The hypothalamus is a critical regulator of
glucose metabolism and is capable of correcting diabetes conditions independently of an effect on energy balance. The
small GTPase Rap1 in the forebrain is implicated in high-fat diet-induced (HFD-induced)
obesity and
glucose imbalance. Here, we report that increasing Rap1 activity selectively in the medial hypothalamus elevated
blood glucose without increasing the
body weight of HFD-fed mice. In contrast, decreasing hypothalamic Rap1 activity protected mice from diet-induced
hyperglycemia but did not prevent
weight gain. The remarkable glycemic effect of Rap1 was reproduced when Rap1 was specifically deleted in steroidogenic factor-1-positive (SF-1-positive) neurons in the ventromedial hypothalamic nucleus (VMH) known to regulate
glucose metabolism. While having no effect on
body weight regardless of sex, diet, and age, Rap1 deficiency in the VMH SF1 neurons markedly lowered
blood glucose and
insulin levels, improved
glucose and
insulin tolerance, and protected mice against HFD-induced neural
leptin resistance and peripheral
insulin resistance at the cellular and whole-body levels. Last, acute pharmacological inhibition of brain exchange
protein directly activated by cAMP 2, a direct activator of Rap1, corrected
glucose imbalance in obese mouse models. Our findings uncover the primary role of VMH Rap1 in
glycemic control and implicate Rap1 signaling as a potential target for therapeutic intervention in diabetes.