Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters.

Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Joslin Diabetes Center, Boston, Massachusetts, USA.
Nature medicine (Impact Factor: 28.05). 09/2009; 15(8):930-9. DOI: 10.1038/nm.2002
Source: PubMed

ABSTRACT Obesity is accompanied by chronic, low-grade inflammation of adipose tissue, which promotes insulin resistance and type-2 diabetes. These findings raise the question of how fat inflammation can escape the powerful armamentarium of cells and molecules normally responsible for guarding against a runaway immune response. CD4(+) Foxp3(+) T regulatory (T(reg)) cells with a unique phenotype were highly enriched in the abdominal fat of normal mice, but their numbers were strikingly and specifically reduced at this site in insulin-resistant models of obesity. Loss-of-function and gain-of-function experiments revealed that these T(reg) cells influenced the inflammatory state of adipose tissue and, thus, insulin resistance. Cytokines differentially synthesized by fat-resident regulatory and conventional T cells directly affected the synthesis of inflammatory mediators and glucose uptake by cultured adipocytes. These observations suggest that harnessing the anti-inflammatory properties of T(reg) cells to inhibit elements of the metabolic syndrome may have therapeutic potential.

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    ABSTRACT: A unique population of Foxp3(+)CD4(+) regulatory T (Treg) cells, with a distinct transcriptome and antigen-receptor repertoire, resides in visceral adipose tissue (VAT) of lean individuals. These cells regulate local inflammation and both local and systemic metabolic indices. Here we focus on expansion of the VAT Treg compartment in aging lean mice-assessing these cells' phenotypic conversion from conventional CD4(+) T cells, influx from lymphoid organs, and local population dynamics. Our findings establish that the VAT Treg compartment is seeded from thymocytes generated during the first weeks of life and expands beyond 10 weeks of age due to indolent proliferation, of certain clones in particular, coupled with enhanced survival. Accumulation of VAT Tregs depends on the antigen(s) presented by MHC class-II molecules and soluble mediators, notably interleukin(IL)-33. Addressing such factors therapeutically promises novel approaches for harnessing Tregs to stem the growing epidemic of obesity and consequent metabolic abnormalities. Copyright © 2015 Elsevier Inc. All rights reserved.
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    ABSTRACT: Low-grade inflammation in the obese AT (AT) and the liver is a critical player in the development of obesity-related metabolic dysregulation, including insulin resistance, type 2 diabetes and non-alcoholic steatohepatitis (NASH). Myeloid as well as lymphoid cells infiltrate the AT and the liver and expand within these metabolic organs as a result of excessive nutrient intake, thereby exacerbating tissue inflammation. Macrophages are the paramount cell population in the field of metabolism-related inflammation; as obesity progresses, a switch takes place within the AT environment from an M2-alternatively activated macrophage state to an M1-inflammatory macrophage-dominated milieu. M1-polarized macrophages secrete inflammatory cytokines like TNF in the obese AT; such cytokines contribute to insulin resistance in adipocytes. Besides macrophages, also CD8(+) T cells promote inflammation in the AT and the liver and thereby the deterioration of the metabolic balance in adipocytes and hepatocytes. Other cells of the innate immunity, such as neutrophils or mast cells, interfere with metabolic homeostasis as well. On the other hand, eosinophils or T-regulatory cells, the number of which in the AT decreases in the course of obesity, function to maintain metabolic balance by ameliorating inflammatory processes. In addition, eosinophils and M2-polarized macrophages may contribute to "beige" adipogenesis under lean conditions; beige adipocytes are located predominantly in the subcutaneous AT and have thermogenic and optimal energy-dispensing properties like brown adipocytes. This chapter will summarize the different aspects of the regulation of homeostasis of metabolic tissues by immune cells.
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