Faculté de médecine Pierre et Marie Curie – Site Saint-Antoine - 7ème étage
27, rue Chaligny – 75571 PARIS cedex 12
Team “Lipodystrophies, metabolic and hormonal adaptations, and aging” (Dir. B. Fève)
The general aim of our project is focused on genetic or acquired forms of lipodystrophies (LD), including their systemic metabolic adaptations, aging consequences, and impact on fertility and reproductive functions. Generally, we will set up a transversal approach that will include the molecular and cellular bases of pathophysiology, the genetic diagnosis, the clinical and biological determinants that influence the metabolic and cardiovascular prognosis, and the investigation of new therapeutic strategies for the prevention or treatment of LD, or metabolic disorders associated with insulin resistance. Beyond the works of our team in the field of genetic or HIV-, and glucocorticoid-associated LD, the arrival of several new members gives us the opportunity to study fundamental and clinical aspects at other systemic and integrated levels, including a higher expertise in endocrine pancreas or intestinal functions, and the emergence of a new axis on the impact of LD on gonadal function and aging. We believe that one of our major strengths is that we can develop both basic and clinical approaches through the combination in the expertise of scientists and physicians.
The investigations on the pathophysiology of genetic LD largely benefit from the recent creation of the CRMR (Centre Référence Maladies Rares) PRISIS (Pathologies Rares de l’Insulinosensibilité et de l’Insulinosécrétion), and include four objectives: i) search for new genes responsible for familial LD of unknown origin; ii) functional studies of new genetic variants and genotype-phenotype correlations in affected patients; iii) pathophysiological studies of laminopathies; iv) influence of LD patients' treatment with recombinant leptin on the metabolic and adipose tissue histological features.
We also investigate HIV-associated LD and the consequences of adipose tissue aging with several pathophysiological objectives: i) The first axis concerns the study of HIV-associated adipose tissue redistribution and the respective role of the anti-retroviral treatment and the virus; ii) The second axis is focused on the study of physiological aging and senescence of adipose tissue, using patients with HIV-infected LD or genetic generalized or partial LD, or in vitro models of human preadipose or adipose cell senescence.
Glucocorticoid-induced LD is studied by using both basic and clinical approaches: i) analysis with pharmacological and/or transgenic murine models of the role of the adipocyte glucocorticoid and mineralocorticoid receptors in the development and metabolism of adipose tissue, and in energy homeostasis; ii) identification of adipose-secreted factors that underlie the communication between adipose tissue, liver, skeletal muscle, pancreatic and entero-endocrine cells.
We also develop a new field studying the impact of metabolic and adipose tissue diseases on the control of fertility, with a specific focus on the interactions between LD, TGF-beta members, and gonadal function. More specifically, we will develop in vitro and in vivo approaches on granulosa cells and rodent models, but also clinical studies in several independent cohorts to investigate the relationships between LD, anti-Müllerian hormone, and fertility.
Beaupere C, Garcia M, Larghero J, Fève B, Capeau J, Lagathu C. The HIV proteins Tat and Nef promote human bone marrow mesenchymal stem cell senescence and alter osteoblastic differentiation. Aging Cell (2015), 14, 534-546.
Bidault G, Garcia M, Vantyghem MC, Ducluzeau PH, Morichon R, Thiyagarajah K, Moritz S, Capeau J, Vigouroux C, Béréziat V. Lipodystrophy-linked LMNA p.R482W mutation induces clinical early atherosclerosis and in vitro endothelial dysfunction. Arterioscler Thomb Vasc Biol (2013) 33, 2162-2171.
Boccara F, Lang S, Meuleman C, Ederhy S, Mary-Krause M, Costagliola D, Capeau J, Cohen A. HIV and coronary heart disease: time for a better understanding. J Am Coll Cardiol (2013) 61, 511-523.
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) 364, 740-748.
Kadiri S, Monnier C, Ganbold M, Ledent T, Capeau J, Antoine B. The nuclear retinoid-related orphan receptor-alpha regulates adipose tissue glyceroneogenesis in addition to hepatic gluconeogenesis. Am J Physiol Endocrinol Metab (2015) 309, E105-E114.
Kuhn E, Bourgeois C, Keo V, Viengchareun S, Muscat A, Meduri G, Le Menuet D, Fève B, Lombès M. Paradoxical resistance to high-fat diet-induced obesity and altered macrophage polarization in mineralocorticoid receptor-overexpressing mice. Am J Physiol Endocrinol Metab (2014) 306, E75-E90.