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Lipodystrophies, metabolic and hormonal adaptations, and aging

Principal investigator :
Bruno FEVE MD-Ph.D.

Research team :

Pascale Cervera, Olivier Lascols, Corinne Vigouroux, Bénédicte Antoine, Martine Caron-Debarle, Jean-Philippe Bastard, Camille Vatier.

Faculty:
UMR_S938, Centre De Recherche Saint-Antoine, Lypodystrophies genetiques et acquises.

Our studies are directed in priority towards lipodystrophies characterized by a complete or segmental loss of body fat associated with a severe resistance to insulin and with alterations in lipid and glucose metabolism. These diseases lead to hepatic complications and to an increased cardio-vascular risk at early ages. Our team is recognized at the national and international level for studies in this domain. We investigate the different aspects of these diseases by using a translational approach: search for the pathophysiological mechanisms, for genetic, diagnostic and prognostic factors, for the taking care of the patients, evaluation of therapeutic strategies. We have discovered in the recent years new genes mutated in genetic forms of complete or partial lipodystrophies (caveolin 1, perilipin) and have described new phenotypes resulting from mutations in known genes (lamin A/C). By using cell models we were able to reveal different aspects of cellular dysfunctions (oxidative stress, inflammation, senescence) induced by proteins mutated in lipodystrophic patients and by HIV-antiretroviral drugs in fibroblasts, adipocytes and endothelial cells. We have also shown altered adipose tissue morphology and
function on patients’ biopsies. Our team is involved in clinical studies to better diagnose and treat these patients. We also revealed that the mineralocorticoid receptor mediates a proadipogenic effect of corticosteroids and that leptin plasma levels can predict the occurrence of a glucocorticoid-induced lipodystrophy.
All these studies are performed in close relations with the hospital departments in which we are working and with a network of physicians who are referring us patients and are involved in studies of the patients’ cohorts. Our team is one of the funding teams of the IHU ICAN.

The aim of our project is focused on the study of genetic or acquired forms of lipodystrophies (LD). We will perform complementary studies adressing the molecular and cellular bases of pathophysiology, genetic diagnosis, clinical investigation of the biological determinants of the metabolic and cardiovascular
complications, and therapeutic interventions in LD patients.
The present team will be reinforced by the arrival of new scientists with recognized expertise in the field of adipose tissue and metabolism. The studies on genetic and HIV-related lipodystrophies will be pursued, and a new program of glucocorticoid-induced LD will be developed.

  • The investigations on the pathophysiology of genetic lipodystrophies will include several aspects:  search for new mutations in familial LD of unknown origin (whole exome sequencing);
  • analysis of the endoplasmic reticulum stress and autophagy in cells and tissues derived from patients;
  • Development of iPSC (induced pluripotent stem cells) obtained from patients’ fibroblasts to decipher the exact influence of different mutations on the differentiation and functions of the derived preadipocytes, endothelial and smooth muscle cells;
  • examine the influence of the treatment with recombinant leptin on the metabolic or histological features, and on gene expression profile in subcutaneous adipose tissue.

HIV-associated LD will be studied with several pathophysiological aims:

  • examine the influence of HIV proteins and of new antiretroviral compounds on several cell lineages derived from iPSC;
  • examine the pathogenesis of trunk lipohypertrophy through different approaches (influence of a drug switch on metabolic or histological features, and on gene expression profile; response of adipose tissue to a bariatric surgery, study of pericardial adipose tissue);
  • analysis of the microbiote of HIV-infected patients to search for a dysbiosis that could contribute to LD and associated disorders;
  • pursue major implication in the metabolic, cardiovascular and liver follow-up of several cohorts of HIV-infected patients (APROCO-COPILOTE, COPANA, COVERTE, ECHAM…).

Glucocorticoid(GC)-induced LD will be studied by both basic and clinical approaches:

  • analysis with transgenic models of the role of glucocorticoid and mineralocorticoid receptors in the development and metabolism of adipose tissue;
  • determination of the role of GC on lyceroneogenesis and modulation in nutrient absorption;
  • identification, in patients with Cushing syndrome (LIPOCUSH), of the proteins that underlie disturbed adipose tissue distribution;
  • search for the clinical and biological predictive factors of LD induced by high dose GC treatment (LIPOCORT);
  • interventional study to prevent GC-induced LD with GLP-1 receptor agonists (LIPREGIL).

 

FOCUS

The aim of our project is focused on the study of genetic or acquired forms of lipodystrophies (LD).


Publications

1. Gandotra S, Le Dour C, Bottomley W, Cervera P, Giral P, Reznik Y, Charpentier G, Auclair M, Delépine M, Barroso I, Semple RK, Lathrop M, Lascols O,  Capeau J, O’Rahilly S, Magré J, Savage DB, Vigouroux C. Perilipin deficiency and autosomal dominant partial lipodystrophy. N Engl J Med. 2011 Feb 24;364(8):740-8.
2. Le Dour C, Schneebeli S, Bakiri F, Darcel F, Jacquemont ML, Maubert MA, Auclair M, Jeziorowska D, Reznik Y, Béréziat V, Capeau J, Lascols O, Vigouroux C. A homozygous mutation of prelamin-A preventing its farnesylation and maturation leads to a severe lipodystrophic phenotype: new insights into the pathogenicity of nonfarnesylated prelamin-A. J Clin Endocrinol Metab. 2011 May;96(5):E856-62.
3. Lefèvre C, Auclair M, Boccara F, Bastard JP, Capeau J, Vigouroux C, Caron-Debarle M. Premature senescence of vascular cells is induced by HIV protease inhibitors: implication of prelamin A and reversion by statin. Arterioscler Thromb Vasc Biol. 2010 Dec;30(12):2611-20.
4. Kim CA, Delépine M, Boutet E, El Mourabit H, Le Lay S, Meier M, Nemani M, Bridel E, Leite CC, Bertola DR, Semple RK, O’Rahilly S, Dugail I, Capeau J, Lathrop M, Magré J. Association of a homozygous nonsense caveolin-1 mutation with Berardinelli-Seip congenital lipodystrophy. J Clin Endocrinol Metab. 2008 Apr;93(4):1129-34.
5. Caron M, Auclair M, Donadille B, Béréziat V, Guerci B, Laville M, Narbonne H, Bodemer C, Lascols O, Capeau J, Vigouroux C. Human lipodystrophies linked to mutations in A-type lamins and to HIV protease inhibitor therapy are both associated with prelamin A accumulation, oxidative stress and premature cellular senescence. Cell Death Differ. 2007 Oct;14(10):1759-67.