Inducible overexpression of adiponectin receptors highlight the roles of adiponectin-induced ceramidase signaling in lipid and glucose homeostasis

Abstract

ObjectiveAdiponectin and the signaling induced by its cognate receptors, AdipoR1 and AdipoR2, have garnered attention for their ability to promote insulin sensitivity and oppose steatosis. Activation of these receptors promotes the deacylation of ceramide, a lipid metabolite that appears to play a causal role in impairing insulin signaling.MethodsHere, we have developed transgenic mice that overexpress AdipoR1 or AdipoR2 under the inducible control of a tetracycline response element. These represent the first inducible genetic models that acutely manipulate adiponectin receptor signaling in adult mouse tissues, which allows us to directly assess AdipoR signaling on glucose and lipid metabolism.ResultsOverexpression of either adiponectin receptor isoform in the adipocyte or hepatocyte is sufficient to enhance ceramidase activity, whole body glucose metabolism, and hepatic insulin sensitivity, while opposing hepatic steatosis. Importantly, metabolic improvements fail to occur in an adiponectin knockout background. When challenged with a leptin-deficient genetic model of type 2 diabetes, AdipoR2 expression in adipose or liver is sufficient to reverse hyperglycemia and glucose intolerance.ConclusionThese observations reveal that adiponectin is critical for AdipoR-induced ceramidase activation which enhances hepatic glucose and lipid metabolism via rapidly acting “cross-talk” between liver and adipose tissue sphingolipids.

Roles of Diacylglycerols and Ceramides in Hepatic Insulin Resistance

“…Despite decreased hepatic triglycerides, hepatic DAG concentrations were reported to be increased in the transgenic mice — an unusual dissociation [61]. Similar findings of protection from hepatosteatosis and hepatic insulin resistance in association with decreased hepatic ceramides were recently reported in mice with adipose- or liver-specific inducible adiponectin receptor overexpression [96]. In summary, mouse models of altered ceramide synthesis appear to develop complex and sometimes dramatic changes in hepatic lipids.…”

Acute loss of adipose tissue-derived adiponectin triggers immediate metabolic deterioration in mice

“…This is consistent with our recent observations that APN receptor overexpression in liver or adipose tissue triggers rapid reductions in tissue and plasma ceramide levels. These effects of the receptors are strictly dependent on the presence of APN [7]. Furthermore, recent structural insights into the APN receptors point directly at a receptor-inherent ceramidase activity and further highlights the sphingolipid axis as a major primary mediator of APN effects [28, 29].…”

“…Although profound beneficial metabolic effects of gain-of-function Adipoq (encoding APN) models have been demonstrated through both the Δgly model and, more recently, overexpression of APN receptors [6, 7], loss-of-function models of Adipoq have had varying outcomes regarding metabolic phenotype. Studies by Kubota et al and Maeda et al showed mild-to-moderate insulin resistance and glucose intolerance in APN-deficient mice [8, 9].…”

Contribution of Adipose Tissue Inflammation to the Development of Type 2 Diabetes Mellitus

“…In the liver, adiponectin improves insulin sensitivity with an accompanying reduction in gluconeogenesis. In addition, work from Holland and colleagues revealed a direct role for adiponectin signaling in regulation of cellular ceramide levels (184, 185). These in vitro and in vivo studies revealed that both AdipoR1 and AdipoR2 exhibit ceramidase activity that is enhanced by adiponectin and reduces cellular ceramide concentration (184, 185).…”

“…In addition, work from Holland and colleagues revealed a direct role for adiponectin signaling in regulation of cellular ceramide levels (184, 185). These in vitro and in vivo studies revealed that both AdipoR1 and AdipoR2 exhibit ceramidase activity that is enhanced by adiponectin and reduces cellular ceramide concentration (184, 185). Consistent with these data, crystal structures of both AdipoR1 and AdipoR2 suggest they possess intrinsic ceramidase activity (487).…”