Adipose tissue (AT) dysfunction in obesity is associated with insulin resistance and an increased risk of cardiometabolic diseases (1). We have read the article by Espinosa De Ycaza et al. (2) with great interest. The authors conclude that AT senescence and inflammation are not causally linked to AT insulin resistance (as determined by the insulin concentration that suppresses AT lipolysis by 50% [IC50]) and suggest that fat cell size (FCS) is a stronger predictor of AT insulin resistance. The team of investigators based their conclusions on cross-sectional analyses in people with normal weight and obesity (n = 86) and a subgroup of people with obesity (n = 25) that was studied before and after a 6-month weight loss intervention.

We believe, however, that the present findings are preliminary in nature. First, it is well established that adipocyte hypertrophy is associated with AT inflammation and insulin resistance (3). The lack of a significant association between AT inflammation (assessed by AT macrophage [ATM] content and AT cytokine expression) and AT insulin sensitivity after adjustment for FCS does not necessarily imply that AT inflammation does not induce insulin resistance. In fact, AT inflammation could mediate the association between FCS and AT insulin resistance. Notably, previous observations indicated that ATM content was higher in abdominal subcutaneous and omental AT in people with obesity with metabolic impairments compared with those without metabolic perturbations (matched for age, sex, and BMI), which was not explained by differences in adipocyte size (4). Second, more detailed examination of the AT inflammatory phenotype (i.e., immunophenotyping and transcriptional profiling of adipocytes and immune cells) would have provided better insight into the association between FCS, inflammation, and AT insulin resistance. Finally, the authors did not find significant associations between ATMs and AT insulin resistance after weight loss. We feel it would have been more informative if the authors had examined weight loss–induced changes in ATM, FCS, AT senescence, and proinflammatory gene expression and alterations in AT insulin sensitivity. Given the dynamic immune response to weight loss, the duration of the weight-stable period (2 weeks) following weight loss might have been too short to exclude that weight loss–induced cellular stress and AT remodeling, which is accompanied by an inflammatory response (5), has influenced these associations. Moreover, because of sexual dimorphism in adipose tissue function and insulin sensitivity (3), and the fact that changes in body composition were different between men and women following weight loss, we were surprised that the correlations assessed following weight loss were not corrected for sex.

Overall, the work of Espinosa De Ycaza et al. (2) contributes to our current understanding of the relationship between abdominal subcutaneous and femoral FSC, AT inflammation, and AT insulin resistance. However, these findings require confirmation in future studies. Because of interindividual differences in the etiology of obesity-related metabolic complications, the importance of FCS, AT inflammation, and AT senescence in tissue-specific insulin resistance warrants further investigation, taking age, sex, body composition, obesity duration, and weight cycling into account.

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

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