A leptin–BDNF pathway regulating sympathetic innervation of adipose tissue

Wang, Putianqi; Loh, Ken H.; Wu, Michael; Morgan, Donald A.; Schneeberger, Marc; Yu, Xiaofei; Chi, Jingyi; Kosse, Christin; Kim, Damian; Rahmouni, Kamal; Cohen, Paul; Friedman, Jeffrey M.

doi:10.1038/s41586-020-2527-y

Cited by 216 publications

(177 citation statements)

References 32 publications

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“…Low sympathetic innervation in WAT from ob/ob mice was ameliorated (anatomically and functionally) following peripheral chronic leptin treatment. They showed that Brain-Derived Neurotrophic Factor (BDNF)-expressing neurons in the paraventricular nucleus were downstream of agouti-related peptide (AGRP) and proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARC), and are essential for the leptin actions restoring sympathetic innervation of WAT in ob/ob mice [154]. These findings also demonstrate that leptin regulates the architecture of the SNS in the adipose tissue.…”

Section: Leptin and Lipolysismentioning

confidence: 94%

“…The authors also showed that the optogenetic activation of these axons increased the levels of noradrenaline, activated HSL, and reduced fat mass. Interestingly, leptin actions in HSL were blocked after disrupting neuronal input surgically, genetically or pharmacologically, signifying that this local innervation is essential for the lipolysis leptin effects [153].Very recently, an important paper was published regarding the mechanisms involved in the effects of leptin on thermogenesis and lipolysis [154]. The effects of acute and chronic leptin treatment on SNS innervation, the main regulator of lipolysis, were evaluated.…”

Section: Leptin and Lipolysismentioning

confidence: 99%

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There and Back Again: Leptin Actions in White Adipose Tissue

Martínez-Sánchez

2020

IJMS

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Leptin is a hormone discovered almost 30 years ago with important implications in metabolism. It is primarily produced by white adipose tissue (WAT) in proportion to the amount of fat. The discovery of leptin was a turning point for two principle reasons: on one hand, it generated promising expectations for the treatment of the obesity, and on the other, it changed the classical concept that white adipose tissue was simply an inert storage organ. Thus, adipocytes in WAT produce the majority of leptin and, although its primary role is the regulation of fat stores by controlling lipolysis and lipogenesis, this hormone also has implications in other physiological processes within WAT, such as apoptosis, browning and inflammation. Although a massive number of questions related to leptin actions have been answered, the necessity for further clarification facilitates constantly renewing interest in this hormone and its pathways. In this review, leptin actions in white adipose tissue will be summarized in the context of obesity.

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Section: Leptin and Lipolysismentioning

confidence: 94%

Section: Leptin and Lipolysismentioning

confidence: 99%

There and Back Again: Leptin Actions in White Adipose Tissue

Martínez-Sánchez

2020

IJMS

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“…Thermogenesis of BAT and lipolysis of WAT are regulated by the sympathetic nervous system 26‐28 . We then asked whether the decreased BAT thermogenesis and WAT lipolysis was caused by an impaired sympathetic nervous system.…”

Section: Resultsmentioning

confidence: 99%

Sirtuin 6 supra‐physiological overexpression in hypothalamic pro‐opiomelanocortin neurons promotes obesity via the hypothalamus‐adipose axis

et al. 2021

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Sirtuin 6 (Sirt6), a member of the Sirtuin family, has important roles in maintaining glucose and lipid metabolism. Our previous studies demonstrated that the deletion of Sirt6 in pro‐opiomelanocortin (POMC)‐expressing cells by the loxP‐Cre system resulted in severe obesity and hepatic steatosis. However, whether overexpression of Sirt6 in hypothalamic POMC neurons could ameliorate diet‐induced obesity is still unknown. Thus, we generated mice specifically overexpressing Sirt6 in hypothalamic POMC neurons (PSOE) by stereotaxic injection of Cre‐dependent adeno‐associated viruses into the arcuate nucleus of Pomc‐Cre mice. PSOE mice showed increased adiposity and decreased energy expenditure. Furthermore, thermogenesis of BAT and lipolysis of WAT were both impaired, caused by reduced sympathetic nerve innervation and activity in adipose tissues. Mechanistically, Sirt6 overexpression decreasing STAT3 acetylation, thus lowering POMC expression in the hypothalamus underlined the observed phenotypes in PSOE mice. These results demonstrate that Sirt6 overexpression specifically in the hypothalamic POMC neurons exacerbates diet‐induced obesity and metabolic disorders via the hypothalamus‐adipose axis.

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“…In addition, central regulation of thermogenesis requires intact sympathetic innervations to adipocytes. Obesity is often accompanied by impaired sympathetic nerve distributions in fat tissues (163), which may jeopardize the anti-obesity effects of AMPK inhibition in the VMH. Moreover, while the β-AR agonist Mirabegron robustly stimulates glucose uptake in BAT of healthy adult humans (164), administration of a panadrenergic agonist Ephedrine produces minimal effects on BAT activity in obese subjects (165), suggesting the development of β-AR resistance in obesity.…”

Section: Targeting Ampk Within the Vmh To Counteract Obesitymentioning

confidence: 99%

AMPK in the Ventromedial Nucleus of the Hypothalamus: A Key Regulator for Thermogenesis

Liu

2020

Front. Endocrinol.

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Obesity has become a global health issue, but effective therapies remain very limited. Adaptive thermogenesis promotes weight loss by dissipating energy in the form of heat, thereby representing a promising target to counteract obesity. Notably, the regulation of thermogenesis is tightly orchestrated by complex neuronal networks, especially those in the hypothalamus. Recent evidence highlights the importance of adenosine monophosphate-activated protein kinase (AMPK) within the ventromedial nucleus of the hypothalamus (VMH) in modulating thermogenesis. Various molecules, such as GLP-1, leptin, estradiol, and thyroid hormones, have been reported to act on the VMH to inhibit AMPK, which subsequently increases thermogenesis through the activation of the sympathetic nervous system (SNS). In this review, we summarize the critical role of AMPK within the VMH in the control of energy balance, focusing on its contribution to thermogenesis and the associated mechanisms.

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A leptin–BDNF pathway regulating sympathetic innervation of adipose tissue

Cited by 216 publications

References 32 publications

There and Back Again: Leptin Actions in White Adipose Tissue

There and Back Again: Leptin Actions in White Adipose Tissue

Sirtuin 6 supra‐physiological overexpression in hypothalamic pro‐opiomelanocortin neurons promotes obesity via the hypothalamus‐adipose axis

AMPK in the Ventromedial Nucleus of the Hypothalamus: A Key Regulator for Thermogenesis

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