Since the discovery of leptin 23 years ago, a major challenge to weight loss strategies in obesity is leptin resistance. The lack of response to exogenous leptin administration in obesity is not only an obstacle to energy homeostasis regulation, but it could also be involved in the type 2 diabetic phenotype associated with obesity.
Our previous work in vivo and ex vivo with diet-induced obese mice (DIO) suggested that contrary to expectations, leptin signalling remains functional and is permanently activated in arcuate nucleus of the hypothalamus (ARH) neurons of DIO mice. This state of constant response to endogenous leptin underpins the lack of response to exogenous leptin. The obese phenotype of DIO mice is also associated to glucose intolerance, caused by a decreased sensitivity to insulin. The immunohistochemistry study of combined leptin and insulin signalling leads us to conclude that there is a common pool of ARH neurons responding to both leptin and insulin.
We then hypothesized that the constant activation of LepRb-neurons in the ARH of DIO mice could prevent insulin signalling in these neurons, leading to impaired glucose homeostasis and type 2 diabetes.
Accordingly, immunohistochemistry and hyperinsulinemic euglycemic clamps experiments demonstrated that antagonizing central leptin signalling in DIO mice restores hypothalamic insulin signalling and decreases hepatic glucose production. Using icv injection of inhibitors and ARH specific gene deletion, we identified protein phosphatase 1B (PTP1B) as the main mechanism by which the constant leptin signalling inhibits insulin response in ARH neurons of DIO mice.
Altogether our results bring new insights in obesity-linked central insulin resistance and open a potential new path of therapeutic strategy to treat type 2 diabetes in obese patients.