(The) effect of serotonin signals through serotonin receptor 2B in visceral adipose tissue on systemic insulin resistance

Abstract

Insulin resistance is a cornerstone of obesity complications such as type 2 diabetes, metabolic syndrome, and non-alcoholic fatty liver disease. A high lipolysis rate is associated with low insulin sensitivity, and inhibiting adipose tissue lipolysis improves obesity-related insulin resistance. Here, I demonstrate that inhibition of adipose serotonin receptor 2B (HTR2B) signaling ameliorates insulin resistance, visceral adipose tissue inflammation, and hepatic steatosis by reducing lipolysis in visceral adipocytes. HTR2B signaling is selectively increased in visceral adipose tissue of obese mice compared to lean mice. Moreover, HTR2B expression in white adipose tissue is increased in obese humans and positively correlated with metabolic parameters. I further found that adipocyte-specific Htr2b-knockout mice are resistant to high-fat diet (HFD)-induced insulin resistance, visceral adipose tissue inflammation, and hepatic steatosis. 5-HT signaling through HTR2B directly activates lipolysis through phosphorylation of hormone sensitive lipase in visceral adipocytes. Moreover, treatment with a selective HTR2B antagonist attenuates HFD-induced insulin resistance, visceral tissue inflammation, and hepatic steatosis. Thus, adipose HTR2B signaling shows potential as a therapeutic target for treatment of obesity-related insulin resistance.