High-fat diet-induced hepatic steatosis reduces glucagon receptor content in rat hepatocytes: potential interaction with acute exercise

• Published in: The Journal of physiology 2007-02, Vol.579 (1), p.255-267
• Main Authors: Charbonneau, Alexandre, Unson, Cecilia G., Lavoie, Jean‐Marc
• Format: Article
• Language: English
• Subjects: Animals; beta-Adrenergic Receptor Kinases - metabolism; Cell Membrane - metabolism; Dietary Fats - pharmacology; Endosomes - metabolism; Fatty Liver - metabolism; Fatty Liver - physiopathology; G-Protein-Coupled Receptor Kinase 2; Glycogen - metabolism; Hepatocytes - metabolism; Hyperglycemia - metabolism; Hyperglycemia - physiopathology; Integrative; Lysosomes - metabolism; Male; Obesity - metabolism; Obesity - physiopathology; Physical Exertion - physiology; Protein Kinase C-alpha - metabolism; Rats; Rats, Sprague-Dawley; Receptors, Glucagon - metabolism; Triglycerides - metabolism
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/jphysiol.2006.121954

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-α, suggesting a role of PKC-α in GR desensitization. EX increased significantly PKC-α protein content in both diets, suggesting a role of PKC-α 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-α.