Obesity is associated with intrahepatic
inflammation that promotes
insulin resistance and
type 2 diabetes.
Tumor necrosis factor receptor-associated factor (TRAF)2 is a key adaptor molecule that is known to mediate proinflammatory
cytokine signaling in immune cells; however, its metabolic function remains unclear. We examined the role of hepatic
TRAF2 in the regulation of
insulin sensitivity and
glucose metabolism.
TRAF2 was deleted specifically in hepatocytes using the Cre/loxP system. The mutant mice were fed a high-fat diet (HFD) to induce
insulin resistance and
hyperglycemia. Hepatic
glucose production (HGP) was examined using
pyruvate tolerance tests, (2)H nuclear magnetic resonance spectroscopy, and in vitro HGP assays. The expression of gluconeogenic genes was measured by quantitative real-time PCR.
Insulin sensitivity was analyzed using
insulin tolerance tests and
insulin-stimulated phosphorylation of
insulin receptors and Akt.
Glucagon action was examined using
glucagon tolerance tests and
glucagon-stimulated HGP, cAMP-responsive
element-binding (CREB) phosphorylation, and expression of gluconeogenic genes in the liver and primary hepatocytes. Hepatocyte-specific
TRAF2 knockout (HKO) mice exhibited normal body weight,
blood glucose levels, and
insulin sensitivity. Under HFD conditions,
blood glucose levels were significantly lower (by >30%) in HKO than in control mice. Both
insulin signaling and the
hypoglycemic response to
insulin were similar between HKO and control mice. In contrast,
glucagon signaling and the hyperglycemic response to
glucagon were severely impaired in HKO mice. In addition,
TRAF2 overexpression significantly increased the ability of
glucagon or a cAMP analog to stimulate CREB phosphorylation, gluconeogenic gene expression, and HGP in primary hepatocytes. These results suggest that the hepatic
TRAF2 cell autonomously promotes hepatic gluconeogenesis by enhancing the hyperglycemic response to
glucagon and other factors that increase cAMP levels, thus contributing to
hyperglycemia in
obesity.