The low-grade inflammatory state present in obesity contributes to obesity-related metabolic dysregulation, including nonalcoholic steatohepatitis (NASH) and insulin resistance. Intercellular interactions between immune cells or between immune cells and hepatic parenchymal cells contribute to the exacerbation of liver inflammation and steatosis in obesity. The costimulatory molecules, B7.1 and B7.2, are important regulators of cell-cell interactions in several immune processes; however, the role of B7 costimulation in obesity-related liver inflammation is unknown. Here, diet-induced obesity (DIO) studies in mice with genetic inactivation of both B7.1 and B7.2 (double knockout; DKO) revealed aggravated obesity-related metabolic dysregulation, reduced insulin signalling in the liver and adipose tissue (AT), glucose intolerance, and enhanced progression to steatohepatitis resulting from B7.1/B7.2 double deficiency. The metabolic phenotype of B7.1/B7.2 double deficiency upon DIO was accompanied by increased hepatic and AT inflammation, associated with largely reduced numbers of regulatory T cells (Tregs) in these organs. In order to assess the role of B7 costimulation in DIO in a non-Treg-lacking environment, we performed antibody (Ab)-mediated inhibition of B7 molecules in wild-type mice in DIO. Antibodyblockade of both B7.1 and B7.2 improved the metabolic phenotype of DIO mice, which was linked to amelioration of hepatic steatosis and reduced inflammation in liver and AT. Conclusion: Our study demonstrates a dual role of B7 costimulation in the course of obesity-related sequelae, particularly NASH. The genetic inactivation of B7.1/B7.2 deteriorates obesity-related liver steatosis and metabolic dysregulation, likely a result of the intrinsic absence of Tregs in these mice, rendering DKO mice a novel murine model of NASH. In contrast, inhibition of B7 costimulation under conditions where Tregs are present may provide a novel therapeutic approach for obesityrelated metabolic dysregulation and, especially, NASH. (HEPATOLOGY 2014;60:1196-1210 O besity is associated with low-grade inflammation, liable for the development of insulin resistance (IR), type 2 diabetes, and nonalcoholic steatohepatitis (NASH). Immune cells of both innate and adaptive immunity are implicated in this process and contribute to the development of

ObjectiveQuitting smoking was associated with an undesirable weight gain. Both, cigarette smoking and obesity were accompanied by subclinical systemic inflammation. This may cause unfavourable changes in (plasma) adipokine concentration. The aim of the present study was to establish the influence of moderate cigarette smoking on the concentration of the adipokines leptin and adiponectin and the pro-inflammatory factors CRP, SAA, IL-6 and TNF-α in non-obese (n = 138) and obese (n = 175) perimenopausal women of the DRECAN-2005 survey.ResultsAmong non-obese women, adiponectin was significantly lower in smokers than in non-smokers (16.88 ± 6.85 vs. 20.63 ± 10.04 μg/ml; P < 0.05). Leptin tended to lower values, too. Among obese women, none significant differences in adiponectin or leptin concentration were observed between smokers and non-smokers. In obese smokers and obese non-smokers, the adiponectin concentrations were significantly lower and the leptin concentrations were significantly higher than in non-obese non-smokers. Non-obese smokers showed significantly higher leukocyte count (6.50 ± 1.83 vs. 5.51 ± 1.31 GPT/l; P < 0.001) and serum amyloid A concentration (7.81 ± 1.25 vs. 4.22 ± 1.43 mg/l; P < 0.05) than non-obese non-smokers. There were only tendencies to higher concentration of CRP, IL-6, and TNF-α. In obese women, moderate cigarette smoking was not associated with higher leukocyte count or concentration of SAA. Among non-smokers, overweight was associated higher concentration of leptin (22.16 ± 12.16 vs. 11.49 ± 6.37 ng/ml; P < 0.001) and with significantly lower concentration of adiponectin (16.29 ± 8.01 vs. 20.77 ± 9.99 μg/ml; P < 0.001). Among smokers, overweight was associated with higher leptin concentration only (obese: 18.62 ± 13.46 vs. non-obese: 8.84 ± 4.92 ng/ml; P < 0.01).ConclusionsIn non-obese middle aged women, even moderate cigarette smoking adversely influences the serum concentration of adiponectin and SAA. Over-weight hides possible effects of smoking on cytokines and adipokines.

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