Nutrient excess enhances glucose-dependent insulinotropic polypeptide (GIP) secretion, which may in turn contribute to the development of liver steatosis. We hypothesized that elevated GIP levels in obesity may affect markers of liver injury through microRNAs. The study involved 128 subjects (body mass index (BMI) 25–40). Fasting and postprandial GIP, glucose, insulin, and lipids, as well as fasting alanine aminotransferase (ALT), γ-glutamyltransferase (GGT), cytokeratin-18, fibroblast growth factor (FGF)-19, and FGF-21 were determined. TaqMan low density array was used for quantitative analysis of blood microRNAs. Fasting GIP was associated with ALT [β = 0.16 (confidence interval (CI): 0.01–0.32)], triglycerides [β = 0.21 (95% CI: 0.06–0.36], and FGF-21 [β = 0.20 (95%CI: 0.03–0.37)]; and postprandial GIP with GGT [β = 0.17 (95%CI: 0.03–0.32)]. The odds ratio for elevated fatty liver index (>73%) was 2.42 (95%CI: 1.02–5.72) for high GIP versus low GIP patients. The miRNAs profile related to a high GIP plasma level included upregulated miR-136-5p, miR-320a, miR-483-5p, miR-520d-5p, miR-520b, miR-30e-3p, and miR-571. Analysis of the interactions of these microRNAs with gene expression pathways suggests their potential contribution to the regulation of the activity of genes associated with insulin resistance, fatty acids metabolism, and adipocytokines signaling. Exaggerated fasting and postprandial secretion of GIP in obesity are associated with elevated liver damage markers as well as FGF-21 plasma levels. Differentially expressed microRNAs suggest additional, epigenetic factors contributing to the gut–liver cross-talk.

There is growing interest in the non-invasive identification and monitoring of the outcome of liver damage in obese patients. Plasma cytokeratin-18 (CK-18) fragment levels correlate with the magnitude of hepatocyte apoptosis and have recently been proposed to independently predict the presence of non-alcoholic steatohepatitis (NASH). The aim of the study was to analyze the associations of CK-18 with obesity and related complications: insulin resistance, impaired lipid metabolism and the secretion of hepatokines, adipokines and pro-inflammatory cytokines. The study involved 151 overweight and obese patients (BMI 25–40), without diabetes, dyslipidemia or apparent liver disease. Liver function was assessed based on alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT) and the fatty liver index (FLI). CK-18 M30 plasma levels, FGF-21, FGF-19 and cytokines were determined by ELISA. CK-18 values >150 U/l were accompanied by high ALT, GGT and FLI, insulin resistance, postprandial hypertriglyceridemia, elevated FGF-21 and MCP-1 and decreased adiponectin. ALT activity was the strongest independent factor influencing high CK-18 plasma levels, even after an adjustment for age, sex and BMI [β coefficient (95%CI): 0.40 (0.19–0.61)]. In conclusion, the applied CK-18 cut-off point at 150 U/l allows to distinguish between two metabolic phenotypes in obesity.

Obesity is associated with numerous pathological processes in the body, including inflammation, oxidative stress, and consequently, mitochondrial dysfunction. In recent years, research in anti-obesity therapy has also focused on the function of adipocytes and the inhibition of adipogenesis. In this study, we investigated the effect of the well-known flavonoid quercetin on mitochondrial function, apoptosis and differentiation of human preadipocytes. The Chub-S7 cell line model was used in the in vitro studies. Mitochondrial function was measured by oxygen consumption rates, intracellular ATP content, mitochondrial membrane potential, apoptosis assay (Annexin-5, caspase-9 activity), and ROS generation. Chub-S7 cell differentiation was assessed by Oil Red O staining. The results showed that the quercetin inhibited differentiation of human Chub-S7 preadipocytes and reduced fat accumulation in lipid droplets. Additionally, quercetin influenced mitochondrial biogenesis and mitochondrial uncoupling by changes in mitochondrial respiratory states and also increased mitochondrial membrane potential. Quercetin decreased routine respiration, R/E and netROUTINE control ratio. Our results demonstrate that quercetin is a dietary component that may modulate mitochondrial bioenergetics and inhibit adipogenesis. If these results were confirmed in in vivo studies, quercetin could be considered a factor used to prevent obesity.

Introduction: Disturbed mitochondrial activity in adipocytes is suggested as one of the mechanisms involved in metabolic dysfunction in obesity. Glucagon-like peptide receptor agonists (GLP-1RAs) are used to normalize glucose level and reduce body weight. GLP-1 activates similar intracellular pathway as irisin, peptide that modulate metabolism by stimulating the ‘browning’ of adipocytes. The aim of the study was to investigate the mechanisms of the GLP-1RA, exendin-4, action at the level of mRNA, proteins and mitochondrial activity in human adipocytes. Material and methods: The human preadipocytes Chub-S7 were differentiated in vitro to mature adipocytes and then stimulated with exendin-4 at 100 nM for 24 h. Expression of mRNA and proteins (irisin, adiponectin, visfatin/NAMPT) were measured. Oxygen consumption rates and intracellular ATP content were determined. Results: The exendin-4 enhanced the secretion of irisin and visfatin by adipocytes. The up-regulated expression of FNDC5, NAMPT and UCP2 genes was accompanied by modest changes in mitochondrial activity in exendin-4 treated adipocytes. Exendin-4 exerted similar effect on mitochondrial oxygen consumption rates as irisin, including increased maximum mitochondrial respiration and reserve capacity with unchanged intracellular ATP. Conclusions: Increasing energy expenditure by exendin-4 may be associated with upregulation of irisin in human adipocytes. Clinical studies are necessary to confirm the hypothesis that nutrients, by stimulating the secretion of GLP-1, may influence the expression of irisin and thus modulate the mitochondrial metabolism of adipocytes.

Elevated glucose-dependent insulinotropic peptide (GIP) levels in obesity may predict the metabolic benefits of n-3 PUFA supplementation. This placebo-controlled trial aimed to analyze fasting and postprandial GIP response to 3-month n-3 PUFA supplementation (1.8 g/d; DHA:EPA, 5:1) along with caloric restriction (1200–1500 kcal/d) in obese subjects. Compliance was confirmed by the incorporation of DHA and EPA into red blood cells (RBCs). Blood analyses of glucose, insulin, non-esterified fatty acids (NEFAs), GIP and triglycerides were performed at fasting, and during an oral glucose tolerance test and a high fat mixed-meal tolerance test. Fatty acid composition of RBC was assessed by gas chromatography and total plasma fatty acid content and composition was measured by gas–liquid chromatography. The DHA and EPA content in RBCs significantly increased due to n-3 PUFA supplementation vs. placebo (77% vs. −3%, respectively). N-3 PUFA supplementation improved glucose tolerance and decreased circulating NEFA levels (0.750 vs. 0.615 mmol/L), as well as decreasing plasma saturated (1390 vs. 1001 µg/mL) and monounsaturated (1135 vs. 790 µg/mL) fatty acids in patients with relatively high GIP levels. The effects of n-3 PUFAs were associated with the normalization of fasting (47 vs. 36 pg/mL) and postprandial GIP levels. Obese patients with elevated endogenous GIP could be a target group for n-3 PUFA supplementation in order to achieve effects that obese patients without GIP disturbances can achieve with only caloric restriction.