Metabolic surgery modulates the enterohormone profile, which leads, among other effects, to changes in food intake. Bitter taste receptors (TAS2Rs) have been identified in the gastrointestinal tract and specific stimulation of these has been linked to the control of ghrelin secretion. We hypothesize that optimal stimulation of TAS2Rs could help to modulate enteroendocrine secretions and thus regulate food intake. To determine this, we have assayed the response to specific agonists for hTAS2R5, hTAS2R14 and hTAS2R39 on enteroendocrine secretions from intestinal segments and food intake in rats. We found that hTAS2R5 agonists stimulate glucagon-like peptide 1 (GLP-1) and cholecystokinin (CCK), and reduce food intake. hTAS2R14 agonists induce GLP1, while hTASR39 agonists tend to increase peptide YY (PYY) but fail to reduce food intake. The effect of simultaneously activating several receptors is heterogeneous depending on the relative affinity of the agonists for each receptor. Although detailed mechanisms are not clear, bitter compounds can stimulate differentially enteroendocrine secretions that modulate food intake in rats.

Obesity and ageing are current issues of global concern. Adaptive homeostasis is compromised in the elderly, who are more likely to suffer age-related health issues, such as obesity, metabolic syndrome, and cardiovascular disease. The current worldwide prevalence of obesity and higher life expectancy call for new strategies for treating metabolic disorders. Grape-seed proanthocyanidin extract (GSPE) is reported to be effective in ameliorating these pathologies, especially in young animal models. In this study, we aimed to test the effectiveness of GSPE in modulating obesity-related pathologies in aged rats fed an obesogenic diet. To do so, 21-month-old rats were fed a high-fat/high-sucrose diet (cafeteria diet) for 11 weeks. Two time points for GSPE administration (500 mg/kg body weight), i.e., a 10-day preventive GSPE treatment prior to cafeteria diet intervention and a simultaneous GSPE treatment with the cafeteria diet, were assayed. Body weight, metabolic parameters, liver steatosis, and systemic inflammation were analysed. GSPE administered simultaneously with the cafeteria diet was effective in reducing body weight, total adiposity, and liver steatosis. However, the preventive treatment was effective in reducing only mesenteric adiposity in these obese, aged rats. Our results confirm that the simultaneous administration of GSPE improves metabolic disruptions caused by the cafeteria diet also in aged rats.

In this study we compare the interaction of three protein sources—insect, beef, and almond—with the gastrointestinal tract. We measured the enterohormone secretion ex vivo in human and pig intestine treated with in vitro digestions of these foods. Insect and beef were the most effective in inducing the secretion of CCK, while almond was the most effective in inducing PYY in pig duodenum. In the human colon, almond was also the most effective in inducing PYY, and GLP-1 levels were increased by insect and beef. The three digested proteins reduced ghrelin secretion in pig duodenum, while only insect reduced ghrelin secretion in human colon. We also found that food intake in rats increased in groups fed a raw insect pre-load and decreased when fed raw almond. In conclusion, the insect Alphitobius diaperinus modulates duodenal and colonic enterohormone release and increases food intake in rats. These effects differ from beef and almond.

Some beneficial effects of grape seed proanthocyanidin extract (GSPE) can be explained by the modulation of enterohormone secretion. As GSPE comprises a combination of different molecules, the pure compounds that cause these effects need to be elucidated. The enterohormones and chemoreceptors present in the gastrointestinal tract differ between species, so if humans are to gain beneficial effects, species closer to humans—and humans themselves—must be used. We demonstrate that 100 mg/L of GSPE stimulates peptide YY (PYY) release, but not glucagon-like peptide 1 (GLP-1) release in the human colon. We used a pig ex vivo system that differentiates between apical and basolateral intestinal sides to analyse how apical stimulation with GSPE and its pure compounds affects the gastrointestinal tract. In pigs, apical GSPE treatment stimulates the basolateral release of PYY in the duodenum and colon and that of GLP-1 in the ascending, but not the descending colon. In the duodenum, luminal stimulation with procyanidin dimer B2 increased PYY secretion, but not CCK secretion, while catechin monomers (catechin/epicatechin) significantly increased CCK release, but not PYY release. The differential effects of GSPE and its pure compounds on enterohormone release at the same intestinal segment suggest that they act through chemosensors located apically and unevenly distributed along the gastrointestinal tract.

When molecular drivers of healthy adipogenesis are perturbed, this can cause hepatic steatosis. The role of arachidonic acid (AA) and its downstream enzymatic cascades, such as cyclooxygenase, in adipogenesis is well established. The exact contribution of the P450 epoxygenase pathway, however, remains to be established. Enzymes belonging to this pathway are mainly encoded by the CYP2J locus which shows extensive allelic expansion in mice. Here we aimed to establish the role of endogenous epoxygenase during adipogenesis under homeostatic and metabolic stress conditions. We took advantage of the simpler genetic architecture of the Cyp2j locus in the rat and used a Cyp2j4 (orthologue of human CYP2J2) knockout rat in two models of metabolic dysfunction: physiological aging and cafeteria diet (CAF). The phenotyping of Cyp2j4-/- rats under CAF was integrated with proteomics (LC-MS/MS) and lipidomics (LC-MS) analyses in the liver and the adipose tissue. We report that Cyp2j4 deletion causes adipocyte dysfunction under metabolic challenges. This is characterized by (i) down-regulation of white adipose tissue (WAT) PPARγ and C/EBPα, (ii) adipocyte hypertrophy, (iii) extracellular matrix remodeling, and (iv) alternative usage of AA pathway. Specifically, in Cyp2j4-/- rats treated with a cafeteria diet, the dysfunctional adipogenesis is accompanied by exacerbated weight gain, hepatic lipid accumulation, and dysregulated gluconeogenesis. These results suggest that AA epoxygenases are essential regulators of healthy adipogenesis. Our results uncover their synergistic role in fine-tuning AA pathway in obesity-mediated hepatic steatosis.