ABSTRACT
Generalized lipodystrophy (GL) syndromes are a group of rare heterogenous disorders, characterized by total subcutaneous fat loss. The frequency of GL is currently assessed as approximately 0,23 cases per million of the population, in Europe - as 0,96 cases per million of the population. They can be congenital (CGL) or acquired (AGL) depending on the etiology and the time of the onset of fat loss. Both CGL and AGL are often associated with different metabolic complications, such as hypertriglyceridemia, insulin resistance and lipoatrophic diabetes mellitus, metabolically associated FLD, arterial hypertension, proteinuria, reproductive system disorders. In this review we aimed to summarize the information on all forms of generalized lipodystrophy, especially the ones of genetic etiology, their clinical manifestations and complications, the perspectives for diagnostics, treatment and further research.
Subject(s)
Lipodystrophy , Acyltransferases/genetics , Age of Onset , Caveolin 1/genetics , DNA-Binding Proteins/genetics , Diabetes Mellitus, Lipoatrophic/complications , Diagnosis, Differential , G Protein-Coupled Inwardly-Rectifying Potassium Channels/genetics , GTP-Binding Protein gamma Subunits/genetics , Genital Diseases/complications , Humans , Hypertension/complications , Hypertriglyceridemia/complications , Insulin Resistance , Lamin Type A/genetics , Lipodystrophy/classification , Lipodystrophy/diagnosis , Lipodystrophy/etiology , Lipodystrophy/genetics , Lipodystrophy, Congenital Generalized/classification , Lipodystrophy, Congenital Generalized/genetics , Mandible/abnormalities , Membrane Proteins/genetics , Metalloendopeptidases/genetics , Mutation , Progeria/genetics , Proteinuria/complications , RNA Polymerase III/genetics , RNA-Binding Proteins/genetics , Syndrome , Werner Syndrome Helicase/geneticsABSTRACT
INTRODUCTION: Metreleptin was recently approved by the Food and Drug Administration for the treatment of generalized lipodystrophy, a condition characterized by leptin deficiency. Its efficacy as hormone replacement therapy suggests broader applications in diseases also characterized by leptin abnormalities, such as familial partial lipodystrophy (FPLD), non-alcoholic fatty liver disease (NAFLD), and common obesity. Metreleptin, in conjunction with other pharmacologic interventions, has the potential to address one of the most widespread epidemics of our time, obesity. AREAS COVERED: This review covers the physiology of leptin, the pharmacologic properties of recombinant methionyl human leptin (R-metHu-Leptin, metreleptin), evidence for metreleptin's efficacy in the treatment of generalized lipodystrophy from both completed and ongoing clinical trials, safety concerns, and future directions in metreleptin research. EXPERT OPINION: Metreleptin's approval for generalized lipodystrophy is the first step in defining and expanding its role to other metabolic diseases. Clinical trials are underway to delineate its efficacy in FPLD, human immunodeficiency virus/highly active anti-retroviral therapy-associated acquired lipodystrophy (HAL), and NAFLD. Additionally, there is growing data that support a therapeutic role in obesity. One of the barriers to development, however, is metreleptin's safety and immunogenicity. Further advances in biologic compatibility are required before metreleptin can be approved for additional indications.
Subject(s)
Leptin/analogs & derivatives , Lipodystrophy, Congenital Generalized/drug therapy , Autoimmunity , Clinical Trials as Topic , Half-Life , Humans , Leptin/chemistry , Leptin/metabolism , Leptin/pharmacokinetics , Leptin/therapeutic use , Lipodystrophy/classification , Lipodystrophy/drug therapy , Lipodystrophy/etiology , Lipodystrophy, Congenital Generalized/classification , Lipodystrophy, Congenital Generalized/etiology , Obesity/drug therapy , Signal TransductionABSTRACT
OBJECTIVE: To review the initial clinical manifestations of congenital and acquired lipodystrophy syndromes, discuss novel classifications associated with genetic mutations, and assess currently available therapeutic options for patients with lipodystrophy. METHODS: This review is the result of the authors' collective clinical experience and a comprehensive MEDLINE literature search on the English-language literature published between January 1966 and October 2009 on "lipodystrophy." This review focuses primarily on severe dystrophy not related to human immunodeficiency virus (HIV) infection, in light of the additional scope required to cover HIV-related lipodystrophy. RESULTS: Congenital lipodystrophy syndromes are characterized by a paucity of adipose tissue and classified on the basis of the extent of fat loss and heritability Paradoxically, they are associated with metabolic abnormalities often found in obese patients, including insulin resistance, diabetes, and severe hypertriglyceridemia. Patients with severe forms of lipodystrophy are also deficient in adipokines such as leptin, which may contribute to metabolic abnormalities. The search for molecular defects has revealed a role for genes that affect adipocyte differentiation (for example, peroxisome proliferator-activated receptor gamma), lipid droplet morphology (seipin, caveolin-1), or lipid metabolism (AGPAT2). Others (lamin A/C) are known to be associated with completely different diseases. There are also acquired forms of lipodystrophy that are thought to occur primarily attributable to autoimmune mechanisms. Recently, recombinant leptin has emerged as a useful therapy. CONCLUSION: Lipodystrophy syndromes have advanced our understanding of the physiologic role of adipose tissue and allowed identification of key molecular mechanisms involved in adipocyte differentiation. Novel therapeutic strategies are being developed on the basis of the pathophysiologic aspects of these syndromes.
