GIP increases adipose tissue expression and blood levels of MCP-1 in humans and links high energy diets to inflammation: a randomised trial

Abstract

Aims/hypothesis 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. Methods 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. Results 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.Özlem Gögebakan and Martin A. Osterhoff contributed equally to this study.Electronic supplementary material The online version of this article (doi:10.1007/s00125-015-3618-4) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Increased fat cell size: a major phenotype of subcutaneous white adipose tissue in non-obese individuals with type 2 diabetes

“…5d) Although we have employed a highly complex protocol with 13 colour FACS sorting of adipose SVF to characterise WAT residing cell populations, the study has some methodological limitations, among which the amount of patient material and small cohort size are most important. Although the number of participants included in the study (n=27) matches well a number reported in many other studies where in-depth characterisation of adipose tissue has been performed [44][45][46], the current dataset should be considered as a pilot report and further studies in larger independent cohorts need to be performed to further strengthen key results. Furthermore, samples obtained by needle biopsies were too small (2.33±1.05 g) and obtained yields of SVF cells (243,500±142,325 cells) were not sufficient to enable analyses of immune cell activation or cytokine secretion as well as differentiation of sorted progenitor cells.…”

Pathogenetic significance of single nucleotide polymorphisms in the gastric inhibitory polypeptide receptor gene for the development of carbohydrate metabolism disorders in obesity

“…Доказано, что снижение «инкретинового эффекта» является ранней характеристикой СД2 [6]. Ис-следованиями многих авторов выявлена значительная лиганднезависимая или базальная активность рецептора GIPR, что может играть важную роль в регуляции уровня глюкозы в крови [13][14][15][16]. Предполагают, что о функци-ональной роли GIPR можно судить не только по пост-прандиальной секреции гормонов поджелудочной железы (инсулина и С-пептида), а также и по их уров-ням натощак, что косвенно может отражать базальную активность GIPR [13,14,15].…”

“…Ис-следованиями многих авторов выявлена значительная лиганднезависимая или базальная активность рецептора GIPR, что может играть важную роль в регуляции уровня глюкозы в крови [13][14][15][16]. Предполагают, что о функци-ональной роли GIPR можно судить не только по пост-прандиальной секреции гормонов поджелудочной железы (инсулина и С-пептида), а также и по их уров-ням натощак, что косвенно может отражать базальную активность GIPR [13,14,15]. Физиологическое значение такой конститутивной активности рецептора не совсем понятно, однако известно, что полиморфные варианты GIPR могут способствовать изменению его базальной активности [17].…”

N-Caffeoyltryptamine, a Potent Anti-Inflammatory Phenolic Amide, Suppressed MCP-1 Expression in LPS-stimulated THP-1 Cells and Rats Fed a High-Fat Diet

“…However, rats fed a HF diet demonstrated increased plasma levels of MCP-1 by more than 10% compared to rats on the C diet (Figure 5), and the rats fed the HFS diet (supplemented with N -caffeoyltryptamine (2 mg per day)) demonstrated significantly lower plasma MCP-1 levels than those fed the HF diet ( p < 0.05), and even slightly lower than those on the control diet (Figure 5). Because plasma levels of MCP-1 are commonly used as a risk indicator for CVD including atherosclerosis [11,12], and because a high-calorie diet often increases plasma levels of the MCP-1 protein in humans [24], these data suggest that N -caffeoyltryptamine may have positive effects in lowering the plasma levels of MCP-1 in individuals with cardiovascular risks fed a high-calorie diet.…”