Feuerer, M. et al. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat. Med. 15, 930-939

Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Joslin Diabetes Center, Boston, Massachusetts, USA.
Nature medicine (Impact Factor: 27.36). 09/2009; 15(8):930-9. DOI: 10.1038/nm.2002
Source: PubMed


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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    • "The pro-inflammatory, IL17-producing effector T cells (Th17) are counterbalanced by the regulatory T cells (Tregs), which play a relevant role in the control of inflammation and can release IL10. Tregs are blunted by high fat diet in the setting of NASH[15], while an upregulation of the Th17 pathway occurs in fatty liver[16]and in liver fibrosis[17]. Much evidence shows that splanchnic inflammation contributes to the initiation and maintenance of portal hypertension, creating a loop between portal hypertension, splanchnic endothelial disorder, portal hypertensive enteropathy with inflammatory cell infiltration and gut microbiota alteration, systemic low-grade inflammation, and metabolic imbalance (due to a switch to predominant lipid metabolism)[18]. "
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    ABSTRACT: Background: Haemodynamic impairment, inflammatory mediators and glucose metabolism disturbances have been implicated in the pathogenesis of Non-Alcoholic Fatty Liver Disease (NAFLD). Aim: To investigate the cytokine profile in NAFLD patients in peripheral (P) and hepatic venous (HV) blood and to compare with histology, haemodynamic and metabolic parameters. Methods: 40 obese patients with an indication for a transjugular liver biopsy were enrolled. Besides an extended liver and metabolic work-up, interleukin (IL) 1B, IL4, IL6, IL10, IL23, tumour necrosis factor (TNF) α and interferon (INF) γ were measured in plasma obtained from P and HV blood by means of multiplex immunoassay. The T helper (Th)1/Th2, the macrophage M1/M2 and the IL10/IL17a ratios were calculated. Results: A decrease of the P-IL10/IL17-ratio and an increase of the P-M1/M2-ratio (p<0.05) were observed in NASH versus no-NASH patients. A P-M1/M2-ratio increase was detected also in patients with portal hypertension in comparison with patients without it (p<0.05). Moreover diabetic patients showed an increase of the P-Th1/Th2-ratio in comparison with non-diabetic ones (p<0.05). The P-M1/M2 ratio positively correlated with steatosis grade (r = 0.39, p = 0.02) and insulin (r = 0.47, p = 0.003). The HV-M1/M2 ratio positively correlated with fasting insulin and Hepatic Venous Pressure Gradient (r = 0.47, p = 0.003). IL6 correlated with the visceral fat amount (r = 0.36, p = 0.02). The P- and HV-IL10/IL17 ratios negatively correlated with fasting insulin (respectively r = -0.4, p = 0.005 and r = 0.4, p = 0.01). Conclusions: A proinflammatory cytokine state is associated with more disturbed metabolic, histological, and haemodynamic features in NAFLD obese patients. An increase of the M1/M2 ratio and a decrease of the IL10/IL17 ratio play a key role in this process.
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    • "In addition, regulatory cells are lost as the inflammatory process progresses. Regulatory T cell numbers decrease in favor of IFN producing Th1 and NKT cells[76,82,123]. ILC2 and eosinophil numbers decline with the increase in adipose tissue mass, which facilitates M1 ATM polarization[83,84]. "
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    • "In over-expressing RBP4 (ox-RBP4) mice, the AT show increasing of both CD11c+ and CD206+ macrophage populations with an unexpected, pro-inflammatory cytokines produced by CD206+ and expression of elevated amounts of co-stimulatory molecules required for CD4 T cell activation, typical behavior of CD11c+ macrophages [13]. Macrophages activation is only part of the immune response that causes insulin resistance, there is also the recruitment of T cells to AT [14] [15] [16]. RBP4 increases the capacity of macrophages to induce a CD4 T cell immune response. "
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    ABSTRACT: Obesity, insulin resistance, metabolic syndrome and type 2 diabetes have reached epidemic proportions, from here the term: diabesity. Vitamin A is delivered by a specific binding protein called retinol-binding protein 4 (RBP4) a soluble protein, emerging to have a role in insulin resistance, the major cause of diabetes highly associated with adipose tissue inflammation and obesity with action. RBP4, interacts with two receptors, the Toll-like receptor 4 (TLR4) and the plasma membrane protein called stimulated by retinoic acid 6 (STRA6) leading to the activation of c-Jun N-terminal protein kinase (JNK) pathways and JAK2/STAT5 cascade, respectively. Both mechanism sustain insulin resistance. In effect, ablation of STRA6 protects mice from RBP4-induced suppression of insulin signaling. In addition, mice harboring deletion of a specific chaperon for retinol, show infiltration of α-cells in the core of pancreatic islets, where usually only β-cells reside, showing a pre-diabetic like phenotype. Not only proteins in vitamin A shuttle and signaling are emerging in diabesity, recently the discovery of 9cis retinoic acid (9cRA) having effects in controlling glucose levels opened a new scenario. So far, only pancreas β-cells have been shown to synthesize it, and high levels of 9cRA correlate with obesity mice models. In this article, we summarize the recent literature present on this topic raising the hypothesis.
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