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This Article Full Text Full Text (PDF) All Versions of this Article: 579/1/255    most recent jphysiol.2006.121954v2 jphysiol.2006.121954v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Charbonneau, A. Articles by Lavoie, J.-M. Search for Related Content PubMed PubMed Citation Articles by Charbonneau, A. Articles by Lavoie, J.-M. Related Collections Integrative

¹ Département de Kinésiologie, Université de Montréal, Montréal, Québec, Canada H3C 3J7
² Laboratory of Molecular Biology and Biochemistry, The Rockefeller University, New York, NY 10021, USA

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

(Received 28 September 2006; accepted after revision 18 October 2006; first published online 19 October 2006)
Corresponding author A. Charbonneau: Center for Lipid Research, CHUL Research Center, 2705, boulevard Laurier, Sainte-Foy, Quebec, Canada G1V 4G2. Email: alexandre.charbonneau{at}crchul.ulaval.ca