Incendiary Leptin

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.

Download Full-text

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.

Download Full-text

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.

Download Full-text

FGF21 does not require interscapular brown adipose tissue and improves liver metabolic profile in animal models of obesity and insulin-resistance

Scientific Reports ◽

10.1038/srep11382 ◽

2015 ◽

Vol 5 (1) ◽

Cited By ~ 30

Author(s):

Barbara Bernardo ◽

Min Lu ◽

Gautam Bandyopadhyay ◽

Pingping Li ◽

Yingjiang Zhou ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Animal Models ◽

Brown Adipose Tissue ◽

Metabolic Profile ◽

Interscapular Brown Adipose Tissue ◽

Brown Adipose

Download Full-text

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.

Download Full-text

Mechanisms in Endocrinology: LOCAL AND SYSTEMIC EFFECTS OF GLUCOCORTICOIDS ON METABOLISM: NEW LESSONS FROM ANIMAL MODELS

Acta Endocrinologica ◽

10.1530/eje-21-0553 ◽

2021 ◽

Author(s):

Michael Swarbrick ◽

Hong Zhou ◽

Markus Seibel

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Energy Homeostasis ◽

Metabolic Diseases ◽

Visceral Obesity ◽

Metabolic Effects ◽

Glucocorticoid Treatment ◽

Brown Adipose ◽

Nutrient Partitioning ◽

Brown Adipose Tissue Thermogenesis

Glucocorticoids regulate a remarkable variety of essential functions, including development, immunomodulation, maintenance of circadian rhythm and the response to stress. Glucocorticoids acutely increase energy availability; this is accomplished not only by mobilizing energy stores, but also by diverting energy away from anabolic processes in tissues such as skeletal muscle and bone. While this metabolic shift is advantageous in the short term, prolonged glucocorticoid exposure frequently results in central obesity, insulin resistance, hyperglycaemia, dyslipidaemia, muscle wasting and osteoporosis. Understanding how glucocorticoids affect nutrient partitioning is therefore critical for preventing the side effects of glucocorticoid treatment. Independently of circulating glucocorticoids, intracellular glucocorticoid activity is regulated by the 11β-hydroxysteroid dehydrogenases 1 and 2 (11β-HSD1 and 2), which activate and inactivate glucocorticoids, respectively. Excessive 11β-HSD1 activity, amplifying local glucocorticoid activity in tissues such as adipose tissue and bone may contribute to visceral obesity, insulin resistance and aging-related bone loss in humans. Several recent findings in animals have considerably expanded our understanding of how glucocorticoids exert their dysmetabolic effects. In mice, disrupting glucocorticoid signalling in either adipose tissue or bone produces marked effects on energy homeostasis. Glucocorticoids have also been shown to influence brown adipose tissue thermogenesis (acute activation, chronic suppression), in both rodents and humans. Lastly, recent studies in mice have demonstrated that many dysmetabolic effects of glucocorticoids are sexually dimorphic, although corresponding results in humans are lacking. Together, these studies have illuminated the mechanisms by which glucocorticoids exert their metabolic effects; and have guided us towards more targeted future treatments for metabolic diseases.

Download Full-text

Adipocyte-specific DKO of Lkb1 and mTOR protects mice against HFD-induced obesity, but results in insulin resistance

The Journal of Lipid Research ◽

10.1194/jlr.m081463 ◽

2018 ◽

Vol 59 (6) ◽

pp. 974-981 ◽

Cited By ~ 7

Author(s):

Yan Xiong ◽

Ziye Xu ◽

Yizhen Wang ◽

Shihuan Kuang ◽

Tizhong Shan

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Energy Homeostasis ◽

Mammalian Target Of Rapamycin ◽

Tissue Mass ◽

Metabolic Phenotypes ◽

Insulin Tolerance ◽

Brown Adipose ◽

Liver Kinase B1 ◽

And Function

Liver kinase B1 (Lkb1) and mammalian target of rapamycin (mTOR) are key regulators of energy metabolism and cell growth. We have previously reported that adipocyte-specific KO of Lkb1 or mTOR in mice results in distinct developmental and metabolic phenotypes. Here, we aimed to assess how genetic KO of both Lkb1 and mTOR affects adipose tissue development and function in energy homeostasis. We used Adiponectin-Cre to drive adipocyte-specific double KO (DKO) of Lkb1 and mTOR in mice. We performed indirect calorimetry, glucose and insulin tolerance tests, and gene expression assays on the DKO and WT mice. We found that DKO of Lkb1 and mTOR results in reductions of brown adipose tissue and inguinal white adipose tissue mass, but in increases of liver mass. Notably, the DKO mice developed fatty liver and insulin resistance, but displayed improved glucose tolerance after high-fat diet (HFD)-feeding. Interestingly, the DKO mice were protected from HFD-induced obesity due to their higher energy expenditure and lower expression levels of adipogenic genes (CCAAT/enhancer binding protein α and PPARγ) compared with WT mice. These results together indicate that, compared with Lkb1 or mTOR single KOs, Lkb1/mTOR DKO in adipocytes results in overlapping and distinct metabolic phenotypes, and mTOR KO largely overrides the effect of Lkb1 KO.

Download Full-text

Brown adipose tissue in prepubertal children: associations with sex, birthweight, and metabolic profile

Yearbook of Paediatric Endocrinology ◽

10.1530/ey.16.11.10 ◽

2019 ◽

Author(s):

Malpique R ◽

Gallego-Escuredo JM ◽

Sebastiani G ◽

Villarroya J ◽

Lopez-Bermejo A ◽

...

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Metabolic Profile ◽

Prepubertal Children ◽

Brown Adipose

Download Full-text

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.

Download Full-text