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Inherited lipodystrophies are rare autosomal recessive and dominant disorders characterized by selective, but variable, loss of adipose tissue. Marked hypertriglyceridemia is a common feature of these disorders and highlights the role of adipose tissue in lipid homeostasis. In the last decade, advances have been made in elucidating the molecular basis of many inherited lipodystrophies. We review the new insights in the pathophysiology and treatment of these disorders based on the current understanding of the biologic role of these lipodystrophy genes.Eight different genetic loci, including 1-acylglycerol-3-phosphate-O-acyltransferase 2, Berardinelli–Seip congenital lipodystrophy 2, caveolin 1, lamin A/C, peroxisome proliferator-activated receptor gamma, v-AKT murine thymoma oncogene homolog 2, zinc metalloprotease and lipase maturation factor 1 have been described linked to different lipodystrophy syndromes. Mutations in these genes may cause fat loss and dyslipidemia through multiple mechanisms, which remain fully elucidated; however, they may involve defects in development and differentiation of adipocytes, and premature death and apoptosis of adipocytes. Hypertriglyceridemia is a consequence of increased VLDL synthesis from the liver, which is also loaded by ectopic triglyceride deposition, reduced clearance of triglyceride-rich lipoproteins or both. A recent study in mice with Agpat2 deficiency reports marked reduction in serum triglyceride upon feeding a fat-free diet, which suggests that low-fat diets are likely to be beneficial in lipodystrophic patients. Leptin replacement therapy is also a promising therapeutic option for lipodystrophic patients with hypoleptinemia.Inherited lipodystrophies are an important cause for monogenic hypertriglyceridemia and serve to highlight the role of adipocytes in maintaining normolipidemia.