Tanya J. Little

Factors underlying disturbed appetite perception in anorexia nervosa (AN) are poorly characterized. We examined in patients with AN whether fasting and postprandial appetite perceptions, gastrointestinal (GI) hormones, GI symptoms and state anxiety (i) differed from healthy controls (HCs) and (ii) were modified by two weeks of refeeding. 22 female adolescent inpatients with restricting AN, studied on hospital admission once medically stable (Wk0), and after one (Wk1) and two (Wk2) weeks of high-calorie refeeding, were compared with 17 age-matched HCs. After a 4 h fast, appetite perceptions, GI symptoms, state anxiety, and plasma acyl-ghrelin, cholecystokinin (CCK), peptide tyrosine tyrosine (PYY) and pancreatic polypeptide (PP) concentrations were assessed at baseline and in response to a mixed-nutrient test-meal (479 kcal). Compared with HCs, in patients with AN at Wk0, baseline ghrelin, PYY, fullness, bloating and anxiety were higher, and hunger less, and in response to the meal, ghrelin, bloating and anxiety were greater, and hunger less (all p < 0.05). After two weeks of refeeding, there was no change in baseline or postprandial ghrelin or bloating, or postprandial anxiety, but baseline PYY, fullness and anxiety decreased, and baseline and postprandial hunger increased (p < 0.05). We conclude that in AN, refeeding for 2 weeks was associated with improvements in PYY, appetite and baseline anxiety, while increased ghrelin, bloating and postprandial anxiety persisted.

Intestinal production of endocannabinoid and oleoylethanolamide (OEA) is impaired in high-fat diet/obese rodents, leading to reduced satiety. Such diets also alter the intestinal microbiome in association with enhanced intestinal permeability and inflammation; however, little is known of these effects in humans. This study aimed to 1) evaluate effects of lipid on plasma anandamide (AEA), 2-arachidonyl- sn-glycerol (2-AG), and OEA in humans; and 2) examine relationships to intestinal permeability, inflammation markers, and incretin hormone secretion. Twenty lean, 18 overweight, and 19 obese participants underwent intraduodenal Intralipid infusion (2 kcal/min) with collection of endoscopic duodenal biopsies and blood. Plasma AEA, 2-AG, and OEA (HPLC/tandem mass spectrometry), tumor necrosis factor-α (TNFα), glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic peptide (GIP) (multiplex), and duodenal expression of occludin, zona-occludin-1 (ZO-1), intestinal-alkaline-phosphatase (IAP), and Toll-like receptor 4 (TLR4) (by RT-PCR) were assessed. Fasting plasma AEA was increased in obese compared with lean and overweight patients ( P < 0.05), with no effect of BMI group or ID lipid infusion on plasma 2-AG or OEA. Duodenal expression of IAP and ZO-1 was reduced in obese compared with lean ( P < 0.05), and these levels related negatively to plasma AEA ( P < 0.05). The iAUC for AEA was positively related to iAUC GIP ( r = 0.384, P = 0.005). Obese individuals have increased plasma AEA and decreased duodenal expression of ZO-1 and IAP compared with lean and overweight subjects. The relationships between plasma AEA with duodenal ZO-1, IAP, and GIP suggest that altered endocannabinoid signaling may contribute to changes in intestinal permeability, inflammation, and incretin release in human obesity.

BACKGROUND AND AIMS: METHODS: RESULTS: CONCLUSIONS:

The human body has evolved with a disposition for nutrient storage, allowing for periods of irregular food availability and famine. In contrast, the modern diet is characterized by excessive consumption of fats and sugars, resulting in a surge in the rates of obesity and type 2 diabetes. Although these metabolic disorders arise from a complex interaction of genetic, social, and environmental factors, evidence now points to fundamental changes in nutrient metabolism at the cellular level contributing to the underlying pathology. Taste receptors detect nutrients in the oral cavity and gastrointestinal tract and can influence the hormonal response to nutrients; they may also become maladaptive in conditions of excess fat or sugar consumption. Precise links between taste receptor activity, and downstream effects on energy intake and glycemia are not well defined. This review outlines the candidate taste receptors for carbohydrates and fats in the oral cavity and within the small intestine, highlighting the contributions of underlying genetics (polymorphisms) and sensory challenges (e.g., a high-fat diet) to the development of obesity and type 2 diabetes.

