In mouse models of lipodystrophy–characterized by severe hypoleptinemia and hyperinsulinemia–treatment with low doses of recombinant leptin significantly improved insulin sensitivity [47, 48] but chronic food restriction does not normalize circulating insulin concentrations [47, 48] suggesting that in lipodystrophic mice leptin modulates insulin sensitivity and glucose homeostasis independently of either food intake or body weight. Here, LEP is linked to hyperinsulinism.