Leptin: a novel therapeutic role in lipodystrophy.

Lipodystrophic syndromes encompass a heterogeneous group of rare disorders characterized by partial or generalized loss of adipose tissue depots (1). They are commonly associated with dyslipidemia, hepatic steatosis, and severe insulin resistance (2). The fact that insulin resistance and the consequent progression to diabetes can result from either obesity or lipodystrophy reflects the crucial role of adipose tissue in carbohydrate and lipid metabolism. In the absence of adequate adipocyte capacity, excess calories cannot be diverted to their normal storage depot; instead they accumulate as increased triglyceride stores in liver, in skeletal and cardiac muscle, and in the pancreatic β cell. This extra-adipose lipid accumulation, through asyet unclear means, is associated with impaired insulin action and, often, diabetes. In addition to their passive role as storage depots, normal adipocytes secrete a number of peptides (“adipokines”) that may influence insulin sensitivity and/or energy balance (3, 4). These include potential insulin sensitizers, such as leptin and Acrp30 (also known as adiponectin), and insulin antagonists, including TNF-α, IL-6, and possibly resistin. The insulin resistance of lipodystrophy may therefore be the result of disturbed lipid fluxes and/or abnormalities of adipokine secretion. The striking similarity of murine models of lipodystrophy to the human phenotype has provided insights into the metabolic disarray observed in this disorder as well as revealing several therapeutic options. Insulin sensitivity improves dramatically following fat transplantation in mice with generalized lipodystrophy, a finding that was first taken to suggest a critical role for adipocyte mass per se (5). However, the failure of fat transplanted from ob/ob (leptin-deficient) mice to reverse the metabolic disturbance highlighted the importance of adipocyte-derived leptin (6). Further support for this notion comes from the previously described beneficial effects of leptin administration in a different lipodystrophic strain of mice (7). More recently, Yamauchi et al. have suggested that combined leptin and adiponectin infusions are required to fully restore normal insulin action in yet another lipodystrophic mouse model (8). Adipose tissue transplantation in humans has been considered but has not yet been reported. As an alternative to such surgery, might adipose mass be stimulated pharmacologically? The nuclear hormone receptor PPARγ plays a key role in adipogenesis, and its agonists increase fat mass in humans and appear to do the same in at least some lipodystrophic patients (9). However, the impact of this approach in generalized lipodystrophy has yet to be convincingly demonstrated. It may also confer some risk of increased hepatic steatosis, as is seen in lipodystrophic mice treated with rosiglitazone, a known PPARγ agonist (10).