metabolism

10.1101/2021.08.10.455823 ◽

2021 ◽

Author(s):

Xi Cao ◽

Tingting Shi ◽

Chuanhai Zhang ◽

Wanzhu Jin ◽

Lini Song ◽

...

Keyword(s):

Adipose Tissue ◽

Energy Expenditure ◽

Brown Adipose Tissue ◽

Knockout Mice ◽

Metabolic Disorders ◽

Energy Homeostasis ◽

Cold Stimulation ◽

Obesity And Diabetes ◽

Brown Adipose ◽

Pka Pathway

Identification of key regulators of energy homeostasis holds important therapeutic promise for metabolic disorders, such as obesity and diabetes. ACE2 cleaves angiotensin II (Ang II) to generate Ang-(1-7) which acts mainly through the Mas receptor. Here, we identify ACE2 pathway as a critical regulator in the maintenance of thermogenesis and energy expenditure. We found that ACE2 is highly expressed in brown adipose tissue (BAT) and that cold stimulation increases ACE2 and Ang-(1-7) levels in BAT and serum. ACE2 knockout mice (ACE2-/y), Mas knockout mice (Mas-/-), and the mice transplanted with brown adipose tissue from Mas-/- mice displayed impaired thermogenesis. In contrast, impaired thermogenesis of db/db obese diabetic mice and high-fat diet-induced obese mice were ameliorated by overexpression of ACE2 or continuous infusion of Ang-(1-7). Activation of ACE2 pathway was associated with improvement of metabolic parameters, including blood glucose, lipids and energy expenditure in multiple animal models. Consistently, ACE2 pathway remarkably enhanced the browning of white adipose tissue. Mechanistically, we showed that ACE2 pathway activated Akt/FoxO1 and PKA pathway, leading to induction of UCP1 and activation of mitochondrial function. Our data propose that adaptive thermogenesis requires regulation of ACE2 pathway and highlight novel therapeutic targets for the treatment of metabolic disorders.

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Novel Browning Agents, Mechanisms, and Therapeutic Potentials of Brown Adipose Tissue

BioMed Research International ◽

10.1155/2016/2365609 ◽

2016 ◽

Vol 2016 ◽

pp. 1-15 ◽

Cited By ~ 32

Author(s):

Umesh D. Wankhade ◽

Michael Shen ◽

Hariom Yadav ◽

Keshari M. Thakali

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Energy Homeostasis ◽

Therapeutic Potential ◽

Uncoupling Protein ◽

Brown Adipocytes ◽

Atp Production ◽

Obesity And Diabetes ◽

Brown Adipose ◽

Beige Adipocytes

Nonshivering thermogenesis is the process of biological heat production in mammals and is primarily mediated by brown adipose tissue (BAT). Through ubiquitous expression of uncoupling protein 1 (Ucp1) on the mitochondrial inner membrane, BAT displays uncoupling of fuel combustion and ATP production in order to dissipate energy as heat. Because of its crucial role in regulating energy homeostasis, ongoing exploration of BAT has emphasized its therapeutic potential in addressing the global epidemics of obesity and diabetes. The recent appreciation that adult humans possess functional BAT strengthens this prospect. Furthermore, it has been identified that there are both classical brown adipocytes residing in dedicated BAT depots and “beige” adipocytes residing in white adipose tissue depots that can acquire BAT-like characteristics in response to environmental cues. This review aims to provide a brief overview of BAT research and summarize recent findings concerning the physiological, cellular, and developmental characteristics of brown adipocytes. In addition, some key genetic, molecular, and pharmacologic targets of BAT/Beige cells that have been reported to have therapeutic potential to combat obesity will be discussed.

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ACE2 pathway regulates thermogenesis and energy metabolism

eLife ◽

10.7554/elife.72266 ◽

2022 ◽

Vol 11 ◽

Author(s):

Xi Cao ◽

Tingting Shi ◽

Chuanhai Zhang ◽

Wanzhu Jin ◽

Lini Song ◽

...

Keyword(s):

