Diseases of adipose tissue: Genetic and acquired lipodystrophies

INSERM U680, Saint-Antoine Faculty of Medicine, Université Pierre et Marie Curie (UPMC), Paris, France.
Biochemical Society Transactions (Impact Factor: 3.19). 12/2005; 33(Pt 5):1073-7. DOI: 10.1042/BST20051073
Source: PubMed

ABSTRACT Human lipodystrophies represent a group of diseases characterized by altered body fat amount and/or repartition and major metabolic alterations with insulin resistance leading to diabetic complications and increased cardiovascular and hepatic risk. Genetic forms of lipodystrophies are rare. Congenital generalized lipodystrophy or Berardinelli-Seip syndrome, autosomal recessive, is characterized by a complete early lipoatrophy and severe insulin resistance and results, in most cases, from mutations either in the seipin gene of unknown function or AGPAT2 encoding an enzyme involved in triacylglycerol synthesis. The Dunnigan syndrome [FPLD2 (familial partial lipodystrophy of the Dunnigan type)] is due to mutations in LMNA encoding the lamin A/C, belonging to the complex group of laminopathies that could comprise muscular and cardiac dystrophies, neuropathies and syndromes of premature aging. Some FPLDs are linked to loss-of-function mutations in the PPAR-gamma gene (peroxisome-proliferator-activated receptor gamma; FPLD3) with severe metabolic alterations but a less severe lipodystrophy compared with FPLD2. The metabolic syndrome, acquired, represents the most common form of lipodystrophy. HIV-infected patients often present lipodystrophies, mainly related to side effects of antiretroviral drugs together with insulin resistance and metabolic alterations. Such syndromes help to understand the mechanisms involved in insulin resistance resulting from altered fat repartition and could benefit from insulin-sensitizing effects of lifestyle modifications or of specific medications.

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    • "For example, a significant subpopulation is metabolically healthy, retains insulin sensitivity, and has normal lipid and inflammation profiles [11]. Likewise, there are other populations, including the " metabolically obese, normal weight " [12] [13] and those with familial lipodystrophy [14] [15] that have pathogenic metabolic profiles. These other populations highlight that inflammatory mediators and increased growth factor availability (e.g., IGF-1, insulin; see [16]) are not the only mechanisms linking obesity with cancer. "
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    ABSTRACT: Currently, there is renewed interest in elucidating the metabolic characteristics of cancer and how these characteristics may be exploited as therapeutic targets. Much attention has centered on glucose, glutamine and de novo lipogenesis, yet the metabolism of fatty acids that arise from extracellular, as well as intracellular, stores as triacylglycerol has received much less attention. This review focuses on the key pathways of fatty acid metabolism, including uptake, esterification, lipolysis, and mitochondrial oxidation, and how the regulators of these pathways are altered in cancer. Additionally, we discuss the potential link that fatty acid metabolism may serve between obesity and changes in cancer progression.
    04/2015; 2015:1-17. DOI:10.1155/2015/274585
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    • "It is not generally known that metabolic syndrome is linked to lipodystrophies as much as to obesity [8, 9]. Congenital lipodystrophies (Berardinelli Seip syndrome, Emery-Dreifuss muscular dystrophy, and Dunnigan-type familial partial lipodystrophy) and acquired lipodystrophies (HIV-associated lipodystrophy, cachexia associated with neoplasias, among others) are characterized indeed by the loss of adipose tissue and also by insulin resistance, fat liver disease, dyslipidemia with hypertriglyceridemia, and many other manifestations of the metabolic syndrome [10–12] (Figure 1). In lipodystrophies, there is a continuous and severe loss of adipocytes by apoptosis leading to an inadequate metabolism of free fatty acids, generating severe organic consequences like lipotoxicity, which are closely related to development of metabolic syndrome [13, 14]. "
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    ABSTRACT: One of the most important and complex diseases of modern society is metabolic syndrome. This syndrome has not been completely understood, and therefore an effective treatment is not available yet. We propose a possible stem cell mechanism involved in the development of metabolic syndrome. This way of thinking lets us consider also other significant pathologies that could have similar etiopathogenic pathways, like lipodystrophic syndromes, progeria, and aging. All these clinical situations could be the consequence of a progressive and persistent stem cell exhaustion syndrome (SCES). The main outcome of this SCES would be an irreversible loss of the effective regenerative mesenchymal stem cells (MSCs) pools. In this way, the normal repairing capacities of the organism could become inefficient. Our point of view could open the possibility for a new strategy of treatment in metabolic syndrome, lipodystrophic syndromes, progeria, and even aging: stem cell therapies.
    06/2011; 2011(2):943216. DOI:10.4061/2011/943216
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    • "Lipoatrophic diabetes is primarily a result of defective adipose tissue lipid storage resulting in severe dyslipidemia and insulin resistance. Multiple alterations can cause lipoatrophic diabetes, and rare single gene defects have been identified in patients (1). The recent discovery of mutations in the human caveolin-1 gene in Berardinelli-Seip congenital lipodystrophy, and mutations in polymerase I and transcript release factor (PTRF)/cavin causing secondary deficiency of caveolins and generalized lipodystrophy, brings into focus caveolin proteins in the pathogeny of lipoatrophic diabetes in humans (2,3). "
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    ABSTRACT: Defective caveolin-1 expression is now recognized as a cause of lipoatrophic diabetes in patients, due to primary caveolin gene mutations or secondary caveolin deficiency caused by PTRF/cavin gene defects. The goal of this study was to establish the relative contribution of endothelial cells and adipocytes, both highly expressing caveolin-1 to the lipoatrophic phenotype of mice with global caveolin-1 gene invalidation (Cav1-KO). We compared adipose tissue development and metabolic phenotype of wild-type (WT), lipoatrophic Cav1-KO, and a murine model with specific rescue of caveolin-1 expression in endothelial cells (caveolin-1-reconstituted [Cav1-RC]). Defective adipose tissue development, reduced adipocyte size, and global alteration in adipose tissue gene expression that characterize lipoatrophic caveolin-1 null mice were still observed in Cav1-RC, indicating a prominent role of adipocyte-derived caveolin in lipoatrophy. We also observed that Cav1-KO adipose tissue contained an increased proportion of infiltrated macrophages compared with control mice, mostly with an alternate activation M2 phenotype. In contrast with defective lipid storage and lipoatrophy, macrophage infiltration was normalized in Cav1-RC mice, pointing to caveolin-1-dependent endothelium permeability as the causing factor for adipose tissue macrophage infiltration in this model. This is the first report of a specific role for adipocyte caveolin expression in lipid storage. Our study also shows that endothelium caveolin critically participates in the control of macrophage extravasation from the blood into adipose tissue, therefore establishing distinct roles depending on topology of caveolin expression in different cell types of adipose tissue.
    Diabetes 02/2011; 60(2):448-53. DOI:10.2337/db10-0856 · 8.10 Impact Factor
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