Lipid stimulation of fatty acid sensors in the human duodenum: relationship with gastrointestinal hormones, BMI and diet.

BACKGROUND AND AIMS: The small intestinal free fatty acid (FFA) sensors, FFA receptor 1 (FFAR1), FFAR4, G-protein receptor 119 (GPR119) and cluster of differentiation-36 (CD36), mediate the fat-induced release of gastrointestinal (GI) hormones. We investigated whether expression of duodenal FFA sensors in humans was (i) altered by intraduodenal (ID) lipid infusion, (ii) disordered in overweight or obese individuals, (iii) related to lipid-induced GI hormone secretion or (iv) affected by habitual dietary patterns. METHODS: Endoscopic duodenal biopsies were collected from 20 lean (body mass index (BMI): 22±1 kg m-2), 18 overweight (BMI: 27±1 kg m-2) and 19 obese (BMI: 35±1 kg m-2) participants at baseline, and following a 30 min ID Intralipid infusion (2 kcal min-1); FFA sensor expression was quantified by reverse transcription-PCR. On a separate day, participants underwent ID Intralipid infusion (2 kcal min-1) for 120 min, to assess GI hormone responses. Habitual diet was evaluated using food frequency questionnaires. RESULTS: Baseline FFAR1 and FFAR4 expression were lower, and CD36 was higher, in obese participants compared with lean participants. ID lipid increased GPR119 and FFAR1 expression equally across study groups, but did not alter FFAR4 or CD36 expression. Increased FFAR1 expression correlated positively with glucose-dependent insulinotropic polypeptide (GIP) secretion (r=0.3, P<0.05), whereas there was no relationship between habitual diet with the expression of FFA sensors. CONCLUSIONS: Obesity is associated with altered duodenal expression of FFAR1, FFAR4 and CD36, suggesting altered capacity for the sensing, absorption and metabolism, of dietary lipids. GPR119 and FFAR1 are early transcriptional responders to the presence of ID lipid, whereas FFAR1 may be an important trigger for lipid-induced GIP release in humans.

Modulation of murine gastric vagal afferent mechanosensitivity by neuropeptide W.

AIM: Neuropeptide W (NPW) is an endogenous ligand for the receptors GPR7 and GPR8 and is involved in central regulation of energy homeostasis. NPW in the periphery is found in gastric gastrin (G) cells. In the stomach, energy intake is influenced by vagal afferent signals, so we aimed to determine the effect of NPW on mechanosensitive gastric vagal afferents under different feeding conditions. METHODS: Female C57BL/6 mice (N > 10 per group) were fed a standard laboratory diet (SLD), high-fat diet (HFD) or were food restricted. The relationship between NPW immunopositive cells and gastric vagal afferent endings was determined by anterograde tracing and NPW immunohistochemistry. An in vitro gastro-oesophageal preparation was used to determine the functional effects of NPW on gastric vagal afferents. Expression of NPW in the gastric mucosa and GPR7 in whole nodose ganglia was determined by quantitative RT-PCR (QRT-PCR). The expression of GPR7 in gastric vagal afferent neurones was determined by retrograde tracing and QRT-PCR. RESULTS: Neuropeptide W immunoreactive cells were found in close proximity to traced vagal afferents. NPW selectively inhibited responses of gastric vagal tension receptors to stretch in SLD but not HFD or fasted mice. In the nodose ganglia, GPR7 mRNA was specifically expressed in gastric vagal afferent neurones. In fasted mice gastric mucosal NPW and nodose GPR7, mRNA was reduced compared with SLD. A HFD had no effect on gastric NPW mRNA, but down-regulated nodose GPR7 expression. CONCLUSION: Neuropeptide W modulates gastric vagal afferent activity, but the effect is dynamic and related to feeding status.

Identifying spinal sensory pathways activated by noxious esophageal acid.

BACKGROUND: The transient receptor potential vanilloid 1 (TRPV1) channel is critical for spinal afferent signaling of burning pain throughout the body. Such pain frequently originates from the esophagus, following acid reflux. The contribution of TRPV1 to spinal nociceptor signaling from the esophagus remains unclear. We aimed to identify the spinal afferent pathways that convey nociceptive signaling from the esophagus, specifically those sensitive to acid, and the extent to which TRPV1 contributes. METHODS: Acid/pepsin (150 mM HCl/1 mg mL(-1) pepsin) or saline/pepsin was perfused into the esophageal lumen of anesthetized wild-type and TRPV1 null mice over 20 min, followed by atraumatic perfuse fixation and removal of the cervical and thoracic spinal cord and dorsal root ganglia (DRG). To identify neurons responsive to esophageal perfusate, immunolabeling for neuronal activation marker phosphorylated extracellular receptor-regulated kinase (pERK) was used. Labeling for calcitonin gene-related peptide (CGRP) and isolectin B4 (IB4) was then used to characterize responsive neurons. KEY RESULTS: Esophageal acid/pepsin perfusion significantly increased the number of pERK-immunoreactive (IR) neurons in the DRG and the cervical and thoracic spinal cord dorsal horn (DH) relative to saline/pepsin (DRG P < 0.01; cervical DH P < 0.05 and thoracic DH P < 0.005). The number of pERK-IR neurons following acid perfusion was significantly attenuated in TRPV1 -/- mice (DH P < 0.05 and DRG P < 0.05). CONCLUSIONS & INFERENCES: This study has identified populations of spinal afferent DRG neurons and DH neurons involved in signaling of noxious acid from the esophagus. There is a major contribution of TRPV1 to signaling within these pathways.