Adipose Tissue ◽

Energy Expenditure ◽

Brown Adipose Tissue ◽

Knockout Mice ◽

Metabolic Disorders ◽

Energy Homeostasis ◽

Cold Stimulation ◽

Obesity And Diabetes ◽

Brown Adipose ◽

Pka Pathway

Identification of key regulators of energy homeostasis holds important therapeutic promise for metabolic disorders, such as obesity and diabetes. ACE2 cleaves angiotensin II (Ang II) to generate Ang-(1-7) which acts mainly through the Mas1 receptor. Here, we identify ACE2 pathway as a critical regulator in the maintenance of thermogenesis and energy expenditure. We found that ACE2 is highly expressed in brown adipose tissue (BAT) and that cold stimulation increases ACE2 and Ang-(1-7) levels in BAT and serum. Ace2 knockout mice (Ace2-/y) and Mas1 knockout mice (Mas1-/-) displayed impaired thermogenesis. Mice transplanted with brown adipose tissue from Mas1-/- display metabolic abnormalities consistent with those seen in the Ace2 and Mas1 knockout mice. In contrast, impaired thermogenesis of Leprdb/db obese diabetic mice and high-fat diet-induced obese mice were ameliorated by overexpression of Ace2 or continuous infusion of Ang-(1-7). Activation of ACE2 pathway was associated with improvement of metabolic parameters, including blood glucose, lipids and energy expenditure in multiple animal models. Consistently, ACE2 pathway remarkably enhanced the browning of white adipose tissue. Mechanistically, we showed that ACE2 pathway activated Akt/FoxO1 and PKA pathway, leading to induction of UCP1 and activation of mitochondrial function. Our data propose that adaptive thermogenesis requires regulation of ACE2 pathway and highlight novel potential therapeutic targets for the treatment of metabolic disorders.

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Neuronal Modulation of Brown Adipose Activity Through Perturbation of White Adipocyte Lipogenesis

10.1101/324160 ◽

2018 ◽

Author(s):

Adilson Guilherme ◽

David J Pedersen ◽

Felipe Henriques ◽

Alexander H. Bedard ◽

Elizabeth Henchey ◽

...

Keyword(s):

Adipose Tissue ◽

White Adipose Tissue ◽

Fatty Acid Synthase ◽

Sympathetic Neurons ◽

Sympathetic Innervation ◽

Long Distance ◽

Brown Adipocytes ◽

White Adipocyte ◽

Brown Adipose ◽

Beige Adipocytes

ABSTRACTWhite adipose tissue (WAT) secretes factors to communicate with other metabolic organs to maintain energy homeostasis. We previously reported that perturbation of adipocyte de novo lipogenesis (DNL) by deletion of fatty acid synthase (FASN) causes expansion of sympathetic neurons within white adipose tissue (WAT) and the appearance of “beige” adipocytes. Here we report evidence that white adipocyte DNL activity is also coupled to neuronal regulation and thermogenesis in brown adipose tissue (BAT). Induced deletion of FASN in all adipocytes in mature mice (iAdFASNKO) enhanced sympathetic innervation and neuronal activity as well as UCP1 expression in both WAT and BAT. In contrast, selective ablation of FASN in brown adipocytes of mice (iUCP1FASNKO) failed to modulate sympathetic innervation and the thermogenic program in BAT. Surprisingly, DNL in brown adipocytes was also dispensable in maintaining euthermia when UCP1FASNKO mice were cold-exposed. These results indicate that DNL in white adipocytes influences long distance signaling to BAT, which can modify BAT sympathetic innervation and expression of genes involved in thermogenesis.

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Multifaceted Roles of Beige Fat in Energy Homeostasis Beyond UCP1

Endocrinology ◽

10.1210/en.2018-00371 ◽

2018 ◽

Vol 159 (7) ◽

pp. 2545-2553 ◽

Cited By ~ 9

Author(s):

Carlos Henrique Sponton ◽

Shingo Kajimura

Keyword(s):

Adipose Tissue ◽

Energy Homeostasis ◽

Uncoupling Protein ◽

Developmental Regulation ◽

Brown Adipocytes ◽

Adipose Tissue Depots ◽

Brown Adipose ◽

Beige Adipocytes ◽

Beige Fat ◽

Adipose Cells

Abstract Beige adipocytes are an inducible form of thermogenic adipose cells that emerge within the white adipose tissue in response to a variety of environmental stimuli, such as chronic cold acclimation. Similar to brown adipocytes that reside in brown adipose tissue depots, beige adipocytes are also thermogenic; however, beige adipocytes possess unique, distinguishing characteristics in their developmental regulation and biological function. This review highlights recent advances in our understanding of beige adipocytes, focusing on the diverse roles of beige fat in the regulation of energy homeostasis that are independent of the canonical thermogenic pathway via uncoupling protein 1.

