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Relative adipose tissue failure in Alström syndrome drives obesity-induced insulin resistance

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posted on 29.09.2020 by Ada Admin, Tarekegn Geberhiwot, Shanat Baig, Cathy Obringer, Dorothée Girard, Charlotte Dawson, Konstantinos Manolopoulos, Nadia Messaddeq, Pierre Bel Lassen, Karine Clement, Jeremy W Tomlinson, Richard P Steeds, Hélène Dollfus, Nikolai Petrovsky, Vincent Marion
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 (Almsflin/flin) and ALMS1-silenced human primary adipocytes. Whereas, selective reactivation of ALMS1 gene in adipose tissue of an ALMS conditional knockdown mice model (Almsflin/flin;Adipo-Cre+/-) 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.

Funding

We would like to thank all participants for their involvement in the study. In the UK, this work was supported by Queen Elizabeth Hospital NHS-FT and Prometic Pharmaceuticals. In Australia, this work was supported by Flinders University and Vaxine. In France,this work was supported by the French National Institute for Health and Medical Research (INSERM), the University of Strasbourg and by SATT Conectus Alsace maturation program.

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