Fatty acids (FAs) stimulate the secretion of gastrointestinal hormones, including cholecystokinin (CCK) and glucagon like peptide-1 (GLP-1), which suppress energy intake. In obesity, gastrointestinal responses to FAs are attenuated. Recent studies have identified a key role for the FA-sensing receptors cluster of differentiation (CD)36, G protein-coupled receptor (GPR)40, GPR120, and GPR119 in mediating gastrointestinal hormone secretion. This study aimed to determine the expression and localization of these receptors in the duodenum of humans and to examine relationships with obesity. Duodenal mucosal biopsies were collected from nine lean [body mass index (BMI): 22 ± 1 kg/m²], six overweight (BMI: 28 ± 1 kg/m²), and seven obese (BMI: 49 ± 5 kg/m²) participants. Absolute levels of receptor transcripts were quantified using RT-PCR, while immunohistochemistry was used for localization. Transcripts were expressed in the duodenum of lean, overweight, and obese individuals with abundance of CD36>>GPR40>GPR120>GPR119. Expression levels of GPR120 ( r = 0.46, P = 0.03) and CD36 ( r = 0.69, P = 0.0004) were directly correlated with BMI. There was an inverse correlation between expression of GPR119 with BMI ( r² = 0.26, P = 0.016). Immunolabeling studies localized CD36 to the brush border membrane of the duodenal mucosa and GPR40, GPR120, and GPR119 to enteroendocrine cells. The number of cells immunolabeled with CCK ( r = −0.54, P = 0.03) and GLP-1 ( r = −0.49, P = 0.045) was inversely correlated with BMI, such that duodenal CCK and GLP-1 cell density decreased with increasing BMI. In conclusion, CD36, GPR40, GPR120, and GPR119 are expressed in the human duodenum. Transcript levels of duodenal FA receptors and enteroendocrine cell density are altered with increasing BMI, suggesting that these changes may underlie decreased gastrointestinal hormone responses to fat and impaired energy intake regulation in obesity.

Fat is the most potent stimulus for glucagon-like peptide-1 (GLP-1) secretion. The aims of this study were to determine whether dipeptidyl peptidase IV (DPP-IV) inhibition would enhance plasma active incretin [glucose-dependent insulinotropic polypeptide (GIP), GLP-1] concentrations and modulate the glycemic, gut hormone, triglyceride, energy expenditure, and energy intake responses to intraduodenal fat infusion. In a double-blind, randomized, placebo-controlled crossover design, 16 healthy lean males received 50 mg vildagliptin (V), or matched placebo (P), before intraduodenal fat infusion (2 kcal/min, 120 min). Blood glucose, plasma insulin, glucagon, active GLP-1, and GIP and peptide YY (PYY)-(3–36) concentrations; resting energy expenditure; and energy intake at a subsequent buffet meal (time = 120–150 min) were quantified. Data are presented as areas under the curve (0–120 min, means ± SE). Vildagliptin decreased glycemia (P: 598 ± 8 vs. V: 573 ± 9 mmol·l⁻¹·min⁻¹, P < 0.05) during intraduodenal lipid. This was associated with increased insulin (P: 15,964 ± 1,193 vs. V: 18,243 ± 1,257 pmol·l⁻¹·min⁻¹, P < 0.05), reduced glucagon (P: 1,008 ± 52 vs. V: 902 ± 46 pmol·l⁻¹·min⁻¹, P < 0.05), enhanced active GLP-1 (P: 294 ± 40 vs. V: 694 ± 78 pmol·l⁻¹·min⁻¹) and GIP (P: 2,748 ± 77 vs. V: 4,256 ± 157 pmol·l⁻¹·min⁻¹), and reduced PYY-(3–36) (P: 9,527 ± 754 vs. V: 4,469 ± 431 pM/min) concentrations compared with placebo ( P < 0.05, for all). Vildagliptin increased resting energy expenditure (P: 1,821 ± 54 vs. V: 1,896 ± 65 kcal/day, P < 0.05) without effecting energy intake. Vildagliptin 1) modulates the effects of intraduodenal fat to enhance active GLP-1 and GIP, stimulate insulin, and suppress glucagon, thereby reducing glycemia and 2) increases energy expenditure. These observations suggest that the fat content of a meal, by enhancing GLP-1 and GIP secretion, may contribute to the response to DPP-IV inhibition.