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Human White Adipose Tissue Displays Selective Insulin Resistance in the Obese State

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posted on 16.04.2021, 17:37 by Enrichetta Mileti, Kelvin HM. Kwok, Daniel P. Andersson, Anthony Mathelier, Amitha Raman, Jesper Bäckdahl, Jutta Jalkanen, Lucas Massier, Anders Thorell, Hui Gao, Peter Arner, Niklas Mejhert, Carsten O. Daub, Mikael Rydén
Selective hepatic insulin resistance is a feature of obesity and type 2 diabetes. Whether similar mechanisms operate in white adipose tissue (WAT) of obese subjects and to what extent these are normalized by weight loss is unknown. We determined insulin sensitivity by hyperinsulinemic euglycemic clamp and the insulin response in subcutaneous WAT by RNA-sequencing in 23 women with obesity before and two years after bariatric surgery. To control for effects of surgery, women post-surgery were matched to never-obese subjects. Multidimensional analyses of 138 samples allowed us to classify the effects of insulin into three distinct expression responses: a common set was present in all three groups and included genes encoding several lipid/cholesterol biosynthesis enzymes; a set of obesity-attenuated genes linked to tissue remodelling and protein translation was selectively regulated in the two non-obese states and several post obesity-enriched genes encoding proteins involved in e.g. one carbon metabolism were only responsive to insulin in the women who had lost weight. Altogether, human WAT displays a selective insulin response in the obese state where most genes are normalized by weight loss. This comprehensive atlas provides insights into the transcriptional effects of insulin in WAT and may identify targets to improve insulin action.

Funding

This work was supported by grants from Margareta af Uggla’s foundation (MR), the Swedish Research Council (MR, PA, NM), ERC-SyG SPHERES (856404 to MR), the NovoNordisk Foundation (including the Tripartite Immuno-metabolism Consortium Grant Number NNF15CC0018486, the MSAM consortium NNF15SA0018346 and the MeRIAD consortium Grant number 0064142, all three MR and NNF20OC0061149 to NM), CIMED (DPA, PA, NM and MR), the Swedish Diabetes Foundation (MR), the Stockholm County Council (MR, DPA), the Research Council of Norway [187615], Helse Sør-Øst, and University of Oslo through the Centre for Molecular Medicine Norway (NCMM) (to A.M.), the Research Council of Norway [288404 to A.M.], the Norwegian Cancer Society [197884 to A.M.], the Erling-Persson Family Foundation (Grant 140604 to AT) and the Strategic Research Program in Diabetes at Karolinska Institutet (MR, PA, DPA, HG and COD). The computations and data handling were enabled by resources in project [2017/7-412] provided by the Swedish National Infrastructure for Computing (SNIC) at UPPMAX, partially funded by the Swedish Research Council through grant agreement no. 2018-05973. Kelvin HM. Kwok is funded by a Novo Nordisk Postdoc Fellowship.

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