Association between Subcutaneous Adipose Tissue Inflammation, Insulin Resistance, and Calorie Restriction in Obese Females

Abstract

The worldwide epidemic of overweight and obesity has led to an increase in associated metabolic comorbidities. Obesity induces chronic low-grade inflammation in white adipose tissue (WAT). However, the function and regulation of both innate and adaptive immune cells in human WAT under conditions of obesity and calorie restriction (CR) is not fully understood yet. Using a randomized interventional design, we investigated postmenopausal overweight or obese female subjects who either underwent CR for 3 mo followed by a 4-wk phase of weight maintenance or had to maintain a stable weight over the whole study period. A comprehensive immune phenotyping protocol was conducted using validated multiparameter flow cytometry analysis in blood and s.c. WAT (SAT). The TCR repertoire was analyzed by next-generation sequencing and cytokine levels were determined in SAT. Metabolic parameters were determined by hyperinsulinemic-euglycemic clamp. We found that insulin resistance correlates significantly with a shift toward the memory T cell compartment in SAT. TCR analysis revealed a diverse repertoire in SAT of overweight or obese individuals. Additionally, whereas weight loss improved systemic insulin sensitivity in the intervention group, SAT displayed no significant improvement of inflammatory parameters (cytokine levels and leukocyte subpopulations) compared with the control group. Our data demonstrate the accumulation of effector memory T cells in obese SAT and an association between systemic glucose homeostasis and inflammatory parameters in obese females. The long-standing effect of obesity-induced changes in SAT was demonstrated by preserved immune cell composition after short-term CR-induced weight loss.

T cell phenotypes associated with insulin resistance: Results from the Berlin Aging Study II

“…As expected, the BMI was negatively associated with ISI OGTT in both male and female participants ( Figure 1A). The ISI OGTT also correlated negatively with the total number of leukocytes, obtained from complete blood count results ( Figure 1B), in line with previous results from another study of ours (18). To assess the association of metabolic parameters (BMI, HOMA-IR, ISI OGTT ) with systemic leukocyte subpopulations, we analyzed multiparameter ow cytometric data derived from blood samples of older participants.…”

“…Reduced circulating Treg cell numbers were detected in obese compared with non-obese study participants (41), and another study identi ed a signi cant inverse correlation of Th2 cells in peripheral blood with systemic insulin resistance (12). Additionally, our group found recently that insulin resistance correlates signi cantly with a shift in the ratio of naïve and differentiated memory CD4 + and CD8 + T cells in abdominal subcutaneous adipose tissue in female obese subjects (18). Furthermore, it has been found that peripheral frequencies of Thelper (Th)22 cells and IL-22 levels were increased in obese subjects with or without type 2 diabetes compared with lean subjects, and that Th22 cell frequencies correlated positively with HOMA-IR (40).…”

Adipose Tissue Immunomodulation: A Novel Therapeutic Approach in Cardiovascular and Metabolic Diseases

“…Interestingly, a sustained scWAT low-grade inflammation extending beyond weight loss was reported (353,354). This sustained inflammation has been attributed to the accumulation of effector memory T cells (354). This contradicts with recent reports that demonstrated VAT but not scWAT inflammation as a manifestation of obesity (355,356).…”

“…Indeed, scWAT inflammation is linked to the development of IR (214,352). Interestingly, a sustained scWAT low-grade inflammation extending beyond weight loss was reported (353,354). This sustained inflammation has been attributed to the accumulation of effector memory T cells (354).…”

T cell phenotypes associated with metabolically healthy obesity: Results from the Berlin Aging Study II

“…Additionally, our group found recently that insulin resistance correlates signi cantly with a shift in the ratio of naïve and differentiated memory CD4 + and CD8 + T cells in abdominal subcutaneous adipose tissue in female obese subjects (18). Furthermore, it has been found that peripheral frequencies of Thelper (Th)22 cells and IL-22 levels were increased in obese subjects with or without type 2 diabetes compared with lean subjects, and that Th22 cell frequencies correlated positively with HOMA-IR (38).…”