Mice Deficient for an Intestinal G Protein-Coupled Receptor Expression Have Increased Satiety During Rebound Hyperphagia

Gut-derived hormones have been successfully developed as the therapeutic targets to combat the increasing prevalence of diabetes and obesity. G protein-coupled receptors (GPCRs) in the gastrointestinal (GI) tract are involved in maintaining glucose and energy homeostasis by regulating the release of gut hormones in response to luminal dietary nutrients as well as microbial metabolites. We identified that an orphan GPCR, Gpr17, was expressed in the intestinal epithelium and found that loss of intestinal Gpr17 expression increased gut incretin hormone secretion from enteroendocrine cells (EECs). However, it is unknown how Gpr17 ablation in the intestinal epithelium affects feeding behavior and satiety regulation. To address this question, we used genetic knockout approach to generate intestinal Gpr17-deficient mice and analyzed their feeding behavior. Here we show that intestinal Gpr17-deficient mice had similar growth curve, body composition, and ad libitum food intake compared with littermate controls. Interestingly, intestinal Gpr17-deficient mice responded to fasting-refeeding challenge with reduced fasting locomotor activity and less food intake after refeeding, suggesting increased satiety during the phase of rebound hyperphagia. Moreover, we performed fasting-refeeding challenge with Gpr17-deficient mice fed on high-fat diet (HFD), and our meal pattern analysis revealed that these mice had reduced meal duration of the first meal after refeeding. In conclusion, our genetic knockout studies in rodents showed that ablating intestinal Gpr17 increased satiety during rebound hyperphagia in the fasting-refeeding experimental paradigm. Intestinal Gpr17 could be developed as a therapeutic target to treat obesity by improving energy balance through gut hormone secretion and meal pattern control.

Synergistic Control of KNDy Neuronal Influence on Energy Balance by Ghrelin and Estradiol

The gut peptide, ghrelin, mediates negative energy homeostasis and the neuroendocrine control of energy homeostasis by acting through its receptor, growth hormone secretagogue receptor (GHSR). GHSR, expressed in hypothalamic Kisspeptin/Neurokinin B/Dynorphin (KNDy) neurons in the arcuate (ARC), is well known to regulate energy balance. We have previously shown 17-beta-estradiol (E2) robustly increases Ghsr expression in KNDy neurons, enhancing their sensitivity to ghrelin. We hypothesize that E2-induced increase in GHSR expression augments KNDy sensitivity in a fasting state by elevating ghrelin to reduce energy expenditure in females. We developed a Kiss1-specific GHSR knockout to determine the role of GHSR in ARC KNDy neurons and fed them either a low-fat diet (LFD) or a high-fat diet (HFD). Knockout (experimental) females were resistant to HFD in terms of body weight gain, adiposity, and food intake compared to HFD-fed controls. HFD-fed experimental females also exhibited slower glucose clearance compared to HFD-fed controls. Experimental females, regardless of diet, exhibited elevated fasting (5h) glucose. Metabolic rates (V.O2, V.CO2) and energy expenditure (heat) were not different. Respiratory Exchange Ratio (RER) was elevated in LFD-fed females, indicating the utilization of carbohydrates over fat for energy. Further meal pattern analysis revealed a reduction in meal duration in HFD-fed females, but elevated meal frequency, while HFD-fed experimental females exhibited a reduced meal size. In two separate meal pattern experiments, experimental and control females were fasted for 24h and refed or injected with ghrelin (I.P. 1mg/kg) or saline. We observed a striking delay in refeeding behavior in experimental females compared to controls during the refeeding period after fasting. After injection, control females responded to ghrelin with a rapid and sustained increase in food intake which was blunted in experimentals. Collectively, these data suggest that GHSR activation in KNDy neurons modulates metabolism, glucose homeostasis, and feeding behavior, illustrating a novel mechanism for E2 and ghrelin to synergistically control KNDy neuronal output and their subsequent behavioral and physiological outcomes.

