Abstract
Lipodystrophy is a disease characterized by a partial or total absence of adipose tissue leading to severe metabolic derangements including marked insulin resistance, type 2 diabetes, hypertriglyceridemia, and steatohepatitis. Lipodystrophy is also a source of major cardiovascular disorders which, in addition to hepatic failure and infection, contribute to a significant reduction in life expectancy. Metreleptin, the synthetic analog of the adipocyte-derived hormone leptin and current therapy of choice for patients with lipodystrophy, successfully improves metabolic function. However, while leptin has been associated with hypertension, vascular diseases, and inflammation in the context of obesity, it remains unknown whether its daily administration could further impair cardiovascular function in patients with lipodystrophy. The goal of this short review is to describe the cardiovascular phenotype of patients with lipodystrophy, speculate on the etiology of the disorders, and discuss how the use of murine models of lipodystrophy could be beneficial to address the question of the contribution of leptin to lipodystrophy-associated cardiovascular disease.
Highlights
Lipodystrophy is a group of clinically heterogeneous diseases characterized by either complete or partial absence of adipose tissue which may occur in conjunction with adipose mass redistribution and can be of either congenital or acquired origin[1]
Metabolic derangements associated with lipodystrophy develop early in life and predispose patients to pancreatitis, non-alcoholic steatohepatitis (NASH), and hepatic failure[2,5,6,17,18,19,20], the latter being the first cause of morbidity and mortality and of substantial reduction in lifespan in patients with lipodystrophy[21]
Diabetes, and, hyperlipidemia are leading risk factors for atherosclerosis, compelling evidence from relatively large (66 patients) studies have demonstrated that long-term treatment with metreleptin resulted in sustained improvements in hypertriglyceridemia, glycemic control, and liver volume which led to discontinuation of insulin, oral anti-diabetics, and lipid-lowering medications in more than 25% of patients on metreleptin[18]
Summary
Lipodystrophy is a group of clinically heterogeneous diseases characterized by either complete or partial absence of adipose tissue which may occur in conjunction with adipose mass redistribution and can be of either congenital or acquired origin[1]. These data derived from murine models support a beneficial role for leptin in cardiac function and metabolism (protection from lipotoxicity) but drastically contrast with the clinical studies This further raises the question of the potential contribution of leptin deficiency to the cardiac disorders associated with lipodystrophy and of the effects of daily metreleptin injections on the severely impaired heart function of lipodystrophic patients. One can soundly anticipate that metreleptin will significantly reduce the risk for atherosclerosis in lipodystrophy patients through centrally orchestrated mechanisms reducing food intake and through direct and local effects of leptin activating β-oxidation of fatty acids and preventing lipogenesis in the liver and skeletal muscles[98] Another recent study reported that metreleptin treatment for 1 year reduced plasma levels of the proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of cholesterol metabolism, in humans with congenital
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