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DSS-induced colitis is associated with adipose tissue dysfunction and disrupted hepatic lipid metabolism leading to hepatosteatosis and dyslipidemia in mice

Scientific Reports ◽

10.1038/s41598-021-84761-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jeonghyeon Kwon ◽

Chungho Lee ◽

Sungbaek Heo ◽

Bobae Kim ◽

Chang-Kee Hyun

Keyword(s):

Adipose Tissue ◽

Energy Homeostasis ◽

Molecular Mechanisms ◽

Activity Index ◽

Intestinal Barrier ◽

Intestinal Barrier Function ◽

Acid Oxidation ◽

Barrier Dysfunction ◽

Alcoholic Fatty Liver ◽

Brown Adipose

AbstractConsidering high prevalence of non-alcoholic fatty liver diseases (NAFLD) in patients with inflammatory bowel disease (IBD), this study aimed to elucidate molecular mechanisms for how intestinal inflammatory conditions are causally linked to hepatic steatosis and dyslipidemia. Both younger and older mice treated with acute or chronic dextran sodium sulfate (DSS) developed colitis, which was evidenced by weight loss, colon length shortening, and elevated disease activity index and inflammation score. They also showed decreased expression of intestinal barrier function-related proteins and elevated plasma lipopolysaccharide level, indicating DSS-induced barrier dysfunction and thereby increased permeability. Interestingly, they displayed phenotypes of hepatic fat accumulation and abnormal blood lipid profiles. This DSS-induced colitis-associated lipid metabolic dysfunction was due to overall disruption of metabolic processes including fatty acid oxidation, lipogenesis, lipolysis, reverse cholesterol transport, bile acid synthesis, and white adipose tissue browning and brown adipose tissue thermogenesis, most of which are mediated by key regulators of energy homeostasis such as FGF21, adiponectin, and irisin, via SIRT1/PGC-1α- and LXRα-dependent pathways. Our study suggests a potential molecular mechanism underlying the comorbidity of NAFLD and IBD, which could provide a key to understanding how the two diseases are pathogenically linked and discovering critical therapeutic targets for their treatment.

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Centrally Administered Resistin Enhances Sympathetic Nerve Activity to the Hindlimb but Attenuates the Activity to Brown Adipose Tissue

Endocrinology ◽

10.1210/en.2010-1492 ◽

2011 ◽

Vol 152 (7) ◽

pp. 2626-2633 ◽

Cited By ~ 17

Author(s):

S. Kosari ◽

J. A. Rathner ◽

F. Chen ◽

S. Kosari ◽

E. Badoer

Keyword(s):

Cardiovascular Disease ◽

Heart Rate ◽

Adipose Tissue ◽

Brown Adipose Tissue ◽

Sympathetic Nerve ◽

Energy Homeostasis ◽

Sympathetic Nerve Activity ◽

Nerve Activity ◽

Obesity And Diabetes ◽

Brown Adipose

Resistin, an adipokine, is believed to act in the brain to influence energy homeostasis. Plasma resistin levels are elevated in obesity and are associated with metabolic and cardiovascular disease. Increased muscle sympathetic nerve activity (SNA) is a characteristic of obesity, a risk factor for diabetes and cardiovascular disease. We hypothesized that resistin affects SNA, which contributes to metabolic and cardiovascular dysfunction. Here we investigated the effects of centrally administered resistin on SNA to muscle (lumbar) and brown adipose tissue (BAT), outputs that influence cardiovascular and energy homeostasis. Overnight-fasted rats were anesthetized, and resistin (7 μg) was administered into the lateral cerebral ventricle (intracerebroventricular). The lumbar sympathetic nerve trunk or sympathetic nerves supplying BAT were dissected free, and nerve activity was recorded. Arterial blood pressure, heart rate, body core temperature, and BAT temperature were also recorded. Responses to resistin or vehicle were monitored for 4 h after intracerebroventricular administration. Acutely administered resistin increased lumbar SNA but decreased BAT SNA. Mean arterial pressure and heart rate, however, were not significantly affected by resistin. BAT temperature was significantly reduced by resistin, and there was a concomitant fall in body temperature. The findings indicate that resistin has differential effects on SNA to tissues involved in metabolic and cardiovascular regulation. The decreased BAT SNA and the increased lumbar SNA elicited by resistin suggest that it may contribute to the increased muscle SNA and reduced energy expenditure observed in obesity and diabetes.

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Inhibition of Sam68 triggers adipose tissue browning

Journal of Endocrinology ◽

10.1530/joe-14-0727 ◽

2015 ◽

Vol 225 (3) ◽

pp. 181-189 ◽

Cited By ~ 6

Author(s):

Junlan Zhou ◽

Min Cheng ◽

Chan Boriboun ◽

Mariam M Ardehali ◽

Changfei Jiang ◽

...

