Proper control of hepatic glucose production is central to whole body glucose homeostasis and its disruption plays a major role in diabetes. Here we demonstrate that, although established as an intracellular lipid chaperone, aP2 is in fact actively secreted from adipocytes to regulate liver glucose metabolism. Fasting and lipolysisrelated signals regulate secretion of aP2 from adipocytes, and circulating aP2 levels are markedly elevated in mouse and human obesity. Recombinant aP2 stimulates glucose production and gluconeogenic activity in primary hepatocytes in vitro and in lean mice in vivo. In contrast, neutralization of secreted aP2 reduces glucose production and corrects the diabetic phenotype of obese mice. Hyperinsulinemiceuglycemic and pancreatic clamp studies demonstrated actions of aP2 in liver upon aP2 administration or neutralization. We conclude that aP2 is a novel adipokine linking adipocytes to hepatic glucose production and that neutralizing secreted aP2 may represent an effective therapeutic strategy for diabetes.

The lipid chaperone aP2/FABP4 has been implicated in the pathology of many immunometabolic diseases, including diabetes in humans, but aP2 has not yet been targeted for therapeutic applications. aP2 is not only an intracellular protein but also an active adipokine that contributes to hyperglycemia by promoting hepatic gluconeogenesis and interfering with peripheral insulin action. Serum aP2 levels are markedly elevated in mouse and human obesity and strongly correlate with metabolic complications. These observations raise the possibility of a new strategy to treat metabolic disease by targeting serum aP2 with a monoclonal antibody (mAb) to aP2. We evaluated mAbs to aP2 and identified one, CA33, that lowered fasting blood glucose, improved systemic glucose metabolism, increased systemic insulin sensitivity, and reduced fat mass and liver steatosis in obese mouse models. We examined the structure of the aP2-CA33 complex and resolved the target epitope by crystallographic studies in comparison to another mAb that lacked efficacy in vivo. In hyperinsulinemic-euglycemic clamp studies, we found that the antidiabetic effect of CA33 was predominantly linked to the regulation of hepatic glucose output and peripheral glucose utilization. The antibody had no effect in aP2-deficient mice, demonstrating its target specificity. We conclude that an aP2 mAb-mediated therapeutic constitutes a feasible approach for the treatment of diabetes.

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Ethnobotanical surveys have shown that the stem bark of Hancornia speciosa Gomes (Apocynaceae) is popularly used to treat obesity and diabetes. However, there is no experimental evidence that confirms such use. The present study investigated the effects of the aqueous extract of the stem bark of H. speciosa (AEHS) on the glycemic and adipogenic profiles of obese mice. Mice were divided into four groups that received standard diet (SD), standard diet plus AEHS (SDE), high-fat diet (HD) and high-fat diet plus AEHS (HDE). The administration of AEHS (in a concentration of 0.3 mg.mL-1. ad libitum in the drinking water) was performed for the last 8 weeks totaling a period of 18 weeks, in which the animals received the diets. Whole body weight, liquid intake and food consumption were measured during the entire experiment. Blood glucose levels, insulin sensitivity, glucose tolerance and adipose pads weight were evaluated. Animals from the HD group presented higher body weight in comparison to animals from the SD group. That was associated with insulin resistance and glucose intolerance, as well as increased blood glucose levels (p < 0.05) and weight of adipose tissue pad (p < 0.05), when compared to the SD group. The treatment with AEHS did not alter obesity induced by high-fat diet, because no significant difference was observed between the HD and the HDE groups in all of the parameters evaluated. These findings allowed the conclusion that AEHS does not reverse the alterations caused by high-fat diet in mice, what goes against the popular use.