title: High-fat diet-induced hepatic steatosis reduces glucagon receptor content in rat hepatocytes: potential interaction with acute exercise.
abstract: Studies have revealed that high-fat (HF) diets promote hyperglycaemia, whole-body insulin resistance and non-alcoholic fatty liver disease (NAFLD). Recently, hepatic glucagon resistance has been shown to occur in rats fed a HF diet. More precisely, diet-induced obesity (DIO) reduces the number of hepatic plasma membrane glucagon receptors (GR), which results in a diminished response to glucagon during a hyperglucagonaemic clamp. The present study was undertaken to test the hypothesis that a HF-DIO is associated with a desensitization and destruction of the hepatic GR. We also hypothesized that a single bout of endurance exercise would modify the GR cellular distribution under our DIO model. Male rats were either fed a standard (SD) or a HF diet for two weeks. Each group was subdivided into a non-exercised (Rest) and an acute exercised (EX) group. The HF diet resulted in a reduction of total hepatic GR (55%) and hepatic plasma membrane GR protein content (20%). These changes were accompanied by a significant increase in endosomal and lysosomal GR content with the feeding of a HF diet. The reduction of GR plasma membrane as well as the increase in endosomal GR was strongly correlated with an increase of PKC-alpha, suggesting a role of PKC-alpha in GR desensitization. EX increased significantly PKC-alpha protein content in both diets, suggesting a role of PKC-alpha in EX-induced GR desensitization. The present results suggest that liver lipid infiltration plays a role in reducing glucagon action in the liver through a reduction in total cellular and plasma membrane GR content. Furthermore, the GR desensitization observed in our in vivo model of HF diet-induced hepatic steatosis and in EX individuals may be regulated by PKC-alpha.
authors.affiliation: Department of Kinésiologie, Université de Montréal, Montréal, Québec, Canada. alexandre.charbonneau@crchul.ulaval.ca
authors.forename: Alexandre
authors.initials: A
authors.lastname: Charbonneau
authors.forename: Cecilia G
authors.initials: CG
authors.lastname: Unson
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Lavoie
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D004041:Dietary Fats / Q000494:pharmacology*; D011992:Endosomes / Q000378:metabolism; D005234:Fatty Liver / Q000378:metabolism* / Q000503:physiopathology*; D054769:G-Protein-Coupled Receptor Kinase 2; D006003:Glycogen / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006943:Hyperglycemia / Q000378:metabolism / Q000503:physiopathology; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology; D005082:Physical Exertion / Q000502:physiology*; D051571:Protein Kinase C-alpha / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018027:Receptors, Glucagon / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism; D051552:beta-Adrenergic Receptor Kinases / Q000378:metabolism
chemical_list: D004041:Dietary Fats; D018027:Receptors, Glucagon; D014280:Triglycerides; D006003:Glycogen; D051571:Protein Kinase C-alpha; C496569:Grk2 protein, rat; D051552:beta-Adrenergic Receptor Kinases; D054769:G-Protein-Coupled Receptor Kinase 2