Liver Adenosine Monophosphate-Activated Kinase-α2 Catalytic Subunit Is a Key Target for the Control of Hepatic Glucose Production by Adiponectin and Leptin But Not Insulin

Abstract

The AMP-activated kinase (AMPK) is a serine threonine kinase that functions as a fuel sensor to regulate energy balance at both cellular and whole-body levels. Here we studied how hepatic AMPKalpha2 isoform affects hepatic glucose production and peripheral glucose uptake in vivo. We generated mice deleted for the AMPKalpha2 gene specifically in the liver (liveralpha2KO). Liveralpha2KO mice were glucose intolerant and hyperglycemic in the fasted state. Hyperglycemia was associated with a 50% higher endogenous glucose production than in controls as assessed in vivo. We then investigated whether this increased glucose production was sensitive to insulin. Insulin, when infused at a rate inducing physiological hyperinsulinemia, totally inhibited endogenous glucose production in liveralpha2KO mice, showing that they had normal insulin sensitivity. This was confirmed in vivo by normal insulin-induced phosphorylation of Akt and transcriptional regulation of the phosphoenolpyruvate carboxykinase, glucose-6 phosphatase, and pyruvate kinase in liver during the fasted/fed transition. Leptin and adiponectin regulate hepatic glucose production, so we then infused these adipokines into liveralpha2KO mice. Neither of these adipokines regulated hepatic glucose production in mice lacking hepatic AMPKalpha2, whereas both did so in control mice. In conclusion, we show that the hepatic AMPKalpha2 isoform is essential for suppressing hepatic glucose production and maintaining fasting blood glucose levels in the physiological range. We also demonstrate that regulation of hepatic glucose production by leptin and adiponectin, but not insulin, requires hepatic AMPKalpha2 activity.

Changes in milk performance and hepatic metabolism in mid-lactating dairy goats after being fed a high concentrate diet for 10 weeks

“…acetate) (van Knegsel et al, 2005). In this study, plasma cholesterol and LDL-C concentrations were significantly increased in HC goats, but plasma TG concentration was markedly decreased in HC group, which might be associated with an increase of AMPK activity in the liver (Andreelli et al, 2006). AMPK is a nutrient and energy sensor that controls energy homeostasis involved in glucose and lipid metabolism (Hardie et al, 2012).…”

Adiponectin as a tissue regenerating hormone: more than a metabolic function

“…AMPK plays an essential role in the decrease of glucose production since AMPK activation by adiponectin in both isolated hepatocytes and in murine liver in vivo was associated with a reduction of circulating glucose levels [24]. In addition, adiponectin-mediated regulation of hepatic glucose production is abolished in a liver-specific AMPK knockout mouse model [36]. Although the true mechanism underlying the insulin-sensitization of adiponectin in liver has not been yet defined, it is reported that fAd enhances hepatic insulin sensitivity through the up-regulation of insulin receptor substrate-2 (IRS-2) via the macrophage-secreted interleukin-6 [37].…”

AMP-activated protein kinase (AMPK) activity is not required for neuronal development but regulates axogenesis during metabolic stress

“…However, to date there is no published evidence reporting the consequence of a genetic loss of function for the catalytic activity of mammalian AMPK in the mammalian nervous system. To assess the role of AMPKα during cortical development, we used transgenic mice that were ubiquitously inactivated for the AMPKα1 gene (AMPKα1 −/− ) (11) and conditionally inactivated for AMPKα2 (AMPKα2 F/F ) (12,13). AMPKα2 was selectively deleted using the Emx1 Cre mouse line, which induces recombination only in dorsal telencephalic progenitors giving rise to all pyramidal projection neurons in the cortex, but not in ventral telencephalon-derived cortical GABAergic interneurons, which constitutes ∼25% of all cortical neurons (14).…”