Mouse models of inherited lipodystrophy.

Insulin resistance is a major factor in the pathogenesis of type 2 diabetes and underpins the strong association between obesity and diabetes. Paradoxically, the metabolic consequences of having 'too much' fat (obesity) are remarkably similar to those of having 'too little' fat (lipodystrophy): a finding that has generated considerable interest in a rare disease. In both cases, excess energy accumulates as lipid in ectopic sites such as the liver (fatty liver) and skeletal muscle, where it plays a central role in the pathogenesis of insulin resistance, dyslipidemia and type 2 diabetes. Human lipodystrophies are characterised by a total or partial deficiency of body fat, and may be inherited or acquired in origin. Genetically engineered mice with generalised lipodystrophy manifest many of the features of the human disorder, including hyperphagia, fatty liver, hypertriglyceridaemia, insulin resistance and type 2 diabetes, providing a useful tractable model of the human disorder. Partial lipodystrophy, which causes similar, albeit milder, metabolic problems in humans has been more difficult to mimic in the mouse. This review discusses key translational studies in mice with generalised lipodystrophy, including fat transplantation and the use of recombinant leptin replacement therapy. These studies have been instrumental in advancing our understanding of the underlying molecular pathogenesis of ectopic lipid accumulation and insulin resistance, and have prompted the initiation and subsequent adoption of leptin replacement therapy in human lipodystrophies. This review also considers the possible reasons for the apparent difficulties in generating mouse models of partial lipodystrophy, such as interspecies differences in the distribution of fat depots and the apparent lack of sexual dimorphism in fat mass and distribution in mice compared with the dramatic differences present in adult humans.