Inhibiting serotonin signaling through HTR2B in visceral adipose tissue improves obesity-related insulin resistance
Won Gun Choi, … , Sung Hee Choi, Hail Kim
Won Gun Choi, … , Sung Hee Choi, Hail Kim
Published October 7, 2021
Citation Information: J Clin Invest. 2021;131(23):e145331. https://doi.org/10.1172/JCI145331.
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Research Article Cell biology Metabolism

Inhibiting serotonin signaling through HTR2B in visceral adipose tissue improves obesity-related insulin resistance

Abstract

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.

Authors

Won Gun Choi, Wonsuk Choi, Tae Jung Oh, Hye-Na Cha, Inseon Hwang, Yun Kyung Lee, Seung Yeon Lee, Hyemi Shin, Ajin Lim, Dongryeol Ryu, Jae Myoung Suh, So-Young Park, Sung Hee Choi, Hail Kim

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Figure 7

Pharmacological inhibition of HTR2B improves HFD-induced metabolic dysfunction.

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Pharmacological inhibition of HTR2B improves HFD-induced metabolic dysfu...
(A–M) Twelve-week-old mice were fed a HFD for 10 weeks and treated with vehicle or SB 204741 daily via i.p. injection for 3 weeks while continuing HFD feeding. (A) IPGTTs of HFD-fed vehicle and SB 204741–treated mice (n = 6/group). (B) Plasma insulin levels in HFD-fed mice treated with vehicle or SB 204741 (n = 6/group). (C) Representative eWAT histology in HFD-fed mice treated with SB 204741, as assessed by H&E staining. Scale bars: 100 μm. (D) Histogram showing the distribution of adipocyte frequency according to diameter (vehicle, n = 4; SB 204741, n = 5, 5 images per mouse) (E) IF staining for perilipin 1 (red) and F4/80 (green) in eWAT from HFD-fed mice treated with vehicle or SB 204741, and counterstaining of nuclei with DAPI (blue). (F) F4/80 mRNA expression in SVF isolated from eWAT, as assessed by qRT-PCR (vehicle, n = 6; SB 204741, n = 6). (G–I) Relative expression of mRNA for genes involved in proinflammatory pathways in adipocytes and SVF isolated from eWAT, as assessed by qRT-PCR (n = 6/group). (J) Plasma FFA levels (n = 6/group). (K) Representative liver histology in HFD-fed mice treated with vehicle or SB 204741, as assessed by H&E staining. Scale bars: 100 μm. (L) Hepatic TG levels (n = 6/group). (M) Plasma AST and ALT levels (n = 6/group). Data are expressed as mean ± SEM (*P < 0.05, **P < 0.01, ***P < 0.001, Student’s t test used in A, B, D, F–J, L, and M).