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

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 (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.

SUBMITTER: Geberhiwot T

PROVIDER: S-EPMC7881858 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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

Geberhiwot Tarekegn T Baig Shanat S Obringer Cathy C Girard Dorothée D Dawson Charlotte C Manolopoulos Konstantinos K Messaddeq Nadia N Bel Lassen Pierre P Clement Karine K Tomlinson Jeremy W JW Steeds Richard P RP Dollfus Hélène H Petrovsky Nikolai N Marion Vincent V

Diabetes 20200929 2

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 ...[more]

PMID: 32994277

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Project description:AbatractObesity is known to be associated with adipose tissue inflammation and insulin resistance. Importantly, in obesity, the accumulation of proinflammatory macrophages in adipose tissue correlates with insulin resistance. We hypothesized that the receptor for advanced glycation end products (RAGE) and associated ligands are involved in adipose tissue insulin resistance, and that the activation of the AGE-RAGE axis plays an important role in obesity-associated inflammation. C57BL/6J mice (WT) and RAGE deficient (RAGE-/-) mice were fed a high fat diet (HFD) and subjected to glucose and insulin tolerance tests. Epdidymal adipose tissue (eAT) was collected and adipose stromal vascular cells isolated using flow cytometry. Visceral adipose tissue macrophage polarization was assessed by quantitative real time PCR. Immunoblotting was performed to evaluate the insulin signaling in adipose tissues. In additional studies, cell trafficking was assessed by injecting labeled blood monocytes into recipient mice. RAGE-/- mice displayed improved insulin sensitivity and glucose tolerance, accompanied by decreased body weight and eAT mass. Exogenous methylglyoxal (MGO) impaired insulin-stimulated AKT signaling in adipose tissues from WT mice fed a normal chow diet, but not in RAGE-/- mice. In contrast, in obese mice, treatment with MGO did not reduce insulin-induced phosphorylation of AKT in WT-HFD mice. Moreover, insulin-induced AKT phosphorylation was found to be impaired in adipose tissue from RAGE-/--HFD mice. RAGE-/- mice displayed improved inflammatory profiles and evidence for increased adipose tissue browning. This observation is consistent with the finding of reduced plasma levels of FFA, glycerol, IL-6, and leptin in RAGE-/- mice compared to WT mice. Collectively the data demonstrate that RAGE-mediated adipose tissue inflammation and insulin-signaling are potentially important mechanisms that contribute to the development of obesity-associated insulin resistance.

Dataset Information

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

Publications

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

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