Leptin Signaling in the Arcuate Nucleus Reduces Insulin’s Capacity to Suppress Hepatic Glucose Production in Obese Mice

Insulin action in the hypothalamus results in the suppression of hepatic glucose production (HGP). Obesity is often associated with a diminished response to insulin, leading to impaired suppression of HGP in obese mice. Here, we demonstrate that blocking central leptin signaling in diet-induced obese (DIO) mice restores the liver's ability to suppress glucose production. Leptin increases the expression of the insulin receptor phosphatase PTP1B, which is highly expressed in the hypothalamus of DIO mice. We demonstrate that the central pharmacological inhibition or ARH-targeted deletion of PTP1B restores the suppression of HGP in obese mice. Additionally, mice that lack PTP1B in AgRP neurons exhibit enhanced ARH insulin signaling and have improved glucose tolerance and insulin sensitivity. Overall, our findings indicate that obesity-induced increases in PTP1B diminish insulin action in the hypothalamus, resulting in unconstrained HGP and contributing to hyperglycemia in obesity.