Notch signaling regulates adipogenesis and energy metabolism
Evolutionarily unprepared for high caloric diets and sedentary lifestyles, humans are now unprecedentedly susceptible to obesity and its associated metabolic disorders. Obesity is resulted from malfunction of the overloaded white adipocytes, which are the primary default storage sites of energy surplus. Another two types of adipocytes can also be found in human: beige and brown adipocytes. In opposite to white adipocytes, beige and brown adipocytes ameliorate obesity by burning lipids for thermogenesis. Thus, an increase in beige/brown adipocyte content in adipose tissue, termed browning would raise energy expenditure and reduce adiposity. Notch signaling is a fundamental signal transduction pathway, which is critical for development and metabolism. Here I report that adipose-specific Notch mutant mice showed browning of white adipose tissue (WAT) and elevated expression of UCP1, a key regulator of thermogenesis. Consequently, Notch mutants exhibit elevated energy expenditure, improved glucose tolerance and insulin sensitivity, and are more resistant to high fat diet (HFD)-induced obesity. At the molecular level, constitutive activation of Notch signaling inhibits, whereas Notch inhibition induces transcription of Ppargc1a and Prdm16, two master regulators of beige adipocyte biogenesis. Notably, pharmacological inhibition of Notch signaling in obese mice increases insulin sensitivity and ameliorates obesity, accompanied by elevated UCP1 expression in white fat. In contrast to Notch-inhibition, the mice with constitutive activation of Notch signaling specifically in adipocytes, henceforth referred to as Adipoq/N1ICD showed defect of beige adipocyte biogenesis, accompanied by severe glucose intolerance and insulin resistance. Surprisingly, instead of developing obesity, Adipoq/N1ICD mice showed scarcity of WAT, or lipodystrophy under both standard diet and obesogenic HFD feeding regimes. This result indicates a potent inhibitory effect of Notch signaling on white adipogenesis. Supporting this notion, expressions of many white adipocyte marker genes were dramatically reduced in WAT of Adipoq/N1ICD mice. Remarkably, chronic lipodystrophy in Adipoq/N1ICD mice leads to development of fatty liver, hyperglycemia, hyperinsulinemia and cancers. In summary, this study revealed two previously unknown functions of Notch signaling in regulating adipocyte plasticity. While Notch inhibition promotes the beige adipogenesis, chronic activation of Notch leads to paucity of both white and beige adipocytes. Consequently, inhibition of Notch signaling improves, while activation of Notch signaling deteriorates glucose metabolism. Therefore, Notch signaling may be therapeutically targeted to treat obesity and its affiliated comorbidities.
Kuang, Purdue University.
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