| First Author | Geberhiwot T | Year | 2021 |
| Journal | Diabetes | Volume | 70 |
| Issue | 2 | Pages | 364-376 |
| PubMed ID | 32994277 | Mgi Jnum | J:302160 |
| Mgi Id | MGI:6507778 | Doi | 10.2337/db20-0647 |
| Citation | Geberhiwot T, et al. (2021) Relative adipose tissue failure in Alstrom Syndrome drives obesity-induced insulin resistance. Diabetes 70(2):364-376 |
| abstractText | 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. |
