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Introduction: The mechanisms behind the detrimental effects of ethanol on the liver remain uncertain. It has been suggested that the presence of ethanol in the gut lumen promotes a ’leaky gut’ allowing bacterial products to translocate to the bloodstream causing an inflammatory response. Furthermore, the ethanol-induced hormone fibroblast growth factor 21 (FGF-21) has emerged as a potential safeguard from ethanol-induced liver injury. Here, we aimed to investigate how ethanol administered intragastrically and intravenously, respectively, influences circulating markers of inflammation and FGF-21. Materials and Method: In a double-blinded, randomized cross-over design, we subjected 12 fasted healthy men (age 25.3±3.9 years; body mass index (BMI) 22.6±2.6 kg/m2 (mean±SD)) to intragastrically instilled ethanol (0.70 g ethanol per kg body weight in a 20% (v/w) solution infused over 5 minutes) and isoethanolaemic iv ethanol infusion, respectively, on two separate experimental days, and evaluated a range of circulating markers of inflammation and liver function as well as FGF-21. Results: No increment in plasma sCD163, or any other inflammation markers (lipopolysaccharide binding protein, tumor necrosis factor-α, interferon-γ, interleukin-10 (IL), IL-12p70, IL-13, IL-1β, IL-2, IL-4, IL-6, and IL-8), was observed. Plasma FGF-21 levels increased significantly (nine times baseline level), similarly and throughout both experimental days. Conclusion: Neither ’oral’ nor iv ethanol elicited significant changes in circulating markers of macrophage activation or inflammation, but increased plasma FGF-21 significantly regardless of the administration form suggesting a direct ethanol effect on FGF-21 secretion. Disclosure A.R. Lanng: None. L.S. Gasbjerg: Stock/Shareholder; Self; Antag Therapeutics. N.C. Bergmann: Employee; Self; Zealand Pharma A/S. H. Møller: Other Relationship; Self; IQ-products. M. Gillum: None. H. Gronbaek: Board Member; Self; Ipsen Biopharmaceuticals, Inc., Novartis AG. Research Support; Self; Intercept Pharmaceuticals, Inc., AbbVie Inc., Novo Nordisk A/S. T. Vilsbøll: Advisory Panel; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Consultant; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Speaker's Bureau; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Research Support; Self; Eli Lilly and Company, Novo Nordisk A/S. F.K. Knop: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Amgen Inc.. Speaker's Bureau; Self; Merck Sharp & Dohme Corp.. Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Consultant; Self; Amgen Inc.. Advisory Panel; Self; MedImmune, Sanofi. Consultant; Self; Sanofi. Research Support; Self; Sanofi. Speaker's Bureau; Self; Sanofi.

Dietary modulation of carcinogenesis-related pathwaysDietary item or component studied: fish oilPathways studied: adiponectin gene expressionStudy type (in vitro, animals, humans): 129Sv miceTissue/biological material/sample size: total plasmaMode of exposure (if in vivo) (acute, chronic, root of exposure): chronic (15 days) and acute dietImpact on pathway (including dose-response): 31+-2.8, n=4 vs 25.6+-3.5, n=4μgr/ml plasma adiponectin in 14.5%fish oil-fed mice. KEYWORDS CLASSIFICATION: Adiponectin;Adipose Tissue;Animals;Antigens,CD36;blood;deficiency;dietary modulation of carcinogenesis-related pathways;drug effects;DNA Primers;Epididymis;Epoxy Compounds;Fish Oils;genetics;Gene Expression Regulation;Male;Mice;Mice,Inbred Strains;Mice,Knockout;Oils;pharmacology;physiology;PPAR gamma;Research;Reverse Transcriptase Polymerase Chain Reaction;secretion;Transcription,Genetic; Adiponectin has insulin-sensitizing, antiatherogenic, and anti-inflammatory properties, but little is known about factors that regulate its secretion. To examine the effect of fish oil on adiponectin secretion, mice were fed either a control diet or isocaloric diets containing 27% safflower oil or 27, 13.5, and 8% menhaden fish oil. Within 15 days, fish oil feeding raised plasma adiponectin concentrations two- to threefold in a dose-dependent manner, and the concentrations remained approximately twofold higher for 7 days when the fish oil diet was replaced by the safflower oil diet. Within 24 h, fish oil markedly induced transcription of the adiponectin gene in epididymal adipose tissue but not in subcutaneous fat. The increase of plasma adiponectin by fish oil was completely blocked by administration of the peroxisome proliferator-activated receptor (PPAR)gamma inhibitor bisphenol-A-diglycidyl ether. In contrast, there was no effect of fish oil feeding on adiponectin secretion in PPARalpha-null mice. These data suggest that fish oil is a naturally occurring potent regulator of adiponectin secretion in vivo and that it does so through a PPARgamma-dependent and PPARalpha-independent manner in epididymal fat.

OBJECTIVE Macrophage recruitment to adipose tissue is a reproducible feature of obesity. However, the events that result in chemokine production and macrophage recruitment to adipose tissue during states of energetic excess are not clear. Sirtuin 1 (SirT1) is an essential nutrient-sensing histone deacetylase, which is increased by caloric restriction and reduced by overfeeding. We discovered that SirT1 depletion causes anorexia by stimulating production of inflammatory factors in white adipose tissue and thus posit that decreases in SirT1 link overnutrition and adipose tissue inflammation. RESEARCH DESIGN AND METHODS We used antisense oligonucleotides to reduce SirT1 to levels similar to those seen during overnutrition and studied SirT1-overexpressing transgenic mice and fat-specific SirT1 knockout animals. Finally, we analyzed subcutaneous adipose tissue biopsies from two independent cohorts of human subjects. RESULTS We found that inducible or genetic reduction of SirT1 in vivo causes macrophage recruitment to adipose tissue, whereas overexpression of SirT1 prevents adipose tissue macrophage accumulation caused by chronic high-fat feeding. We also found that SirT1 expression in human subcutaneous fat is inversely related to adipose tissue macrophage infiltration. CONCLUSIONS Reduction of adipose tissue SirT1 expression, which leads to histone hyperacetylation and ectopic inflammatory gene expression, is identified as a key regulatory component of macrophage influx into adipose tissue during overnutrition in rodents and humans. Our results suggest that SirT1 regulates adipose tissue inflammation by controlling the gain of proinflammatory transcription in response to inducers such as fatty acids, hypoxia, and endoplasmic reticulum stress.