title: Leptin contributes to the adaptive responses of mice to high-fat diet intake through suppressing the lipogenic pathway.
abstract: BACKGROUND
  Leptin is an adipocyte-derived hormone that plays a critical role in energy homeostasis and lipid metabolism. Overnutrition-associated obesity is known to be accompanied by hyperleptinemia. However, the physiological actions of leptin in the metabolic responses to high-fat diet (HFD) intake remain to be completely elucidated. Here we characterized the metabolic features of mice fed high-fat diets and investigated the impact of leptin upon the lipogenic program which was found to be suppressed by HFD feeding through a proteomics approach.
  
  
  RESULTS
  When maintained on two types of high-fat diets for up to 16 weeks, mice with a higher fat intake exhibited increased body fat accumulation at a greater pace, developing more severely impaired glucose tolerance. Notably, HFD feeding at 4 weeks elicited the onset of marked hyperleptinemia, prior to the occurrence of apparent insulin resistance and hyperinsulinemia. Proteomic analysis revealed dramatically decreased expression of lipogenic enzymes in the white adipose tissue (WAT) from HFD-fed mice, including ATP-citrate lyase (ACL) and fatty acid synthase (FAS). The expression of ACL and FAS in the liver was similarly suppressed in response to HFD feeding. By contrast, HFD-induced downregulation of hepatic ACL and FAS was significantly attenuated in leptin receptor-deficient db/db mice. Furthermore, in the liver and WAT of wild type animals, intraperitoneal leptin administration was able to directly suppress the expression of these two lipogenic enzymes, accompanied by reduced triglyceride levels both in the liver and serum.
  
  
  CONCLUSIONS
  These results suggest that leptin contributes to the metabolic responses in adaptation to overnutrition through suppressing the expression of lipogenic enzymes, and that the lipogenic pathway represents a key targeted peripheral component in exerting leptin's liporegulatory actions.
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Jiang
authors.forename: Qiong
authors.initials: Q
authors.lastname: Wang
authors.forename: Yue
authors.initials: Y
authors.lastname: Yu
authors.forename: Feng
authors.initials: F
authors.lastname: Zhao
authors.forename: Ping
authors.initials: P
authors.lastname: Huang
authors.forename: Rong
authors.initials: R
authors.lastname: Zeng
authors.forename: Robert Z
authors.initials: RZ
authors.lastname: Qi
authors.forename: Wenjun
authors.initials: W
authors.lastname: Li
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000818:Animals; D004041:Dietary Fats; D007333:Insulin Resistance; D020738:Leptin / Q000378:metabolism / Q000502:physiology*; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D009765:Obesity / Q000378:metabolism; D040901:Proteomics / Q000379:methods; D054411:Receptors, Leptin / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction
chemical_list: D004041:Dietary Fats; D020738:Leptin; D054411:Receptors, Leptin