Keyword(s):

Body Weight ◽

Adipose Tissue ◽

Energy Homeostasis ◽

Molecular Mechanisms ◽

Acid Oxidation ◽

M2 Macrophage ◽

Fat Depots ◽

Reduced Body ◽

Brown Adipose ◽

The Difference

Obesity is associated with insulin resistance and type 2 diabetes; molecular mechanisms that promote energy expenditure can be utilized for effective therapy. Src-associated in mitosis of 68 kDa (Sam68) is potentially significant, because knockout (KO) of Sam68 leads to markedly reduced adiposity. In the present study, we sought to determine the mechanism by which Sam68 regulates adiposity and energy homeostasis. We first found that Sam68 KO mice have a significantly reduced body weight as compared to controls, and the difference is explained entirely by decreased adiposity. Interestingly, these effects were not mediated by a difference in food intake; rather, they were associated with enhanced physical activity. When they were fed a high-fat diet, Sam68 KO mice gained much less body weight and fat mass than their WT littermates did, and they displayed an improved glucose and insulin tolerance. In Sam68 KO mice, the brown adipose tissue (BAT), inguinal, and epididymal depots were smaller, and their adipocytes were less hypertrophied as compared to their WT littermates. The BAT of Sam68 KO mice exhibited reduced lipid stores and expressed higher levels of Ucp1 and key thermogenic and fatty acid oxidation genes. Similarly, depots of inguinal and epididymal white adipose tissue (WAT) in Sam68 KO mice appeared browner, their multilocular Ucp1-positive cells were much more abundant, and the expression of Ucp1, Cidea, Prdm16, and Ppargc1a genes was greater as compared to WT controls, which suggests that the loss of Sam68 also promotes WAT browning. Furthermore, in all of the fat depots of the Sam68 KO mice, the expression of M2 macrophage markers was up-regulated, and that of M1 markers was down-regulated. Thus, Sam68 plays a crucial role in controlling thermogenesis and may be targeted to combat obesity and associated disorders.

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Incendiary Leptin

Nutrients ◽

10.3390/nu12020472 ◽

2020 ◽

Vol 12 (2) ◽

pp. 472 ◽

Cited By ~ 2

Author(s):

Patricia Seoane-Collazo ◽

Noelia Martínez-Sánchez ◽

Edward Milbank ◽

Cristina Contreras

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Metabolic Profile ◽

Metabolic Disorders ◽

Energy Homeostasis ◽

Scientific Evidence ◽

Rodent Models ◽

Leptin Receptors ◽

Brown Adipose ◽

Dual Capacity

Leptin is a hormone released by adipose tissue that plays a key role in the control of energy homeostasis through its binding to leptin receptors (LepR), mainly expressed in the hypothalamus. Most scientific evidence points to leptin’s satiating effect being due to its dual capacity to promote the expression of anorexigenic neuropeptides and to reduce orexigenic expression in the hypothalamus. However, it has also been demonstrated that leptin can stimulate (i) thermogenesis in brown adipose tissue (BAT) and (ii) the browning of white adipose tissue (WAT). Since the demonstration of the importance of BAT in humans 10 years ago, its study has aroused great interest, mainly in the improvement of obesity-associated metabolic disorders through the induction of thermogenesis. Consequently, several strategies targeting BAT activation (mainly in rodent models) have demonstrated great potential to improve hyperlipidemias, hepatic steatosis, insulin resistance and weight gain, leading to an overall healthier metabolic profile. Here, we review the potential therapeutic ability of leptin to correct obesity and other metabolic disorders, not only through its satiating effect, but by also utilizing its thermogenic properties.

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Omega-3 Fatty Acids and Adipose Tissue: Inflammation and Browning

Annual Review of Nutrition ◽

10.1146/annurev-nutr-122319-034142 ◽

2020 ◽

Vol 40 (1) ◽

pp. 25-49 ◽

Cited By ~ 3

Author(s):

Nishan Sudheera Kalupahana ◽

Bimba Lakmini Goonapienuwala ◽

Naima Moustaid-Moussa

Keyword(s):

Fatty Acids ◽

Weight Loss ◽

Adipose Tissue ◽

Metabolic Regulation ◽

Energy Homeostasis ◽

Molecular Mechanisms ◽

Whole Body ◽

Omega 3 ◽

Brown Adipose ◽

Body Energy

White adipose tissue (WAT) and brown adipose tissue (BAT) are involved in whole-body energy homeostasis and metabolic regulation. Changes to mass and function of these tissues impact glucose homeostasis and whole-body energy balance during development of obesity, weight loss, and subsequent weight regain. Omega-3 polyunsaturated fatty acids (ω-3 PUFAs), which have known hypotriglyceridemic and cardioprotective effects, can also impact WAT and BAT function. In rodent models, these fatty acids alleviate obesity-associated WAT inflammation, improve energy metabolism, and increase thermogenic markers in BAT. Emerging evidence suggests that ω-3 PUFAs can also modulate gut microbiota impacting WAT function and adiposity. This review discusses molecular mechanisms, implications of these findings, translation to humans, and future work, especially with reference to the potential of these fatty acids in weight loss maintenance.

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