Increased leptin supply to hypothalamus by gene therapy confers life-long benefits on energy homeostasis, disease cluster of metabolic syndrome- diabetes type 1 and 2, dyslipidemia and cardiovascular ailments- and bone remodeling

Abstract

Leptin insufficiency in the hypothalamus is causally linked to increased fat accrual, diseases of the metabolic syndrome, skeletal abnormalities and shortened life-span. We show that leptin sufficiency attained with hypothalamic leptin gene therapy (i) suppressed food intake, the age-related and energy enriched diet-induced fat accrual, and dyslipidemia, (ii) attenuated episodic insulin secretion and enhanced insulin sensitivity, (iii) enhanced glucose tolerance and maintained euglycemia by concurrently stimulating glucose metabolism and non-shivering thermogenesis, even in the absence of circulating insulin, and (iv) augmented ghrelin secretion. Aside from these metabolic benefits, similar optimal leptin sufficiency in the hypothalamus (i) decreased risks for cardiovascular diseases as indicated by suppression of circulating levels of the systemic proinflammatory markers, C-reactive protein and interleukin-6, and hyperglycemia-induced risk factors for cardiomyopathy, (ii) improved bone health by promoting growth of long bones and reduction of cancellous bone volume in association with increased release of osteoblast-specific osteocalcin, and (111) reduced early mortality and doubled the life-span of obese ob/ob mice. On the basis of these global long-lasting health benefits, we advocate clinical testing of central leptin gene therapy or of long acting leptin mimetics to prevent life-threatening pathophysiologic sequalae attending the worldwide epidemic of obesity and the metabolic syndrome.