Insulin resistance and type-2 diabetes often accompany obesity and have been linked to obesity by the low- grade chronic inflammation of adipose tissue that occurs in the obese state. Recently, cells of the adaptive immune system have been shown to be involved in the regulation of adipose tissue inflammation. Specifically, regulatory T cells (Tregs), a subset of T lymphocytes with an immunosuppressive function, are enriched in adipose tissue of lean, but not obese, mice. These fat-resident Tregs (fTregs) may have a role in suppressing inflammation and preventing insulin resistance in the visceral fat. Their abundance in the visceral fat of mice inversely correlates with the level of inflammation in the visceral fat as well as insulin resistance. A recent study showed that fTregs have a different gene expression signature compared to Tregs isolated from the spleen or lymph nodes in mice. In particular, one of the genes specifically upregulated in fTregs is peroxisome proliferator-activated receptor gamma (PPAR!), a key regulator of adipogenesis and organismal metabolism. In addition, preliminary studies have shown that when PPAR! is specifically deleted in Tregs in mice, Tregs are no longer enriched in the visceral fat. It is thus hypothesized that th fat-specific adaptation of fTregs is dependent upon the expression and transcriptional activity of PPAR! in these cells. This proposal seeks to characterize the key molecular mechanisms involved in the upstream induction of PPAR!""""""""and its downstream transcriptional targets in fTregs. Furthermore, the necessity of PPAR!""""""""in fTregs for the therapeutic mechanism of action of thiazolidinediones (TZDs), an important anti-diabetic class of drugs that are PPAR!""""""""agonists, will be investigated using a mouse model generated in our lab. First, it is hypothesized that the unique expression of PPAR! in fTregs is due to a distinct adipokine/cytokine milieu within visceral adipose tissue. The upstream signaling pathways involved in PPAR! induction in fTregs will be dissected using in vitro loss-of-function experiments. Second, it is hypothesized that, once expressed, PPAR! acts in a unique way to reshape the transcriptional signature of fTregs and to enable fTreg-specific function, including maintenance of Treg enrichment in visceral fat and potentially protection against insulin resistance. Thus, ChIP-Seq and microarray expression technologies will be used to map the PPAR! cistrome in fTregs and identify key PPAR! downstream targets that could potentially mediate fTreg function. Third, it is hypothesized that expression of PPAR! in fTregs is critical for TZDs to exert their full therapeutic, insulin-sensitizing potential in mice under metabolic stress. Mice with a Treg-specific PPAR! deletion will be generated and fed high fat diet with or without TZD. The ability of TZDs to protect against progression of insulin resistance and metabolic syndrome in these mice will be compared to their wild-type counterparts. Taken together, these studies will systematically characterize the role of PPAR! in fTregs and illuminate the role of fTregs in the pathogenesis of obesity-related type-2 diabetes.

Public Health Relevance

Obesity-related type-2 diabetes is a growing global epidemic with clinical interventions that are insufficient to prevent premature morbidity and mortality arising from the common debilitating sequelae of type-2 diabetes including retinopathy, neuropathy, vascular disease, heart disease, and kidney disease. Our research seeks to characterize, on a molecular level, a newly discovered population of cells, fat-resident regulatory T cells, that could possibly play a role in protection against insulin resistance and type-2 diabetes. This research could lay the groundwork for a novel cell-based therapy for patients suffering from obesity-related type-2 diabetes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZDK1-GRB-R (O1))
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Castle, Arthur
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Salk Institute for Biological Studies
La Jolla
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Bapat, Sagar P; Myoung Suh, Jae; Fang, Sungsoon et al. (2015) Depletion of fat-resident Treg cells prevents age-associated insulin resistance. Nature 528:137-41
Zhang, Ling-juan; Guerrero-Juarez, Christian F; Hata, Tissa et al. (2015) Innate immunity. Dermal adipocytes protect against invasive Staphylococcus aureus skin infection. Science 347:67-71