PRESENTATION
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Relative adipose tissue failure in Alström syndrome drives obesity-induced insulin resistance
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posted on 2020-09-29, 19:43 authored by Ada AdminAda 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 MarionObesity 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.