Effect of GHS-R deletion on growth, pulsatile GH secretion and meal pattern in male and female mice

Introduction. While the vast majority of research investigating the role of ghrelin or its receptor, GHS-R1a, on growth, feeding and metabolism has been conducted in male rodents, very little is known about sex differences in this system. Furthermore, the role of GHS-R1a signaling in the control of pulsatile GH secretion and its link with growth or metabolic parameters has never been characterized. Methods. We assessed the sex-specific contribution of GHS-R1a signaling on the activity of the GH/IGF-1 axis, metabolic parameters and feeding behavior in adolescent (5-6 weeks old) or adult (10-19 weeks old) GHS-R KO (Ghsr-/-) and WT (Ghsr+/+) male and female mice. Results. Adult Ghsr-/- male and female mice displayed deficits in weight and linear growth that was correlated with reduced GH pituitary contents in males only. GHS-R1a deletion was associated with reduced meal frequency and increased meal intervals, as well as reduced hypothalamic GHRH and NPY mRNA in males, not females. In adult, GH release from Ghsr-/- mice pituitary explants ex vivo was reduced independently of the sex. However, in vivo pulsatile GH secretion decreased in adult but not adolescent Ghsr-/- females, while in males, GHS-R1a deletion was associated with reduction in pulsatile GH secretion during adolescence exclusively. In males, linear growth did not correlate with pulsatile GH secretion, but rather with ApEn, a measure that reflects irregularity of the rhythmic secretion. Fat mass, plasma leptin concentrations or ambulatory activity did not predict differences in GH secretion. Discussion/Conclusion. These results point to a sex-dependent dimorphic effect of GHS-R1a signaling to modulate pulsatile GH secretion and meal pattern in mice with different compensatory mechanisms occuring in the hypothalamus of adult males and females after GHS-R1a deletion. Altogether, we show that GHS-R1a signaling plays a more critical role in the regulation of pulsatile GH secretion during adolescence in males and adulthood in females.

Changes in Child and Adult Care Food Program (CACFP) Practices at Participating Childcare and Education Centers in the United States Following Updated National Standards, 2017–2019

The U.S. Department of Agriculture’s (USDA) Child and Adult Care Food Program (CACFP) updated meal pattern standards took effect in October 2017. The aim of this quasi-experimental, pre-post study is to identify changes in food and beverage practices of CACFP-participating centers due to implementation of updated CACFP meal patterns over a 21-month period. Eight hundred and fifty-eight centers located in 47 states and the District of Columbia completed a survey (primarily electronic) at both time points (67.6% follow-up response rate). Multivariable logistic regressions with robust standard errors assessed changes over time, accounting for repeated observations within each site. From baseline to follow-up, centers reported the increased familiarity and implementation, albeit with time, money, and staffing-related challenges. Significant improvements were seen in not serving sugary cereals or flavored milk, in serving 100% whole grains, and serving processed meats less than once a week. While CACFP-participating centers reported making significant progress in meeting the updated meal pattern standards and suggested best practices within 15–19 months of their effective date, reported compliance and adherence to the standards and best practices was not universal. USDA, state agencies, and technical assistance providers should work to provide centers with additional guidance to help them with implementation.

Impact of changes to the Child and Adult Care Food Program on children’s dietary intake in family child care homes

Objective:To estimate the impact of recent changes to the Child and Adult Care Food Program (CACFP) meal pattern on young children’s diets in family child care homes (FCCHs) serving racially/ethnically diverse children.Design:In a natural experimental study of thirteen CACFP-participating FCCHs, we used digital photographs taken of children’s plates before and after meals matched with menus to measure children’s dietary intake both prior to implementation of the new meal patterns (summer/fall of 2017) and again 1 year later (summer/fall of 2018). Generalised estimating equations tested for change in intake of fruits, vegetables, whole grains, 100 % juice, grain-based desserts, meat/meat alternates and milk, adjusting for clustering of observations within providers.Setting:FCCHs in Boston, MA, USA.Participants:Three- to 5-year-old children attending FCCHs.Results:We observed 107 meals consumed by twenty-eight children at the thirteen FCCHs across an average of 2·5 (sd 1·3) d before the CACFP policy change, and 239 meals consumed by thirty-nine children across 3·8 d (sd 1·4) 1 year later. During lunch, fruit intake increased by about a third of a serving (+0·38 serving, 95 % CI 0·04, 0·73, P = 0·03), and whole grain intake increased by a half serving (+0·50 serving, 95 % CI 0·19, 0·82, P = 0·002). No changes were seen in other meal components.Conclusion:Young children’s dietary intake in CACFP-participating FCCHs improved following the CACFP meal pattern change, particularly for fruits and whole grains, which were targets of the new policy. Additional research should examine impacts of the changes in other child care settings, age groups and locales.