Functional Dichotomy of Developmental Foxp3+ Treg Cell Subsets in the Visceral Adipose Tissue of Lean and Obese Mice

Chronic inflammation and loss of Foxp3+ regulatory T (Treg) cells in the visceral adipose tissue (VAT) are hallmarks of the pathogenesis of insulin resistance and obesity. This study explores the roles of VAT Treg cells from thymic (tTreg) and peripheral (pTreg) developmental origin, revealing their opposing roles in metabolic inflammation. Obesity destabilized VAT tTreg cells, causing them to clonally expand into obesogenic Foxp3-IFN-{gamma}+ T effector cells, enhancing pro-inflammatory type 1 responses. Genetic tTreg ablation prevented this shift, promoting anti-inflammatory type 2 response, reduced body weight, and improved insulin resistance. Compared to their tTreg counterpart, pTreg cells were functionally well adapted to maintain VAT homeostasis and protect against obesity. Genetic pTreg ablation promoted spontaneous obesity symptoms even with physiological calorie intake, and worsened VAT inflammation and liver steatosis on a high-calorie diet. These findings highlight tTreg instability as a pathogenic threat and pTreg cells as crucial regulators of metabolic homeostasis. HighlightsO_LIVAT Tregs of lean mice originate from both thymic and peripheral Treg development C_LIO_LIHigh-calorie diet destabilizes tTregs that clonally expand into obesogenic IFN-{gamma}+ Th1 cells C_LIO_LIGenetic tTreg deficiency improves steady-state metabolism and prevents diet-induced obesity C_LIO_LIGenetic pTreg deficiency promotes obesity in both sexes even with normal calorie intake C_LIO_LIVAT pTregs are particularly adapted to regulate VAT homeostasis, including adipogenesis C_LI In BriefObesity and type 2 diabetes are characterized by insulin resistance, regulatory T (Treg) cell loss, and chronic inflammation in visceral adipose tissue (VAT). In this context, Yilmazer et al. dissect the functional roles of tTreg and pTreg cells. They show that VAT pTreg cells are particularly adapted to exert non-redundant homeostatic functions, and that pTreg deficiency predisposes to obesity even with normal calorie intake. In contrast, VAT tTreg cells can contribute to local inflammation by dedifferentiating into Foxp3- Th1-polarized effector cells. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/642664v1_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@19c740corg.highwire.dtl.DTLVardef@86d52borg.highwire.dtl.DTLVardef@152a88org.highwire.dtl.DTLVardef@19b7b13_HPS_FORMAT_FIGEXP M_FIG C_FIG