Role of the peripheral endocannabinoid system in leptin resistance

Leptin, expressed in and secreted by adipocytes proportionally to their size and number, reduces food intake and lipogenesis as well as increases sympathetic tone and energy homeostasis through activation of its hypothalamic receptor. In obese humans and animals, the failure of the elevated leptin levels to restore energy and metabolic homeostasis indicates ‘leptin resistance’. Besides a peripheral form of leptin resistance due to decreased transport of circulating leptin through the blood-brain-barrier (BBB), there is also central leptin resistance due to chronic overstimulation of the leptin receptor.

 

The molecules and signaling pathways responsible for the development of leptin resistance are largely unknown, but would be attractive targets for anti-obesity therapy. Recently, we have demonstrated that the endocannabinoid system regulates the obesity-related hyperleptinemia, and that peripheral CB1 receptor blockade increases leptin sensitivity in obese mice.

 

In an effort to further understand the molecular mechanisms underlying the development of leptin resistance and its reversal by peripheral CB1 receptor blockade, our current efforts are aimed to further elucidate the central leptin signaling pathways activated by peripheral CB1 antagonism, and uncover the role of the hepatic endocannabinoid system in the regulation of leptin resistance.

 

Role of the endocannabinoid system in the development of obesity in Prader-Willi syndrome (PWS)

Prader-Willi syndrome (PWS), a rare genetic disorder that is caused by the loss of paternal inherited imprinted cluster of genes at human chromosome 15q11-q13, is primarily characterized by childhood-onset hyperphagia and extreme obesity, which are the major medical problems associated this disease. Many studies have tried to identify the molecular mechanisms that lead to the development of obesity in PWS; yet, no direct or indirect link has been established between either genetic or hormonal dysfunction related to PWS, and consequently no pharmacological treatment is available for treating obesity in these patients.

 

Among the numerous appetite regulators, endocannabinoids appear to be critically involved in the regulation of appetite, body weight and metabolism. By using both human clinical data and animal models that recapitulate major features of PWS, we aim to identify a role for the endocannabinoid system in the development of obesity and altered metabolism in PWS. This would pave the way to the development and clinical testing of novel pharmacological strategies to combat obesity and its devastating consequences in PWS. Additionally, results obtained under this research topic would contribute to our understanding of mechanisms related to “syndromic obesity” and other obesity-related rare diseases (such as Alström syndrome) with the consequent development of new therapies.