Relative Adipose Tissue Failure in Alström Syndrome Drives Obesity-Induced Insulin Resistance.
Fiche publication
Date publication
septembre 2020
Journal
Diabetes
Auteurs
Membres identifiés du Cancéropôle Est :
Mme MESSADDEQ Nadia
Tous les auteurs :
Geberhiwot T, Baig S, Obringer C, Girard D, Dawson C, Manolopoulos K, Messaddeq N, Lassen PB, Clement K, Tomlinson JW, Steeds RP, Dollfus H, Petrovsky N, Marion V
Lien Pubmed
Résumé
Obesity is a major risk factor for insulin resistance (IR) and its attendant complications. The pathogenic mechanisms linking them remain poorly understood, partly due to a lack of intermediary monogenic human phenotypes. Here, we report on a monogenic form of IR-prone obesity, Alström syndrome (ALMS). Twenty-three subjects with monogenic or polygenic obesity underwent hyperinsulinaemic-euglycemic clamping with concomitant adipose tissue (AT) microdialysis and an in-depth analysis of subcutaneous AT histology. We have shown a relative adipose tissue failure in monogenic obese cohort; a finding supported by observations in a novel conditional mouse model ( ) and ALMS1-silenced human primary adipocytes. Whereas, selective reactivation of ALMS1 gene in adipose tissue of an ALMS conditional knockdown mice model ( ) restores systemic insulin sensitivity and glucose tolerance. Hence, we show for the first time the relative adipose tissue failure in human obese cohorts to be a major determinant of accelerated IR without evidence of lipodystrophy. These new insights into adipocyte driven insulin resistance may assist development of adipose tissue targeted therapeutic strategies for diabetes.
Référence
Diabetes. 2020 Sep 29;: