While extreme obesity and hyperphagia are well recognized as core phenotypic features of Prader-Willi syndrome (PWS), the underlying molecular mechanisms are largely unknown. The endocannabinoid (eCB) system is critically involved in the control of feeding and body weight and cannabinoid type-1 (CB1) receptor blockade in central and/or peripheral tissues reduces food intake and reverses obesity. Interestingly, the first-in-class CB1 antagonist, rimonabant, was found to be effective in inducing weight loss in adults with PWS. However, rimonabant is no longer available due to its centrally-mediated neuropsychiatric side-effects.
The goal of this research project is to elucidate the contribution of the peripheral eCB system to the development of obesity in PWS. Peripheral CB1 blockade has been proven effective in reducing food intake and body weight via reversing the hyperleptinemia and leptin resistance in diet-induced obesity and without causing CNS-mediated side effects. Reversal of leptin resistance occurs by reducing leptin production and release from adipocytes and increase leptin elimination via the kidney.
Here, we propose: (1) to determine the presence and degree of hypothalamic leptin resistance; (2) to measure the expression, activity and tissue levels of the different elements of the peripheral eCB system; and (3) to compare the efficacy of global vs. peripheral CB1 blockade in reducing body weight and adiposity. These studies will be conducted in an established mouse model for obesity in PWS, Magel2-null mice. These mice develop increased adiposity as they age and have defects in hypothalamic function.
The rationale for the proposed research is that such evaluation has the potential to translate into better understanding of the causes of obesity in PWS and therefore identifying potential novel sites that can be targeted for therapy. The proposed research is significant, because these studies are expected to lead to the development and clinical testing of novel pharmacological strategies, such as peripherally restricted CB1 receptor antagonists for the treatment of obesity in PWS.
Key words: Prader-Willi Syndrome, Syndromic Obesity, Leptin resistance, CB1 receptor blockade, Endocannabinoids, Food intake, Weight loss