Progressive obesity and its associated metabolic syndromes represent a globally growing challenge, yet mechanistic understanding and current therapeutics are unsatisfactory. We discovered that CD4+ T-lymphocytes, resident in visceral adipose tissue (VAT), control insulin-resistance in diet-induced obese (DIO) mice and likely humans. DIO VAT-associated T cells display biased TCR-Vα repertoires suggesting antigen-specific expansion. CD4+ T-lymphocyte control of glucose homeostasis is compromised in DIO when VAT accumulates pathogenic IFNγ-secreting Th1 cells, overwhelming static numbers of Th2 (CD4+GATA-3+) and regulatory Foxp3+ T cells. CD4+ T cell transfer into DIO, lymphocyte-free RAGnull mice reversed weight gain and insulin resistance predominately through Th2 cells. Brief systemic treatment with αCD3 antibody or its F(ab′)2 fragment, restores the Th1/Foxp3+ balance and reverses insulin resistance for months, despite continuing high-fat diet. The progression of obesity-associated metabolic abnormalities is physiologically under CD4+ T cell control, with expansion of adipose tissue-resident T cells that can be manipulated by immunotherapy.

In type 1 diabetes, T cell-mediated death of pancreatic beta cells produces insulin deficiency. However, what attracts or restricts broadly autoreactive lymphocyte pools to the pancreas remains unclear. We report that TRPV1(+) pancreatic sensory neurons control islet inflammation and insulin resistance. Eliminating these neurons in diabetes-prone NOD mice prevents insulitis and diabetes, despite systemic persistence of pathogenic T cell pools. Insulin resistance and beta cell stress of prediabetic NOD mice are prevented when TRPV1(+) neurons are eliminated. TRPV1(NOD), localized to the Idd4.1 diabetes-risk locus, is a hypofunctional mutant, mediating depressed neurogenic inflammation. Delivering the neuropeptide substance P by intra-arterial injection into the NOD pancreas reverses abnormal insulin resistance, insulitis, and diabetes for weeks. Concordantly, insulin sensitivity is enhanced in trpv1(-/-) mice, whereas insulitis/diabetes-resistant NODxB6Idd4-congenic mice, carrying wild-type TRPV1, show restored TRPV1 function and insulin sensitivity. Our data uncover a fundamental role for insulin-responsive TRPV1(+) sensory neurons in beta cell function and diabetes pathoetiology.

Obesity is associated with numerous inflammatory conditions including atherosclerosis, autoimmune disease and cancer. Although the precise mechanisms are unknown, obesity‐associated rises in TNF‐α, IL‐6 and TGF‐β are believed to contribute. Here we demonstrate that obesity selectively promotes an expansion of the Th17 T‐cell sublineage, a subset with prominent pro‐inflammatory roles. T‐cells from diet‐induced obese mice expand Th17 cell pools and produce progressively more IL‐17 than lean littermates in an IL‐6‐dependent process. The increased Th17 bias was associated with more pronounced autoimmune disease as confirmed in two disease models, EAE and trinitrobenzene sulfonic acid colitis. In both, diet‐induced obese mice developed more severe early disease and histopathology with increased IL‐17+ T‐cell pools in target tissues. The well‐described association of obesity with inflammatory and autoimmune disease is mechanistically linked to a Th17 bias.

Early nutritional intervention could benefit patients undergoing ECMO, and those who reached the delivery goal of 80% had significantly better outcomes than other patients. Enteral feeding can begin early and was well tolerated by patients receiving ECMO therapy. Following individual nutrition goals is critical for better outcomes, and this analysis might be useful in establishing individualized nutrition goals for oriental population when caring for critically ill patients.

Aging is accompanied by pathophysiological changes including insulin resistance and fatty liver. Dietary supplementation with (-)-epigallocatechin-3-gallate (EGCG) improves insulin sensitivity and attenuates fatty liver disease. We hypothesized that EGCG could effectively modulate aging-associated changes in glucose and lipid metabolism in senescence-accelerated mice (SAM) prone 8 (SAMP8). Higher levels of glucose, insulin, and free fatty acid, inhibited Akt activity, and decreased glucose transporter 4 (GLUT4) expression were observed in SAMP8 mice compared to the normal aging group, SAM resistant 1 mice. EGCG supplementation for 12 weeks successfully decreased blood glucose and insulin levels via restoring Akt activity and GLUT4 expression and stimulating AMPKα activation in skeletal muscle. EGCG up-regulated genes involved in mitochondrial biogenesis and subsequently restored mitochondrial DNA copy number in skeletal muscle of SAMP8 mice. Decreased adipose triglyceride lipase and increased sterol regulatory element binding proteins-1c (SREBP-1c) and carbohydrate responsive element binding protein at mRNA levels were observed in SAMP8 mice in accordance with hepatocellular ballooning and excess lipid accumulation. The pevention of hepatic lipid accumulation by EGCG was mainly attributed to down-regulation of mTOR and SREBP-1c-mediated lipid biosynthesis via suppression of the positive regulator, Akt, and activation of the negative regulator, AMPKα, in the liver. EGCG beneficially modulates glucose and lipid homeostasis in skeletal muscle and liver, leading to alleviation of aging-associated metabolic disorders.

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OBJECTIVE-Type 1 diabetes reflects autoimmune destruction of ␤-cells and peri-islet Schwann cells (pSCs), but the mechanisms of pSC death and the T-cell epitopes involved remain unclear.RESEARCH DESIGN AND METHODS-Primary pSC cultures were generated and used as targets in cytotoxic T-lymphocyte (CTL) assays in NOD mice. Cognate interaction between pSC and CD8 ϩ T-cells was assessed by transgenic restoration of ␤2-microglobulin (␤2m) to pSC in NOD.␤2m Ϫ/Ϫ congenics. I-A g7 and K d epitopes in the pSC antigen glial fibrillary acidic protein (GFAP) were identified by peptide mapping or algorithms, respectively, and the latter tested by immunotherapy.RESULTS-pSC cultures did not express major histocompatibility complex (MHC) class II and were lysed by ex vivo CTLs from diabetic NOD mice. In vivo, restoration of MHC class I in GFAP-␤2m transgenics significantly accelerated adoptively transferred diabetes. Target epitopes in the pSC autoantigen GFAP were mapped to residues 79 -87 and 253-261 for K d and 96 -110, 116 -130, and 216 -230 for I-A g7 . These peptides were recognized spontaneously in NOD spleens as early as 2.5 weeks of age, with proliferative responses peaking around weaning and detectable lifelong. Several were also recognized by T-cells from new-onset type 1 diabetic patients. NOD mouse immunotherapy at 8 weeks with the CD8 ϩ T-cell epitope, GFAP 79 -87 but not 253-261, significantly inhibited type 1 diabetes and was associated with reduced ␥-interferon production to whole protein GFAP.CONCLUSIONS-Collectively, these findings elucidate a role for pSC-specific CD8 ϩ T-cells in islet inflammation and type 1 diabetes pathogenesis, further supporting neuronal involvement in ␤-cell demise. Diabetes 57:918-928, 2008

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