Relative Adipose Tissue Failure in Alström Syndrome Drives Obesity-Induced Insulin Resistance.
Geberhiwot T., Baig S., Obringer C., Girard D., Dawson C., Manolopoulos K., Messaddeq N., Bel Lassen P., Clement K., Tomlinson JW., Steeds RP., Dollfus H., Petrovsky N., Marion V.
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.