title: Dissociation of hepatic insulin resistance from susceptibility of nonalcoholic fatty liver disease induced by a high-fat and high-carbohydrate diet in mice.
abstract: Liver steatosis in nonalcoholic fatty liver disease is affected by genetics and diet. It is associated with insulin resistance (IR) in hepatic and peripheral tissues. Here, we aimed to characterize the severity of diet-induced steatosis, obesity, and IR in two phylogenetically distant mouse strains, C57BL/6J and DBA/2J. To this end, mice (male, 8 wk old) were fed a high-fat and high-carbohydrate (HFHC) or control diet for 16 wk followed by the application of a combination of classic physiological, biochemical, and pathological studies to determine obesity and hepatic steatosis. Peripheral IR was characterized by measuring blood glucose level, serum insulin level, homeostasis model assessment of IR, glucose intolerance, insulin intolerance, and AKT phosphorylation in adipose tissues, whereas the level of hepatic IR was determined by measuring insulin-triggered hepatic AKT phosphorylation. We discovered that both C57BL/6J and DBA/2J mice developed obesity to a similar degree without the feature of liver inflammation after being fed an HFHC diet for 16 wk. C57BL/6J mice in the HFHC diet group exhibited severe pan-lobular steatosis, a marked increase in hepatic triglyceride levels, and profound peripheral IR. In contrast, DBA/2J mice in the HFHC diet group developed only a mild degree of pericentrilobular hepatic steatosis that was associated with moderate changes in peripheral IR. Interestingly, both C57BL/6J and DBA/2J developed severe hepatic IR after HFHC diet treatment. Collectively, these data suggest that the severity of diet-induced hepatic steatosis is correlated to the level of peripheral IR, not with the severity of obesity and hepatic IR. Peripheral rather than hepatic IR is a dominant factor of pathophysiology in nonalcoholic fatty liver disease.
authors.affiliation: Center for Intestinal and Liver Inflammation Research, Ann & Robert H. Lurie Children's Hospital of Chicago Research Center and.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Asai
authors.forename: Pauline M
authors.initials: PM
authors.lastname: Chou
authors.forename: Heng-Fu
authors.initials: HF
authors.lastname: Bu
authors.forename: Xiao
authors.initials: X
authors.lastname: Wang
authors.forename: M Sambasiva
authors.initials: MS
authors.lastname: Rao
authors.forename: Anthony
authors.initials: A
authors.lastname: Jiang
authors.forename: Christine J
authors.initials: CJ
authors.lastname: DiDonato
authors.forename: Xiao-Di
authors.initials: XD
authors.lastname: Tan
mesh_terms: D000818:Animals; D004040:Dietary Carbohydrates / Q000008:administration & dosage*; D004041:Dietary Fats / Q000008:administration & dosage*; D005234:Fatty Liver / Q000209:etiology / Q000503:physiopathology*; D005947:Glucose / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D065626:Non-alcoholic Fatty Liver Disease; D009765:Obesity / Q000209:etiology
chemical_list: D004040:Dietary Carbohydrates; D004041:Dietary Fats; D005947:Glucose
keywords: hepatic insulin resistance; insulin resistance; mice; nonalcoholic fatty liver disease; steatosis