👤 Natalia Rudovich

Obesity is associated with elevated monocyte chemoattractant protein-1 (MCP-1), a proinflammatory chemokine related to diabetes and cardiovascular disease. Since obesity is triggered by energy dense diets, we hypothesised that nutrient induced intestinal hormones such as glucose-dependent insulinotropic peptide (GIP) may directly stimulate the release of chemokines from adipose tissue and induce low-grade inflammation. GIP effects on gene expression and secretion of inflammatory markers were studied by microarray analysis and PCR from human subcutaneous fat biopsies of slightly obese but healthy volunteers in the metabolic ward of German Institute of Human Nutrition, Department of Clinical Nutrition, Potsdam-Rehbrücke. To allocate the participants to the study arms they were numbered in order of their recruitment and then assigned to the groups by a random number generator. In a randomised, single-blind (participants) crossover design, the participants received GIP infusions in postprandial concentrations (2 pmol kg(-1) min(-1)) or saline (154 mmol/l NaCl) infusions for 240 min either alone, in combination with hyperinsulinaemic-euglycaemic (EU) or hyperinsulinaemic-hyperglycaemic (HC) clamps. Possible mechanisms of GIP effects were investigated in single and co-cultures of macrophage and adipocyte cell lines and in primary human monocytes, macrophages and adipocytes. A total of 17 participants were randomised to the following groups: EU with GIP infusion (n = 9); EU with NaCl infusion (n = 9); HC with GIP infusion (n = 8); HC with NaCl infusion (n = 8); sole GIP infusion (n = 11) and sole placebo infusion (n = 11). All 17 individuals were analysed. The study is completed. In human subcutaneous adipose tissue (hSCAT), infusions of GIP significantly increased inflammatory chemokine and cytokine gene networks in transcriptomic microarray analyses. Particularly MCP-1 (180 ± 26%), MCP-2 (246 ± 58%) and IL-6 (234 ± 40%) mRNA levels in adipose tissue as well as circulating plasma concentrations of MCP-1 (165 ± 12 vs 135 ± 13 pg/ml; GIP vs saline after 240 min; p < 0.05 for all variables) in humans increased independently of circulating insulin or glucose plasma concentrations. GIP stimulation increased Mcp-1 mRNA-expression in co-cultures of differentiated 3T3L1-adipocytes and RAW 264.7 macrophages but not in the isolated cell lines. Similarly, GIP increased MCP-1 transcripts in co-cultures of primary human macrophages with human adipocytes. GIP receptor (GIPR) transcripts were present in primary monocytes and the different cell lines and induced activation of extracellular related kinase (ERK) as well as increases in cAMP, indicating functional receptors. Our findings suggest that the nutrient induced gut hormone GIP may initiate adipose tissue inflammation by triggering a crosstalk of adipocytes and macrophages involving MCP-1. ClinicalTrials.gov NCT00774488. This work was supported by the German Research Foundation (DFG): grant No. Pf164/021002. Show less

Obesity, type 2 diabetes and associated metabolic diseases are characterized by low-grade systemic inflammation which involves interplay of nutrition and monocyte/macrophage functions. We suggested that some factors such as nutrient components, neuropeptides involved in the control of gastrointestinal functions, and gastrointestinal hormones might influence immune cell functions and in this way contribute to the disease pathogenesis. The aim of this study was to investigate the mRNA expression of twelve nutrition-associated receptors in peripheral blood mononuclear cells (PBMC), isolated monocytes and monocyte-derived macrophages and their regulation under the switching from the high-carbohydrate low-fat diet to the low-carbohydrate high-fat (LC/HFD) isocaloric diet in healthy humans. The mRNA expression of receptors for short chain fatty acids (GPR41, GPR43), bile acids (TGR5), incretins (GIPR, GLP1R), cholecystokinin (CCKAR), neuropeptides VIP and PACAP (VIPR1, VIPR2), and neurotensin (NTSR1) was detected in PBMC and monocytes, while GPR41, GPR43, GIPR, TGR5, and VIPR1 were found in macrophages. Correlations of the receptor expression in monocytes with a range of metabolic and inflammatory markers were found. In non-obese subjects, the dietary switch to LC/HFD induced the increase of GPR43 and VIPR1 expression in monocytes. No significant differences of receptor expression between normal weight and moderately obese subjects were found. Our study characterized for the first time the expression pattern of nutrition-associated receptors in human blood monocytes and its dietary-induced changes linking metabolic responses to nutrition with immune functions in health and metabolic diseases. Show less

Glucose-induced insulinomimetic peptide (GIP) is a gut hormone produced by enteroendocrine K-cells in the intestinal mucosa in response to fat, glucose, and also protein. GIP releases insulin from the β cells of the pancreatic islets of Langerhans and therefore is an incretin hormone. GIP acts on a G-protein-coupled receptor that is widely distributed in the body including adipose tissue, stomach, brain, and others. Deletion of the GIP receptor (GIPR) renders mice resistant to weight gain induced by a high fat diet.We observed that weight gain induced by ovarectomy in female mice is prevented by GIPR deletion that is linked to reduced food intake and reduced hypothalamic expression of orectic neurotransmitters. Moreover, old male GIPR(-/-) mice placed on a high glycemic index diet maintained a high insulin sensitivity and were much more active than controls, which was not seen in young animals. Thus, GIP elicits central effects in response to nutrients that protect against obesity and insulin resistance. We then investigated the acute responses of humans to treatment with GIP over 4h in a dose mimicking postprandial plasma levels of about 100pmol/L. At basal glucose, GIP does not elicit insulin release. Fat biopsies taken before and after 4h of GIP treatment were analyzed for transcriptomic responses using Agilent whole human genome assays. There was a highly significant upregulation of an inflammatory expression pattern in a pathway analysis. Show less

Gastric inhibitory polypeptide (GIP) is an insulinotropic duodenal hormone released in response to meals. Recent studies in rodents suggested that GIP directly links overnutrition to obesity. Despite evidence for GIP effects on fat metabolism in humans, the GIP receptor (GIPR) has not been identified in fat tissues. We identified the GIPR gene in human subcutaneous and visceral fat tissues and tested the hypothesis that that the expression of this gene is influenced by central obesity and weight loss. GIPR gene mRNA expression in subcutaneous fat tissue biopsies (n=70) and in paired subcutaneous and visceral fat tissue samples (n=25) of non-diabetic postmenopausal women was studied by real-time reverse transcription polymerase chain reaction. The effect of weight reduction on GIPR gene expression in subcutaneous fat tissue was studied in a subset of 14 women. GIPR adipose tissue gene expression was significantly lower in insulin resistant obese non-diabetic women (p=0.004). The GIPR mRNA expression was higher in the visceral fat tissue compared with subcutaneous fat (p<0.001). Despite adjustment for obesity-associated variables, waist circumference was the most significant predictor of GIPR gene expression in subcutaneous fat depot (F=4.066; beta=-0.997; p=0.0001) and, together with fasting insulin levels, in visceral fat (F=3.553; beta=-0.507 and beta=0.495; p=0.0001). Moderate weight reduction did not change gene expression levels of the GIPR gene (p=0.085). Decreased expression of the GIPR gene in subcutaneous fat tissue is associated with signs of insulin resistance in non-diabetic women with central obesity and demonstrates that fasting hyperinsulinemia is a possible negative regulator of GIPR gene expression in subcutaneous fat. Higher GIPR gene expression levels in visceral fat vs. subcutaneous fat reflect regional differences in adipose tissue biology. Moderate weight reduction did not change gene expression levels of GIPR in subcutaneous fat. Show less