Background Roux-en-Y gastric bypass (RYGB) surgery results in exaggerated postprandial insulin and incretin responses, and increased susceptibility to hypoglycemia. We examined whether these features are due to caloric restriction (CR) or altered nutrient handling. Methods We performed comprehensive analysis of postprandial metabolite responses during a 2-hour mixed-meal challenge test (MMT) in twenty morbidly obese subjects with type 2 diabetes who underwent RYGB surgery or matched CR. Acylcarnitines and amino acids was measured using targeted mass spectrometry. Linear mixed model was used to determine the main effect of interventions, and interaction term to assess the effect of interventions on postprandial kinetics. Results Two-weeks after these interventions, several gut hormones (insulin, GIP and GLP-1), glucose, and multiple amino acids, including branched-chain and aromatic species, exhibited a more rapid rate of appearance and clearance in RYGB subjects compared to CR during the MMT. In the RYGB group, changes in leucine/isoleucine, methionine, phenylalanine and GLP-1 responses were associated with changes in insulin response. Levels of alanine, pyruvate, and lactate decreased significantly at the later stages of meal challenge in RYGB subjects, but increased with CR. Conclusions RYGB surgery results in improved metabolic flexibility (i.e. greater disposal of glucose and amino acids, and more complete β-oxidation of fatty acids) compared to CR. The changes in the amino acid kinetics may augment the hormonal responses seen after RYGB surgery. The reduction in key gluconeogenic substrates in the postprandial state may contribute to increased susceptibility to hypoglycemic symptoms in RYGB subjects.

Advanced fibrosis and portal hypertension influence short-term mortality. Lipocalin 2 (LCN2) regulates infection response and increases in liver injury. We explored the role of intrahepatic LCN2 in human alcoholic hepatitis (AH) with advanced fibrosis and portal hypertension and in experimental mouse fibrosis. We found hepatic LCN2 expression and serum LCN2 level markedly increased and correlated with disease severity and portal hypertension in patients with AH. In control human livers, LCN2 expressed exclusively in mononuclear cells, while its expression was markedly induced in AH livers, not only in mononuclear cells but also notably in hepatocytes. Lcn2−/− mice were protected from liver fibrosis caused by either ethanol or CCl4 exposure. Microarray analysis revealed downregulation of matrisome, cell cycle and immune related gene sets in Lcn2−/− mice exposed to CCl4, along with decrease in Timp1 and Edn1 expression. Hepatic expression of COL1A1, TIMP1 and key EDN1 system components were elevated in AH patients and correlated with hepatic LCN2 expression. In vitro, recombinant LCN2 induced COL1A1 expression. Overexpression of LCN2 increased HIF1A that in turn mediated EDN1 upregulation. LCN2 contributes to liver fibrosis and portal hypertension in AH and could represent a new therapeutic target.

Alcoholic hepatitis (AH) is the most severe form of alcoholic liver disease for which there are no effective therapies. Patients with AH show impaired hepatocyte proliferation, expansion of inefficient ductular cells and high lipopolysaccharide (LPS) levels. It is unknown whether LPS mediates ductular cell expansion. We performed transcriptome studies and identified keratin 23 (KRT23) as a new ductular cell marker. KRT23 expression correlated with mortality and LPS serum levels. LPS-TLR4 pathway role in ductular cell expansion was assessed in human and mouse progenitor cells, liver slices and liver injured TLR4 KO mice. In AH patients, ductular cell expansion correlated with portal hypertension and collagen expression. Functional studies in ductular cells showed that KRT23 regulates collagen expression. These results support a role for LPS-TLR4 pathway in promoting ductular reaction in AH. Maneuvers aimed at decreasing LPS serum levels in AH patients could have beneficial effects by preventing ductular reaction development.

Background and Aim Adipose tissue is the most abundant endocrine tissue in the body, producing leptin, a hormone important in regulating hunger, and adiponectin, a hormone involved in insulin sensitivity and inflammation. The aim of this study was to assess the impact of gastric bypass surgery (GBS) on leptin levels and its relation to adipose tissue expression of adiponectin. Methods Omental and subcutaneous adipose tissue and serum were obtained from 40 obese patients undergoing GBS, 13 patients one-year or more post-GBS, and 16 non-obese individuals (BMI 20-29). Adiponectin gene expression was measured by quantitative real time PCR and the gene expression was normalized for the GAPDH gene. Serum leptin and adiponectin were measured by a high-sensitivity enzymatic assay. Results Leptin levels were significantly lower in the post-GBS patients as compared to pre-GBS patients (19.8±6.7 vs. 59.0±5.1, p=0.0001) and similar to non-obese controls (19.8±6.7 vs. 18.2±4, p=0.8). Univariate analysis showed an inverse correlation between serum leptin levels and omental adiponectin gene expression (r=-0.32, p=0.01). Conclusions Gastric bypass surgery results in resolution of the leptin resistance status that characterizes obese subjects. We also demonstrated a significant correlation between leptin and adiponectin. This correlation provides preliminary evidences for studying a potential adiponectin-leptin cross-talking that may represent one of the physiological pathways responsible for the regulation of food intake in humans.

Background and Aim Circulating adiponectin is known to correlate negatively with insulin resistance in patients with obesity and diabetes. The aim of this study was to assess the effect of gastric bypass (GB) surgery on adiponectin gene expression in subcutaneous and omental adipose tissues. Methods Adipose tissues and plasma were obtained from 25 subjects undergoing GB surgery, 15 non-obese subjects, and 12 subjects after GB surgery. Real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) was used for analysis of the adipose tissues. Adiponectin expression was normalized for GAPDH and expressed as percentage of subject-matched subcutaneous expression which was given an arbitrary value of 100%. Insulin resistance was assessed by the homeostatic model assessment (HOMA). Circulating adiponectin was assayed by ELISA. Results Omental adiponectin gene expression was 5-fold higher in subjects after GB when compared with age matched morbidly obese subjects before GB (P<0.01). There were not statistical differences in omental adiponectin gene expression observed in subjects after GB and age matched non-obese subjects. For the entire cohort of subjects, there was a significant negative correlation between omental adiponectin expression and insulin resistance expressed by HOMA values (r=−0.62, P<0.001). Circulating adiponectin was significantly lower (p<0.05) in the obese group than in the non-obese and post-GB groups. Conclusion Omental adiponectin gene expression significantly increase after GB surgery reaching levels equal to age matched non-obese subjects. Omental adiponectin expression has a significant negative correlation with the insulin resistance status.