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Leptin-deficient ob/ob mice are overweight, develop insulin resistance, and serve as a model for type 2 diabetes (T2D). Studies suggest that inflammatory pathways are linked to the development of insulin resistance and T2D both in animals and humans. We asked whether the induction of regulatory T cells (Tregs) could alleviate the pathological and metabolic abnormalities in ob/ob mice. We induced TGF-β-dependent CD4 + latency-associated peptide (LAP)-positive Tregs by oral administration of anti-CD3 antibody plus β-glucosylceramide. We found a decrease in pancreatic islet cell hyperplasia, fat accumulation in the liver, and inflammation in adipose tissue, accompanied by lower blood glucose and liver enzymes. In addition, treated animals had decreased CD11b + F4/80 + macrophages and TNF-α in adipose tissue. Adoptive transfer of orally induced CD4 + LAP + Tregs ameliorated metabolic and cytokine abnormalities. Our results demonstrate the importance of inflammation in T2D and identify a unique immunological approach for treatment of T2D by the induction of Tregs.eptin-deficient ob/ob mice are overweight, develop severe insulin resistance elevated liver enzymes, and serve as a model for type 2 diabetes (T2D) and the metabolic syndrome (1, 2). These mice are characterized by an absence of functional leptin, thymic atrophy, and defective immune responses manifested by reduced antigen-specific T-cell proliferation and abnormalities in the number and function of dendritic cells (DCs), regulatory T cells (Tregs), and natural killer T (NKT) cells (3, 4). In recent years, it has become clear that inflammation plays an important role in insulin resistance, and the pathogenesis of T2D with experiments showed that adipose tissue-derived proinflammatory cytokines such as TNF-α could cause insulin resistance in experimental models (5-7). Subsequently, other fat-derived cytokines and bioactive substances such as IL-6, IL-1β, and monocyte chemoattractant protein-1 have been identified (8), and investigators have found that obese adipose tissue is characterized by macrophage infiltration, which serves as an important source of inflammation (9-11).These observations raise the possibility that therapeutical strategies designed to decrease inflammation in adipose tissue might have a beneficial effect in T2D. Indeed, early experiments suggested that the antiinflammatory effects of salicylates have an ameliorating effect in T2D (12, 13), and recent studies report that IL-1 receptor antagonists may be beneficial in T2D (14).Tregs play an important role in the maintenance of immunological self-tolerance and have been shown in experimental models to inhibit the development of autoimmune diseases by suppressing potentially autoreactive T cells (15). Treg function is being investigated in a wide range of human inflammatory and infectious diseases and cancer (16-18). We hypothesized that the induction of Tregs might have an ameliorating effect in the ob/ob model of T2D. Consistent with this hypothesis, in a recent report, investigators found ...

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Gut flora and bacterial translocation (BT) play important roles in the pathogenesis of chronic liver disease, including cirrhosis and its complications. Intestinal bacterial overgrowth and increased bacterial translocation of gut flora from the intestinal lumen predispose patients to bacterial infections, major complications and also play a role in the pathogenesis of chronic liver disorders. Levels of bacterial lipopolysaccharide, a component of gram-negative bacteria, are increased in the portal and/or systemic circulation in several types of chronic liver disease. Impaired gut epithelial integrity due to alterations in tight junction proteins may be the pathological mechanism underlying bacterial translocation. Preclinical and clinical studies over the last decade have suggested a role for BT in the pathogenesis of nonalcoholic steatohepatitis (NASH). Bacterial overgrowth, immune dysfunction, alteration of the luminal factors, and altered intestinal permeability are all involved in the pathogenesis of NASH and its complications. A better understanding of the cell-specific recognition and intracellular signaling events involved in sensing gut-derived microbes will help in the development of means to achieve an optimal balance in the gut-liver axis and ameliorate liver diseases. These may suggest new targets for potential therapeutic interventions for the treatment of NASH. Here, we review some of the mechanisms connecting BT and NASH and potential therapeutic developments.