Ectopic fat accumulation has been implicated as a contributing factor in the abnormal metabolic state of obesity. One human model of ectopic fat deposition is generalized lipodystrophy. Generalized lipodystrophy is a rare disorder characterized by a profound deficiency of adipose tissue with resultant loss of triglyceride storage capacity and reduced adipokines, including leptin. Subjects with generalized lipodystrophy and reduced leptin levels often have an increased appetite leading to hyperphagia. Excess fuel consumption, coupled with a lack of adipose tissue, contributes to the significant ectopic triglyceride accumulation in the muscle and liver seen in these subjects. This ectopic fat, along with the deficiency in leptin signaling and perhaps other adipokines, likely contributes to insulin resistance, diabetes, and hepatic steatosis. We report here the long-term effects of leptin replacement in a cohort of these subjects. Fifteen patients with generalized lipodystrophy were treated with twice-daily recombinant methionyl human leptin (r-metHuLeptin) for 12 months. We evaluated metabolic parameters at baseline and every 4 months. Antidiabetes medications were decreased or discontinued as necessary. Reductions were seen in serum fasting glucose (from 205 ؎ 19 to 126 ؎ 11 mg/dl; P < 0.001), HbA 1c (from 9 ؎ 0.4 to 7.1 ؎ 0.5%; P < 0.001), triglycerides (from 1,380 ؎ 500 to 516 ؎ 236 mg/dl; P < 0.001), LDL (from 139 ؎ 16 to 85 ؎ 7 mg/dl; P < 0.01), and total cholesterol (from 284 ؎ 40 to 167 ؎ 21 mg/dl; P < 0.01). HDL was unchanged (from 31 ؎ 3 to 29 ؎ 2 mg/dl; P ‫؍‬ 0.9). Liver volumes were significantly reduced (from 3,663 ؎ 326 to 2,190 ؎ 159 cm 3 ; P < 0.001), representing loss of steatosis. Decreases were seen in total body weight (from 61.8 ؎ 3.6 to 57.4 ؎ 3.4 kg; P ‫؍‬ 0.02) and resting energy expenditure (from 1,929 ؎ 86 to 1,611 ؎ 101 kcal/24 h; P < 0.001). R-metHuLeptin led to significant and sustained improvements in glycemia, dyslipidemia, and hepatic steatosis. Leptin represents the first novel, effective, long-term treatment for severe forms of lipodystrophy. Diabetes 54: 1994 -2002, 2005 T he lipodystrophies represent a group of clinical syndromes characterized by various degrees of adipocyte loss. In the generalized forms, adipocyte loss is the most severe. The discovery of leptin introduced a new concept in energy regulation (1). This formed the basis for understanding that adipose tissue is an endocrine organ and that generalized lipodystrophy in rodents and patients constituted a severe hypoleptinemic state (2,3). The metabolic phenotype is characterized by extreme dyslipidemia, insulin resistance, and diabetes (4).The production of recombinant leptin provided the opportunity to determine whether leptin replacement therapy in a leptin-sensitive state would improve this extreme metabolic phenotype. First in rodent models (5) and then in preliminary short-term studies in humans (6), it was shown that recombinant leptin administration could ameliorate dyslipidemia, insulin resistance, and diab...

Severe lipodystrophy is characterized by diminished adipose tissue and hypoleptinemia, leading to ectopic triglyceride accumulation. In the liver, this is associated with steatosis, potentially leading to nonalcoholic steatohepatitis (NASH). We investigated the prevalence of NASH and the effect of leptin replacement in these patients. Ten patients with either generalized lipodystrophy (8 patients) or Dunnigan's partial lipodystrophy (2 patients) were included in this analysis. Paired liver biopsy specimens were obtained at baseline and after treatment with recombinant methionyl human leptin (r-metHuLeptin), mean duration 6.6 months. The extents of portal and parenchymal inflammation, steatosis, ballooning, presence of Mallory bodies, and fibrosis in liver biopsy specimens were scored using a previously validated system developed to assess NASH activity. Histological disease activity was defined as the sum of ballooning, steatosis, and parenchymal inflammation scores. We concurrently tested serum triglycerides and aminotransferases and estimations of liver volume and fat content by magnetic resonance imaging. Eight of 10 patients met histological criteria for NASH at baseline. After treatment with r-metHuLeptin, repeat histological examinations showed significant improvements in steatosis (P ‫؍‬ .006) and ballooning injury (P ‫؍‬ .005), with a reduction of mean NASH activity by 60% (P ‫؍‬ .002). Fibrosis was unchanged. Significant reductions were seen in mean serum triglycerides (12063226 mg/dL, P ‫؍‬ .002), glucose (2203144 mg/dL, P ‫؍‬ .02), insulin (46.4324.8 IU/mL, P ‫؍‬ .004), ALT (54324 U/L, P ‫؍‬ .02), AST (47322 U/L, P ‫؍‬ .046), liver volume (320932391 cm 3 , P ‫؍‬ .007), and liver fat content (31311%, P ‫؍‬ .006). In conclusion, r-metHuLeptin therapy significantly reduced triglycerides, transaminases, hepatomegaly, and liver fat content. These reductions were associated with significant reductions in steatosis and the hepatocellular ballooning injury seen in NASH. (HEPATOLOGY 2005;41:753-760.) N onalcoholic steatohepatitis (NASH), a progressive metabolic liver disease, is one of the major consequences of the current obesity epidemic. 1-3 It lies on a spectrum of nonalcoholic fatty liver disease that ranges from ectopic lipid accumulation (steatosis) to cirrhosis. 4 Steatosis is believed to sensitize the liver to metabolic injury, leading to inflammation, necrosis, and fibrosis. 2,5-7 Thus, steatosis is a constant feature of NASH, but NASH is only distinguishable by liver biopsy. The assessment and severity of NASH is made histologically based on the patterns and degrees of hepatic steatosis, inflammation, and injury, in the absence of significant alcohol consumption. 8 Although steatosis is seen in both animal and human models, NASH is only fully appreciated in the human condition. 7 Thus, human models of NASH are critical for the development of therapeutic strategies for this condition.Steatosis occurs with decreased leptin action, whether due to leptin deficiency or resistance. 9 Lipodystrophy repr...

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