Inhibition of Notch signaling promotes browning of white adipose tissue and ameliorates obesity

Bi, Pengpeng; Shan, Tizhong; Liu, Weiyi; Feng, Yue; Yang, Xin; Liang, Xin Rong; Wang, Jinghua; Li, Jie; Carlesso, Nadia; Liu, Xiaoqi; Kuang, Shihuan

doi:10.1038/nm.3615

Cited by 240 publications

(255 citation statements)

References 71 publications

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“…Recent studies have suggested that the enhancement of browning of white fat and BAT function can stimulate thermogenesis and energy expenditure, thereby decreasing adiposity (29). In addition, the risks of obesity and metabolic syndrome in humans are reduced by the expansion of brown-specific adipocytes in WAT (30,31).…”

Section: Discussionmentioning

confidence: 99%

β-Lapachone Prevents Diet-Induced Obesity by Increasing Energy Expenditure and Stimulating the Browning of White Adipose Tissue via Downregulation of miR-382 Expression

et al. 2016

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There has been great interest in the browning of fat for the treatment of obesity. Although b-lapachone (BLC) has potential therapeutic effects on obesity, the fat-browning effect and thermogenic capacity of BLC on obesity have never been demonstrated. Here, we showed that BLC stimulated the browning of white adipose tissue (WAT), increased the expression of brown adipocyte-specific genes (e.g., uncoupling protein 1 [UCP1]), decreased body weight gain, and ameliorated metabolic parameters in mice fed a high-fat diet. Consistently, BLC-treated mice showed significantly higher energy expenditure compared with control mice. In vitro, BLC increased the expression of brown adipocyte-specific genes in stromal vascular fraction-differentiated adipocytes. BLC also controlled the expression of miR-382, which led to the upregulation of its direct target, Dio2. Upregulation of miR-382 markedly inhibited the differentiation of adipocytes into beige adipocytes, whereas BLC recovered beige adipocyte differentiation and increased the expression of Dio2 and UCP1. Our findings suggest that the BLC-mediated increase in the browning of WAT and the thermogenic capacity of BAT significantly results in increases in energy expenditure. Browning of WAT by BLC was partially controlled via the regulation of miR-382 targeting Dio2 and may lead to the prevention of diet-induced obesity.

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Section: Discussionmentioning

confidence: 99%

β-Lapachone Prevents Diet-Induced Obesity by Increasing Energy Expenditure and Stimulating the Browning of White Adipose Tissue via Downregulation of miR-382 Expression

et al. 2016

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“…However, in stark contrast, mechanisms that induce mild mitochondrial uncoupling, such as targeted upregulation of uncoupling protein 1, genetic approaches that result in 'browning' of WAT and the administration of artificial mitochondrial uncouplers (i.e. 2,4-dinitrophenol [DNP]), improve insulin sensitivity and decrease obesity [12][13][14]. Mitochondrial uncoupling promotes energy dissipation in the form of heat loss, as the mitochondrial proton gradient is dissociated from ATP production.…”

Section: Introductionmentioning

confidence: 99%

In adipose tissue, increased mitochondrial emission of reactive oxygen species is important for short-term high-fat diet-induced insulin resistance in mice

et al. 2015

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Aims/hypothesis Consuming a high-fat diet (HFD) induces insulin resistance in white adipose tissue (WAT) within 1 week. However, little is known about the initiating events. One potential mechanism that has remained largely unexplored is excessive mitochondrial emission of reactive oxygen species (ROS). Methods To determine the role of mitochondrial ROS emissions at the onset of insulin resistance, wild-type (WT) mice were placed on an HFD for 1 week. WAT insulin sensitivity and inflammation were assessed by western blot. In addition, we optimised/validated a method to determine ROS emissions in permeabilised WAT. Results An HFD for 1 week resulted in impaired insulin signalling, increased c-Jun NH 2 -terminal kinase (JNK) phosphorylation and an increase in oxidative stress. These changes were associated with an increase in fatty-acid-mediated mitochondrial ROS emissions without any change in mitochondrial respiration/content. To determine that mitochondrial ROS causes insulin resistance, we used transgenic mice that express human catalase in mitochondria (MCAT) as a model of upregulated mitochondrial antioxidant enzyme capacity. MCAT mice displayed attenuated mitochondrial ROS emission, preserved insulin signalling and no inflammatory response following an HFD. Conclusions/interpretation Findings from this study suggest that elevated mitochondrial ROS emission contributes to HFD-induced WAT insulin resistance.

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“…Consequently, the inhibition of these pathways in turn leads to the appearance of beige adipocytes. This includes peripheral serotonin levels (Crane et al 2015), the TGFb/SMAD3/myostatin cascade (Shan et al 2013, hepatic PTEN (Peyrou et al 2015), Notch or prolactin receptor signaling (Auffret et al 2012, Bi et al 2014, as well as Cox2 (Madsen et al 2010).…”

Section: Ways Of Browningmentioning

confidence: 99%

Breaking BAT: can browning create a better white?

Warner

Mittag

2015

Journal of Endocrinology

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Obesity and its comorbidities are a growing problem worldwide. In consequence, several new strategies have been proposed to promote weight loss and improve insulin sensitivity.Recently, it has been demonstrated that certain populations of white adipocytes can be 'browned', i.e., recruited to a more brown-like adipocyte, capable of thermogenesis through increased expression of uncoupling protein 1. The list of browning agents that induce these so-called beige adipocytes is growing constantly. However, the underlying mechanisms are often poorly understood, with the possibility that some of these agents cause browning as a secondary effect. Moreover, it remains unclear whether beige adipocytes can contribute sufficiently to affect whole-body energy expenditure in a functionally significant manner. This review presents an overview of the different molecular pathways leading to the induction of beige fat, including direct stimulation and indirect actions on the CNS or the immune system. We discuss the available evidence on the capacity of beige adipocytes to influence whole-body energy expenditure in rodents, and lastly outline the potential problems of translating browning capacity into the potential treatment of human metabolic diseases.

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Inhibition of Notch signaling promotes browning of white adipose tissue and ameliorates obesity

Cited by 240 publications

References 71 publications

β-Lapachone Prevents Diet-Induced Obesity by Increasing Energy Expenditure and Stimulating the Browning of White Adipose Tissue via Downregulation of miR-382 Expression

β-Lapachone Prevents Diet-Induced Obesity by Increasing Energy Expenditure and Stimulating the Browning of White Adipose Tissue via Downregulation of miR-382 Expression

In adipose tissue, increased mitochondrial emission of reactive oxygen species is important for short-term high-fat diet-induced insulin resistance in mice

Breaking BAT: can browning create a better white?

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