HDAC11 Suppresses the Thermogenic Program of Adipose Tissue via BRD2

AbstractLittle is known about the biological function of histone deacetylase 11 (HDAC11), which is the lone class IV HDAC. Here, we demonstrate that deletion of HDAC11 in mice stimulates brown adipose tissue (BAT) formation and beiging of white adipose tissue (WAT). Consequently, HDAC11-deficient mice exhibit dramatically enhanced thermogenic potential and, in response to high fat feeding, attenuated obesity, insulin resistance, and hepatic steatosis. Ex vivo and cell-based assays revealed that HDAC11 catalytic activity suppresses the BAT transcriptional program, in both the basal state and in response to β-adrenergic receptor signaling, through a mechanism that is dependent on physical association with BRD2, a bromodomain and extraterminal (BET) acetyl-histone binding protein. These findings define a novel epigenetic pathway for the regulation of energy homeostasis, and suggest potential for HDAC11-selective inhibitors for the treatment of obesity and diabetes.

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Dopamine receptor D1- and D2-agonists do not spark brown adipose tissue thermogenesis in mice

Scientific Reports ◽

10.1038/s41598-020-77143-6 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Francesca-Maria Raffaelli ◽

Julia Resch ◽

Rebecca Oelkrug ◽

K. Alexander Iwen ◽

Jens Mittag

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Dopamine Receptor ◽

Ex Vivo ◽

Potential Target ◽

D2 Agonist ◽

Obesity And Diabetes ◽

Brown Adipose

AbstractBrown adipose tissue (BAT) thermogenesis is considered a potential target for treatment of obesity and diabetes. In vitro data suggest dopamine receptor signaling as a promising approach; however, the biological relevance of dopamine receptors in the direct activation of BAT thermogenesis in vivo remains unclear. We investigated BAT thermogenesis in vivo in mice using peripheral administration of D1-agonist SKF38393 or D2-agonist Sumanirole, infrared thermography, and in-depth molecular analyses of potential target tissues; and ex vivo in BAT explants to identify direct effects on key thermogenic markers. Acute in vivo treatment with the D1- or D2-agonist caused a short spike or brief decrease in BAT temperature, respectively. However, repeated daily administration did not induce lasting effects on BAT thermogenesis. Likewise, neither agonist directly affected Ucp1 or Dio2 mRNA expression in BAT explants. Taken together, the investigated agonists do not seem to exert lasting and physiologically relevant effects on BAT thermogenesis after peripheral administration, demonstrating that D1- and D2-receptors in iBAT are unlikely to constitute targets for obesity treatment via BAT activation.

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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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Epigenetic Regulators of White Adipocyte Browning

Epigenomes ◽

10.3390/epigenomes5010003 ◽

2021 ◽

Vol 5 (1) ◽

pp. 3

Author(s):

Ravikanth Nanduri

Keyword(s):

Adipose Tissue ◽

Metabolic Disorders ◽

Energy Homeostasis ◽

Molecular Mechanisms ◽

White Adipocyte ◽

Primary Function ◽

Obesity And Diabetes ◽

Brown Adipose ◽

Beige Adipocytes ◽

Epigenetic Regulators

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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High-fat diet-induced hyperinsulinemia and tissue-specific insulin resistance in Cry-deficient mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00512.2012 ◽

2013 ◽

Vol 304 (10) ◽

pp. E1053-E1063 ◽

Cited By ~ 78

Author(s):

Johanna L. Barclay ◽

Anton Shostak ◽

Alexei Leliavski ◽

Anthony H. Tsang ◽

Olaf Jöhren ◽

...

Keyword(s):

Adipose Tissue ◽

Insulin Secretion ◽

High Fat Diet ◽

Energy Homeostasis ◽

Genetic Manipulation ◽

Metabolic Effects ◽

Lipid Uptake ◽

High Fat ◽

Obesity And Diabetes ◽

Deficient Mice

Perturbation of circadian rhythmicity in mammals, either by environmental influences such as shiftwork or by genetic manipulation, has been associated with metabolic disturbance and the development of obesity and diabetes. Circadian clocks are based on transcriptional/translational feedback loops, comprising positive and negative components. Whereas the metabolic effects of deletion of the positive arm of the clock gene machinery, as in Clock- or Bmal1-deficient mice, have been well characterized, inactivation of Period genes ( Per1–3) as components of the negative arm have more complex, sometimes contradictory effects on energy homeostasis. The CRYPTOCHROMEs are critical interaction partners of PERs, and simultaneous deletion of Cry1 and - 2 results in behavioral and molecular circadian arrhythmicity. We show that, when challenged with a high-fat diet, Cry1/2−/− mice rapidly gain weight and surpass that of wild-type mice, despite displaying hypophagia. Transcript analysis of white adipose tissue reveals upregulated expression of lipogenic genes, many of which are insulin targets. High-fat diet-induced hyperinsulinemia, as a result of potentiated insulin secretion, coupled with selective insulin sensitivity in adipose tissue of Cry1/2−/− mice, correlates with increased lipid uptake. Collectively, these data indicate that Cry deficiency results in an increased vulnerability to high-fat diet-induced obesity that might be mediated by increased insulin secretion and lipid storage in adipose tissues.

