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...

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Generalized lipodystrophy is characterized by adipose tissue absence, hypoleptinemia, hypertriglyceridemia, insulin resistance, diabetes, hepatomegaly, and nonalcoholic steatohepatitis. In the course of recruiting patients for treatment with recombinant leptin, we were struck by the frequency and severity of proteinuria. We evaluated 25 patients with generalized lipodystrophy. Eighteen were treated with recombinant leptin, and we have followed 15 on leptin for 4-36 months. We followed renal parameters at baseline and during follow-up visits. Renal biopsies were performed as clinically indicated. At baseline, 22 of 25 patients (88%) had elevated urine albumin excretion (>30 mg/24 h), 15 (60%) had macroalbuminuria (>300 mg/24 h), and five (20%) had nephrotic-range proteinuria (>3500 mg/24 h). Twenty-three (92%) had elevated creatinine clearance (>125 ml/min.1.73 m(2)). Eleven of 15 patients (73%) treated with recombinant leptin exhibited reduction in proteinuria, associated with reduction of hyperfiltration. Four patients who did not improve are discussed individually. Renal biopsy findings were remarkable for focal segmental glomerulosclerosis in four patients, membranoproliferative glomerulonephritis in two patients, and diabetic nephropathy in one patient. In conclusion, generalized lipodystrophy is associated with proteinuria and unique renal pathologies, including focal segmental glomerulosclerosis and membranoproliferative glomerulonephritis. The majority treated with recombinant leptin demonstrated reduction in proteinuria and hyperfiltration.