Altered intestinal neuroendocrine gene expression in humans with obesity

Abstract

Objective: Gastrointestinal hormones are critically involved in the regulation of food intake and body weight. Previous studies support an interplay between gastrointestinal hormones and the serotonergic system. This study explored intestinal neuroendocrine expression patterns in humans with obesity versus nonobese humans. Methods: Jejunum samples were collected from 164 humans with obesity (120 women; BMI (mean 6 SD): 43.5 6 6.6 kg/m 2 ) while they underwent Roux-en-Y gastric bypass surgery and from 18 nonobese humans (7 women; BMI: 23.5 6 3.0 kg/m 2 ) undergoing distinct intestinal surgeries. mRNA expression of cholecystokinin (CCK), peptide YY3-36 (PYY), nesfatin1, ghrelin, ghrelin O-acyltransferase (GOAT), leptin, leptin receptor (leptinR), glucagon-like-peptide 1 receptor (GLP1R), serotonin transporter (SERT), tryptophan hydroxylase 1 (TPH1), and serotonin receptor 3A (5HT 3A R) was determined with qRT-PCR. Ghrelin and GOAT protein expression was quantified using immunohistological stainings. Statistical analyses were performed with SPSS. Results: Jejunum samples from humans with obesity showed a higher expression of GOAT (mRNA and protein), TPH1, and SERT mRNA compared with the nonobese humans (all P < 0.05). Positive correlations were observed between TPH1, CCK, PYY, and nesfatin1 in nonobese and GOAT, ghrelin, TPH1, SERT, CCK, and PYY in humans with obesity (all P < 0.01). Conclusions: Our top-down approach substantiates the dysregulation of jejunal neuroendocrine hormones in obesity.

Gastric ghrelin, GOAT, leptin, and leptinR expression as well as peripheral serotonin are dysregulated in humans with obesity

“…In this study, we measured 21 inflammatory markers in the blood, finding that the interleukins 1Ra, 8, and 12, as well as the monocyte chemoattractant protein 1 (MCP1), are elevated in the humans with obesity compared with the non‐obese humans (Table ). We also correlated these elevated inflammatory markers with the markers we measured in the blood, namely active ghrelin, leptin, and 5HT, and we found a significant negative correlation of IL1Ra and leptin ( r = −0.724; p < 0.05) in obese individuals.…”

“…F). Since circulating ghrelin is produced predominantly in the stomach, we measured active ghrelin in the serum, which appears to be reduced in the obese individuals, although not significantly ( p = 0.06) as compared with the non‐obese group (obese: 338.3 ± 38.3 pg/mL; non‐obese: 534.6 ± 91.46 pg/mL) …”

“…Earlier research has identified gastrointestinal and peripheral hormones which affect appetite regulation, energy expenditure, and body adiposity. Such studies associate a dysregulation of particular gastrointestinal hormones with the development of obesity . Obesity burdens not only humans with obesity but also the health systems of many Western countries that spend millions seeking to deal with obesity and its effects .…”

Glucagon-like peptide 1 in the pathophysiology and pharmacotherapy of clinical obesity

“…Findings from a recent study by Ritze et al[162] studying the gene expression of several proteins in the intestinal neuroendocrine network go some way to suggest intestinal GLP-1 expression and/or function may be altered in obesity. Though GLP-1 was not directly tested in the study, the anorectic neuropeptide PYY shown to co-localise and be co-secreted with GLP-1 in enteroendocrine cells[163] was tested.…”

“…Though GLP-1 was not directly tested in the study, the anorectic neuropeptide PYY shown to co-localise and be co-secreted with GLP-1 in enteroendocrine cells[163] was tested. Taking PYY levels as proxy measures of GLP-1, Ritze et al[162] report significant correlations between GLP-1 with the GLP-1R in non-obese subjects (suggesting physiological ligand-receptor signalling), a correlation lost in obese subjects and replaced by correlations with the orexigen ghrelin ( P < 0.01). Ritze et al[162] also observed correlations between the long-term satiety signal leptin and GLP-1R in obese subjects not seen in their lean counterparts.…”