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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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Short-term resistance to diet-induced obesity in A/J mice is not associated with regulation of hypothalamic neuropeptides

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00114.2004 ◽

2004 ◽

Vol 287 (4) ◽

pp. E662-E670 ◽

Cited By ~ 13

Author(s):

John W. Bullen ◽

Mary Ziotopoulou ◽

Linda Ungsunan ◽

Jatin Misra ◽

Ilias Alevizos ◽

...

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Microarray Analysis ◽

Energy Homeostasis ◽

Uncoupling Protein ◽

High Fat ◽

Diet Induced Obesity ◽

Brown Adipose ◽

Hypothalamic Neuropeptides ◽

Fat Feeding

To investigate the mechanisms underlying long-term resistance of the A/J mouse strain to diet-induced obesity, we studied, over a period of 4 wk, the expression of uncoupling proteins in brown adipose tissue and the expression of hypothalamic neuropeptides known to regulate energy homeostasis and then used microarray analysis to identify other potentially important hypothalamic peptides. Despite increased caloric intake after 2 days of high-fat feeding, body weights of A/J mice remained stable. On and after 1 wk of high-fat feeding, A/J mice adjusted their food intake to consume the same amount of calories as mice fed a low-fat diet; thus their body weight and insulin, corticosterone, free fatty acid, and glucose levels remained unchanged for 4 wk. We found no changes in hypothalamic expression of several orexigenic and/or anorexigenic neuropeptides known to play an important role in energy homeostasis for the duration of the study. Uncoupling protein-2 mRNA expression in brown adipose tissue, however, was significantly upregulated after 2 days of high-fat feeding and tended to remain elevated for the duration of the 4-wk study. Gene array analysis revealed that several genes are up- or downregulated in response to 2 days and 1 wk of high-fat feeding. Real-time PCR analysis confirmed that expression of the hypothalamic IL-1 pathway (IL-1β, IL-1 type 1 and 2 receptors, and PPM1b/PP2C-β, a molecule that has been implicated in the inhibition of transforming growth factor-β-activated kinase-1-mediated IL-1 action) is altered after 2 days, but not 1 wk, of high-fat feeding. The role of additional molecules discovered by microarray analysis needs to be further explored in the future.

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Mfsd2a encodes a novel major facilitator superfamily domain-containing protein highly induced in brown adipose tissue during fasting and adaptive thermogenesis

Biochemical Journal ◽

10.1042/bj20080165 ◽

2008 ◽

Vol 416 (3) ◽

pp. 347-355 ◽

Cited By ~ 43

Author(s):

Martin Angers ◽

Marc Uldry ◽

Dong Kong ◽

Jeffrey M. Gimble ◽

Anton M. Jetten

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Adrenergic Receptor ◽

Common Ancestor ◽

Major Facilitator Superfamily ◽

Adaptive Thermogenesis ◽

Brown Adipose ◽

Exon Junctions ◽

Major Facilitator ◽

Deficient Mice

This study describes the identification of Mfsd2a (major facilitator superfamily domain-containing protein 2a), a novel mammalian major facilitator superfamily domain-containing protein, and an additional closely related protein, Mfsd2b. Most intron/exon junctions are conserved between the two genes, suggesting that they are derived from a common ancestor. Mfsd2a and Mfsd2b share a 12 transmembrane α-helical domain structure that bears greatest similarity to that of the bacterial Na+/melibiose symporters. Confocal microscopy demonstrated that Mfsd2a localizes to the endoplasmic reticulum. Mfsd2a is expressed in many tissues and is highly induced in liver and BAT (brown adipose tissue) during fasting. Mfsd2a displays an oscillatory expression profile in BAT and liver, consistent with a circadian rhythm. Although the basal level of Mfsd2a expression is relatively low in mouse BAT, it is greatly induced during cold-induced thermogenesis and after treatment with βAR (β-adrenergic receptor) agonists. This induction is totally abolished in β-less (βAR-deficient) mice. These findings indicate that Mfsd2a is greatly up-regulated in BAT during thermogenesis and that its induction is controlled by the βAR signalling pathway. The observed induction of Mfsd2a expression in cultured BAT cells by dibutyryl-cAMP is in agreement with this conclusion. The present study suggests that Mfsd2a plays a role in adaptive thermogenesis.

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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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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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