Enteroendocrine cell-derived peptide YY signalling is stimulated by pinolenic acid or Intralipid and involves coactivation of fatty acid receptors FFA1, FFA4 and GPR119.

Long chain fatty acids are sensed by enteroendocrine L cells that express free-fatty acid receptors, including FFA1, FFA4 and the acylethanolamine receptor GPR119. Here we investigated the acute effects of single or multiple agonism at these G protein-coupled receptors in intestinal mucosae where L cell-derived peptide YY (PYY) is anti-secretory and acts via epithelial Y receptors. Mouse ileal or colonic mucosae were mounted in Ussing chambers, voltage-clamped and the resultant short-circuit current (I) recorded continuously.

Structure-Activity Relationship Study of the High-Affinity Neuropeptide Y Receptor Positive Allosteric Modulator VU0506013.

Positive allosteric modulators targeting the Y receptor (YR), a G protein-coupled receptor (GPCR) involved in the regulation of satiety, offer great potential in anti-obesity research. In this study, we selected 603 compounds by using quantitative structure-activity relationship (QSAR) models and tested them in high-throughput screening (HTS). Here, the novel positive allosteric modulator (PAM) VU0506013 was identified, which exhibits nanomolar affinity and pronounced selectivity toward the YR in engineered cell lines and mouse descending colon mucosa natively expressing the YR.

Paracrine relationship between incretin hormones and endogenous 5-hydroxytryptamine in the small and large intestine.

Background: Enterochromaffin (EC) cell-derived 5-hydroxytryptamine (5-HT) is a mediator of toxin-induced reflexes, initiating emesis via vagal and central 5-HT receptors. The amine is also involved in gastrointestinal (GI) reflexes that are prosecretory and promotile, and recently 5-HT's roles in chemosensation in the distal bowel have been described. We set out to establish the efficacy of 5-HT signaling, local 5-HT levels and pharmacology in discrete regions of the mouse small and large intestine.

Vertical Sleeve Gastrectomy Lowers SGLT2/Slc5a2 Expression in the Mouse Kidney.

Bariatric surgery improves glucose homeostasis, but the underlying mechanisms are not fully elucidated. Here, we show that the expression of sodium-glucose cotransporter 2 (SGLT2/Slc5a2) is reduced in the kidney of lean and obese mice following vertical sleeve gastrectomy (VSG). Indicating an important contribution of altered cotransporter expression to the impact of surgery, inactivation of the SGLT2/Slc5a2 gene by clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 attenuated the effects of VSG, with glucose excursions following intraperitoneal injection lowered by ∼30% in wild-type mice but by ∼20% in SGLT2-null animals.

Selective release of gastrointestinal hormones induced by an orally active GPR39 agonist.

Objectives: Obesity is a complex disease associated with a high risk of comorbidities. Gastric bypass surgery, an invasive procedure with low patient eligibility, is currently the most effective intervention that achieves sustained weight loss. This beneficial effect is attributed to alterations in gut hormone signaling.