title: Insulin and insulin signaling play a critical role in fat induction of insulin resistance in mouse.
abstract: The primary player that induces insulin resistance has not been established. Here, we studied whether or not fat can cause insulin resistance in the presence of insulin deficiency. Our results showed that high-fat diet (HFD) induced insulin resistance in C57BL/6 (B6) mice. The HFD-induced insulin resistance was prevented largely by the streptozotocin (STZ)-induced moderate insulin deficiency. The STZ-induced insulin deficiency prevented the HFD-induced ectopic fat accumulation and oxidative stress in liver and gastrocnemius. The STZ-induced insulin deficiency prevented the HFD- or insulin-induced increase in hepatic expression of long-chain acyl-CoA synthetases (ACSL), which are necessary for fatty acid activation. HFD increased mitochondrial contents of long-chain acyl-CoAs, whereas it decreased mitochondrial ADP/ATP ratio, and these HFD-induced changes were prevented by the STZ-induced insulin deficiency. In cultured hepatocytes, we observed that expressions of ACSL1 and -5 were stimulated by insulin signaling. Results in cultured cells also showed that blunting insulin signaling by the PI3K inhibitor LY-294002 prevented fat accumulation, oxidative stress, and insulin resistance induced by the prolonged exposure to either insulin or oleate plus sera that normally contain insulin. Finally, knockdown of the insulin receptor prevented the oxidative stress and insulin resistance induced by the prolonged exposure to insulin or oleate plus sera. Together, our results show that insulin and insulin signaling are required for fat induction of insulin resistance in mice and cultured mouse hepatocytes.
authors.affiliation: Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill,Chapel Hill, NC 27559, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Ning
authors.forename: Tao
authors.initials: T
authors.lastname: Hong
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Yang
authors.forename: Shuang
authors.initials: S
authors.lastname: Mei
authors.forename: Zhenqi
authors.initials: Z
authors.lastname: Liu
authors.forename: Hui-Yu
authors.initials: HY
authors.lastname: Liu
authors.forename: Wenhong
authors.initials: W
authors.lastname: Cao
mesh_terms: D000214:Acyl Coenzyme A / Q000378:metabolism; D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000273:Adipose Tissue / Q000502:physiology*; D000818:Animals; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D008113:Liver Neoplasms; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009765:Obesity / Q000378:metabolism* / Q000503:physiopathology; D034741:RNA, Small Interfering / Q000494:pharmacology; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D000214:Acyl Coenzyme A; D002867:Chromones; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D007328:Insulin; D009025:Morpholines; D034741:RNA, Small Interfering; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D011972:Receptor, Insulin