Hypothalamic mechanisms underlying the cardiovascular and metabolic actions of leptin

Obesity is a global health crisis. As the second-leading cause of preventable death in the United States, obesity is a major public health concern primarily because it is a risk factor for numerous co-morbid conditions including cardiovascular disease. The mechanisms underlying the relationship between obesity and hypertension are not fully understood, but previous research has implicated inappropriate actions of the hormone leptin. Leptin circulates in proportion to fat mass and acts on the brain as a signal of energy reserve status, serving as a negative feedback mechanism to prevent excess weight gain by suppressing food intake and increasing energy expenditure, in part through activation of the sympathetic nervous system. Leptin also increases sympathetic nerve activity to a number of tissues involved in cardiovascular regulation. During obesity, patients become resistant to the beneficial metabolic actions of leptin while remaining sensitive to the cardiovascular effects, demonstrating that the mechanisms underlying these processes are somehow distinct. Using genetically modified mouse models to disrupt specific aspects of leptin action, we identified several processes that explain the ability of leptin to differentially control the functions of various tissues. Our findings provide unique insight into the relationship between obesity and hypertension and suggest that the molecular mechanisms linking these diseases could be targeted therapeutically.