Graduate School of Medical Science and Engineering, Biomedical Research Center, KAIST, Daejeon, South Korea.
Department of Internal Medicine, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun, South Korea.
J Clin Invest. 2021 Dec 1;131(23). doi: 10.1172/JCI145331.
Insulin resistance is a cornerstone of obesity-related complications such as type 2 diabetes, metabolic syndrome, and nonalcoholic fatty liver disease. A high rate of lipolysis is known to be associated with insulin resistance, and inhibiting adipose tissue lipolysis improves obesity-related insulin resistance. Here, we demonstrate that inhibition of serotonin (5-hydroxytryptamine [5-HT]) signaling through serotonin receptor 2B (HTR2B) in adipose tissues ameliorates insulin resistance by reducing lipolysis in visceral adipocytes. Chronic high-fat diet (HFD) feeding increased Htr2b expression in epididymal white adipose tissue, resulting in increased HTR2B signaling in visceral white adipose tissue. Moreover, HTR2B expression in white adipose tissue was increased in obese humans and positively correlated with metabolic parameters. We further found that adipocyte-specific Htr2b-knockout mice are resistant to HFD-induced insulin resistance, visceral adipose tissue inflammation, and hepatic steatosis. Enhanced 5-HT signaling through HTR2B directly activated lipolysis through phosphorylation of hormone-sensitive lipase in visceral adipocytes. Moreover, treatment with a selective HTR2B antagonist attenuated HFD-induced insulin resistance, visceral adipose tissue inflammation, and hepatic steatosis. Thus, adipose HTR2B signaling could be a potential therapeutic target for treatment of obesity-related insulin resistance.
胰岛素抵抗是肥胖相关并发症的基石，如 2 型糖尿病、代谢综合征和非酒精性脂肪性肝病。已知脂肪分解率高与胰岛素抵抗有关，抑制脂肪组织脂肪分解可以改善肥胖相关的胰岛素抵抗。在这里，我们证明通过抑制脂肪组织中 5-羟色胺（5-羟色胺）信号转导受体 2B（HTR2B）来抑制 5-羟色胺信号转导可以通过减少内脏脂肪细胞的脂肪分解来改善胰岛素抵抗。慢性高脂肪饮食（HFD）喂养增加了附睾白色脂肪组织中 Htr2b 的表达，导致内脏白色脂肪组织中 HTR2B 信号转导增加。此外，肥胖人群的白色脂肪组织中 HTR2B 的表达增加，并且与代谢参数呈正相关。我们进一步发现，脂肪细胞特异性 Htr2b 敲除小鼠对 HFD 诱导的胰岛素抵抗、内脏脂肪组织炎症和肝脂肪变性具有抗性。通过 HTR2B 增强的 5-羟色胺信号直接通过内脏脂肪细胞中激素敏感脂肪酶的磷酸化激活脂肪分解。此外，选择性 HTR2B 拮抗剂的治疗可减轻 HFD 诱导的胰岛素抵抗、内脏脂肪组织炎症和肝脂肪变性。因此，脂肪组织 HTR2B 信号可能是治疗肥胖相关胰岛素抵抗的潜在治疗靶点。
