GABA-stimulated adipose-derived stem cells suppress subcutaneous adipose inflammation in obesity

[Amanita Research]

Significance

Adipose tissue inflammation is a key mediator linking obesity to metabolic complications. In obesity, proinflammatory responses are rapidly elevated in visceral adipose tissue, whereas inflammatory responses in subcutaneous adipose tissues are relatively down-regulated. Nonetheless, among the adipose tissue components other than immune cells, the modulators of fat depot-selective inflammatory response is not well understood. Here, we show that γ-aminobutyric acid (GABA) reduces obesity-induced adipose tissue macrophage (ATM) infiltration in subcutaneous inguinal adipose tissues (IAT), but not in visceral epididymal adipose tissue. Our data show that adipose-derived stem cells from IAT respond to GABA to suppress ATM infiltration. Consequently, GABA shows enhanced insulin action in obese IAT, which could be a possible contributor in the regulation of whole-body glucose metabolism.

Abstract

Accumulating evidence suggests that subcutaneous and visceral adipose tissues are differentially associated with metabolic disorders. In obesity, subcutaneous adipose tissue is beneficial for metabolic homeostasis because of repressed inflammation. However, the underlying mechanism remains unclear. Here, we demonstrate that γ-aminobutyric acid (GABA) sensitivity is crucial in determining fat depot-selective adipose tissue macrophage (ATM) infiltration in obesity. In diet-induced obesity, GABA reduced monocyte migration in subcutaneous inguinal adipose tissue (IAT), but not in visceral epididymal adipose tissue (EAT). Pharmacological modulation of the GABAB receptor affected the levels of ATM infiltration and adipose tissue inflammation in IAT, but not in EAT, and GABA administration ameliorated systemic insulin resistance and enhanced insulin-dependent glucose uptake in IAT, accompanied by lower inflammatory responses. Intriguingly, compared with adipose-derived stem cells (ADSCs) from EAT, IAT-ADSCs played key roles in mediating GABA responses that repressed ATM infiltration in high-fat diet-fed mice. These data suggest that selective GABA responses in IAT contribute to fat depot-selective suppression of inflammatory responses and protection from insulin resistance in obesity.


https://www.pnas.org/content/116/24/11936