Diet Supplementation of Luteolin before Fatty Liver Formation Improves Hepatic Steatosis in Obese Mice by Inhibiting Visceral Adipose Tissue Lipolysis

Scope Serotonin (5‐HT)‐induced visceral adipocyte lipolysis is essential for the development of obesity‐related complications. Diet supplementation of luteolin prevents high‐fat diet (HFD)‐fed mice against obesity and associated fatty liver. However, independent of the body weight loss, whether dietary luteolin can substantially reduce hepatic steatosis remains unclear. Methods and results In differentiated 3T3‐L1 cells, 5‐HT treatment promotes adipocyte lipolysis, while luteolin significantly inhibits 5‐HT‐induced lipolysis, Ca 2+ ‐PKG cascade, and SIRT1/FoxO1/AMPKα signaling through binding to 5‐HT receptor HTR2B. Further, 5‐week‐old mice are fed with an HFD for 16 weeks. At the 6th, 8th, or 10th weeks of HFD feeding, some mice are switched to a luteolin‐containing HFD, respectively. In all HFD‐fed mice, body weight gain and body component are unaffected by dietary luteolin. However, diet supplementation of luteolin at the 6th or 8th, rather than at the 10th weeks, alleviates hepatic steatosis. Meanwhile, dietary luteolin reduces epididymal adipose tissue (EAT) lipolysis, and represses the level of lipolytic enzyme, the expression of Htr2b , and the activation of PKG and SIRT1/FoxO1/AMPKα signaling in EAT. Conclusions Diet supplementation of luteolin before the formation of fatty liver protects HFD‐fed mice against ectopic lipid deposition in liver by inhibiting visceral adipocyte lipolysis.