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

Geberhiwot, Tarekegn, Baig, Shanat, Obringer, Cathy, Girard, Dorothée, Dawson, Charlotte, Manolopoulos, Konstantinos, Messaddeq, Nadia, Bel Lassen, Pierre, Clement, Karine, Tomlinson, Jeremy W, Steeds, Richard Paul, Dollfus, Hélène, Petrovsky, Nikolai and Marion, Vincent (2021) Relative Adipose Tissue Failure in Alström Syndrome Drives Obesity-Induced Insulin Resistance. Diabetes, 70 (2). pp. 364-376. ISSN 1939-327X. This article is available to all UHB staff and students via ASK Discovery tool http://tinyurl.com/z795c8c by using their UHB Athens login IDs

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Abstract

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 ( ) and ALMS1-silenced human primary adipocytes, whereas selective reactivation of ALMS1 gene in AT of an ALMS conditional knockdown mouse model ( ) 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.

Item Type:	Article
Additional Information:	This article is available to all UHB staff and students via ASK Discovery tool http://tinyurl.com/z795c8c by using their UHB Athens login IDs
Subjects:	WD Diseases and disorders of systemic, metabolic or environmental origin WD Diseases and disorders of systemic, metabolic or environmental origin > WD250 Metabolic diseases WG Cardiovascular system. Cardiology WK Endocrine system. Endocrinology
Divisions:	Ambulatory Care > Diabetes
Related URLs:	https://pubmed.ncbi.nlm.nih.gov/32994277...
Depositing User:	Jamie Edgar
Date Deposited:	17 May 2021 12:34
Last Modified:	17 May 2021 12:34
URI:	http://www.repository.uhblibrary.co.uk/id/eprint/4324

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