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

Abstract

Selective hepatic insulin resistance is a feature of obesity and type 2 diabetes. Whether similar mechanisms operate in white adipose tissue (WAT) of those with obesity and to what extent these are normalized by weight loss are unknown. We determined insulin sensitivity by hyperinsulinemic euglycemic clamp and insulin response in subcutaneous WAT by RNA sequencing in 23 women with obesity before and 2 years after bariatric surgery. To control for effects of surgery, women postsurgery were matched to never-obese women. 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 remodeling and protein translation was selectively regulated in the two nonobese states; and several postobesity-enriched genes encoding proteins involved in, for example, 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.

Spatial mapping reveals human adipocyte subpopulations with distinct sensitivities to insulin

“…For determination of whole-body insulin resistance, four subjects underwent euglycemic hyperinsulinemic clamps as described previously (Mileti et al, 2021). In brief, subjects came to the laboratory after an overnight fast.…”

Identifying interactions in omics data for clinical biomarker discovery using symbolic regression

“…The data was retrieved from Mileti et al [29]. The dataset consists of gene expression from a total of 23 never obese and 23 obese women sequenced before and 2 years after bariatric surgery (post obese) using RNA sequencing (CAGE) [29]. The only pre-processing done was to normalise the data from raw counts to TPM (tag-per-million normalisation, the gold standard for CAGE data [29]).…”

“…The data was retrieved from Mileti et al [29]. The dataset consists of gene expression from a total of 23 never obese and 23 obese women sequenced before and 2 years after bariatric surgery (post obese) using RNA sequencing (CAGE) [29].…”

Obesity treatment: Weight loss versus increasing fitness and physical activity for reducing health risks

“…It has been suggested that exercise may increase the secretion of myokines and adipokines that facilitate “cross-talk” between muscle and adipose tissue to improve overall metabolic health ( Stanford and Goodyear, 2018 ). These studies should not be interpreted to reject the effect of weight loss on insulin sensitivity, as weight loss achieved via caloric restriction improves insulin sensitivity in white adipose tissue ( Mileti et al, 2021 ; Eriksson-Hogling et al., 2015 ). However, as demonstrated by the studies described above, weight loss is not a prerequisite for improvement in insulin sensitivity.…”