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Obesity is a leading cause of diabetes mellitus and hypertension, which are both important risk factors for cardiovascular diseases. In the past 5 years, I have been focused on understanding the mechanisms that contribute to the development of obesity-induced hypertension. We have dedicated special attention to the role of leptin, a hormone secreted primarily by adipocytes that plays a major role in appetite and body weight regulation.
We have shown, for example, that increasing leptin levels in lean animals to those found in obesity leads to sustained increases in arterial pressure and heart rate (HR). In addition, we showed that these pressor actions of leptin are dependent of peripheral adrenergic receptor activation and requires a functional central nervous system (CNS) melanocortin pathway, since blockade of the brain melanocortin 3 and 4 receptors (MC3/4-R) or adrenergic blockade completely abolished the chronic cardiovascular actions of leptin.
Our most recent studies also demonstrated that leptin not only plays a major role in the regulation of appetite and cardiovascular function but it also has a powerful action, mediated by the CNS, to fully restore euglycemia in streptozotocin-induced diabetic rats. In addition to the normalization of blood glucose levels, chronic intracerebroventricular leptin infusion also reversed the hyperphagia and the cardiovascular disturbances associated with uncontrolled diabetes such as bradycardia, impaired baroreceptor sensitivity, reduced intrinsic HR, increased HR variability and reduced cardiac sympathetic tonus.
Although most of the cardiovascular effects or leptin are mediated by activation of the sympathetic nervous system, chronic adrenergic receptor blockade did not impair leptin’s ability to reduce glucose levels in these insulin-deficient diabetic animals, and the mechanisms responsible for the CNS actions of leptin on peripheral glucose homeostasis are still largely unknown.
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