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

Diabetes. 2021 Feb;70(2):364-376. doi: 10.2337/db20-0647. Epub 2020 Sep 29.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / metabolism
  • Adipose Tissue / metabolism*
  • Alstrom Syndrome / genetics
  • Alstrom Syndrome / metabolism*
  • Animals
  • Diet, High-Fat
  • Glucose Clamp Technique
  • Humans
  • Insulin Resistance / genetics
  • Insulin Resistance / physiology*
  • Mice
  • Obesity / genetics
  • Obesity / metabolism*
  • Phenotype

Associated data

  • figshare/10.2337/figshare.13135370