Adiponectin serenades ceramidase to improve metabolism

Adiponectin and its signaling through the receptors AdipoR1 and AdipoR2 rank highly in the ongoing search for the holy grail that might improve insulin sensitivity, modulating inflammatory responses, and regulating energy metabolism in patients with obesity and/or Type 2 Diabetes (T2D). Adiponectin is secreted by adipose tissue and binds to its ubiquitously expressed receptors AdipoR1 and AdiopoR2. Overexpression of adiponectin promotes insulin action and improves insulin resistance as well as suppressing inflammatory responses. Over 15 years ago, Philipp Scherer and colleagues demonstrated that intraperitoneal injection of full-length adiponectin into mice reduced plasma glucose levels and suppressed gluconeogenesis, revealing the liver as a major target tissue of adiponectin [1]. Since then, many studies have tried to delineate the molecular mechanisms and signal transduction pathways behind this seemingly wonder adipokine, with a view to the development of novel therapeutics to treat T2D. In this issue of Molecular Metabolism, Holland and colleagues studied transgenic mouse models that over-express AdipoR1 and AdipoR2 in adipose tissue and liver to assess the impact of AdipoR signaling on glucose and lipid metabolism [2]. This is the first time the overexpression of the receptors could be controlled by using an inducible tetracycline element, which allowed the pathway to be switched on following full maturation. Holland et al.’s work focuses on the effects of enhanced ceramidase activity as a result of enhanced adiponectin signaling, supporting their previous work [3]. In the present study, they demonstrate that over-expression of AdiopR1 and AdipoR2 improves whole body glucose metabolism and hepatic insulin sensitivity and opposes hepatic steatosis in obesity. In their previous work, Holland and colleagues demonstrated that ceramide metabolism predominantly influenced the insulin-sensitizing effects of adiponectin on its primary target tissue, the liver [3]. In this recent publication, the authors extended this work by showing that over-expressing AdipoR1 and AdiopoR2 not only in liver but also in adipose tissue increased ceramidase activity in mesenteric and gonadal fat pads and liver lysates, respectively. When mice were challenged with a HFD for 8 weeks, switching on the over-expression of AdiopR1 and AdipoR2 in adipose tissue or liver resulted in improved glucose tolerance during OGTTs compared with littermate control mice (WT). The AdiopR1 and AdipoR2 mice also showed increased whole