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Relative Adipose Tissue Failure in Alström Syndrome Drives Obesity-Induced Insulin Resistance.

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Geberhiwot, Tarekegn | Baig, Shanat | Obringer, Cathy | Girard, Dorothée | Dawson, Charlotte | Manolopoulos, Konstantinos | Messaddeq, Nadia | Bel Lassen, Pierre | Clement, Karine | Tomlinson, Jeremy W. | Steeds, Richard P. | Dollfus, Hélène | Petrovsky, Nikolai | Marion, Vincent

Edité par CCSD ; American Diabetes Association -

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 hyperinsulinemic-euglycemic clamping with concomitant adipose tissue (AT) microdialysis and an in-depth analysis of subcutaneous AT histology. We have shown a relative AT failure in a monogenic obese cohort, a finding supported by observations in a novel conditional mouse model (Alms flin/flin ) and ALMS1-silenced human primary adipocytes, whereas selective reactivation of ALMS1 gene in AT of an ALMS conditional knockdown mouse model (Alms flin/flin ; Adipo-Cre +/- ) restores systemic insulin sensitivity and glucose tolerance. Hence, we show for the first time the relative AT failure in human obese cohorts to be a major determinant of accelerated IR without evidence of lipodystrophy. These new insights into adipocyte-driven IR may assist development of AT-targeted therapeutic strategies for diabetes.

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