TMEM16A deficiency in hepatocytes inhibits HFD‐induced obesity and insulin resistance. A) Liver‐specific TMEM16A deletion mice (TMLKO) and control mice (TMFlox) were fed with chow diet or HFD for 32 weeks and then body weight was measured. *P < 0.05 versus TMFlox chow, #P < 0.05 versus TMFlox HFD, n = 14–18 per group. B,C) Adipose tissue depots iBAT and iWAT were analyzed for weight (B) and adipocyte size (C). Scale bar, 50 µm. #P < 0.05 versus TMFlox HFD, n = 6 per group. D–F) Hepatic glycogen content (D,E), fasting blood glucose, fasting insulin, and HOMA‐IR index (F) were measured in TMFlox and TMLKO mice on the indicated diet for 32 weeks. Scale bar, 50 µm. *P < 0.05 versus TMFlox chow, #P < 0.05 versus TMFlox HFD, n = 10 per group. G,H) GTT (G) and ITT (H) were performed on TMFlox mice and TMLKO mice after 32 weeks on chow diet or HFD. *P < 0.05 versus TMFlox chow, #P < 0.05 versus TMFlox HFD, n = 12 per group. AUC, area under the curve. I) Levels of IRS1 (Tyr608, Ser307), AKT (Ser473), and mTOR (Ser2448) phosphorylation in response to an intraperitoneal injection of insulin (1.0 IU kg−1 for 15 min) in the liver tissues of TMFlox and TMLKO mice after HFD treatment. #P < 0.05 versus TMFlox insulin, n = 6 per group.