Joseph (Yossi) Tam D.M.D., Ph.D.

There is a strong evidence to support the concept that leptin resistance is an important component in the development of obesity and its related metabolic consequences. Leptin resistance is referring to the reduced ability of circulating leptin to suppress feeding, induce weight loss and restore normal energy and metabolic homeostasis in obese animals and humans. As leptin resistance results in obesity and its related metabolic abnormalities, therapeutics, which can resensitize the obese to leptin would have considerable therapeutic value. To date, the underlying molecular mechanisms responsible for the pathogenesis of leptin resistance are largely unknown, and therefore the development of effective interventions to attenuate its development remains a challenging clinical problem.

My recent findings have provided strong evidence for a functional role of the endocannabinoid (eCB) system in potentially regulating obesity-related leptin resistance. Briefly, chronic cannabinoid type-1 (CB1) receptor blockade in peripheral tissues reduces leptin resistance in obese mice by rapidly reversing their hyperleptinemia.

The purpose of this project is to further uncover the molecular mechanisms by which the peripheral eCB system contributes to the development of leptin resistance, obesity and its related metabolic complications. We, therefore, aim to demonstrate that the peripheral eCB system and CB1 receptors are important modulators of leptin signaling in obesity. This project is expected to further lead to the development and clinical testing of pharmacological strategies, such as peripheral CB1 receptor antagonists. By re-sensitizing the obese to the anorectic and antisteatotic effect of leptin, these drugs could be considered for the treatment of not only obesity per-se but also to its related metabolic consequences.

Key words: Obesity, Leptin resistance, Endocannabinoids, CB1 receptor, Peripheral CB1 blockade, weight loss