Dataset Information

The PYY/Y2R-Deficient Mouse Responds Normally to High-Fat Diet and Gastric Bypass Surgery.

ABSTRACT: BACKGROUND/GOALS:The gut hormone peptide YY (PYY) secreted from intestinal L-cells has been implicated in the mechanisms of satiation via Y2-receptor (Y2R) signaling in the brain and periphery and is a major candidate for mediating the beneficial effects of bariatric surgery on appetite and body weight. METHODS:Here we assessed the role of Y2R signaling in the response to low- and high-fat diets and its role in the effects of Roux-en-Y gastric bypass (RYGB) surgery on body weight, body composition, food intake, energy expenditure and glucose handling, in global Y2R-deficient (Y2RKO) and wildtype (WT) mice made obese on high-fat diet. RESULTS:Both male and female Y2RKO mice responded normally to low- and high-fat diet in terms of body weight, body composition, fasting levels of glucose and insulin, as well as glucose and insulin tolerance for up to 30 weeks of age. Contrary to expectations, obese Y2RKO mice also responded similarly to RYGB compared to WT mice for up to 20 weeks after surgery, with initial hypophagia, sustained body weight loss, and significant improvements in fasting insulin, glucose tolerance, insulin resistance (HOMA-IR), and liver weight compared to sham-operated mice. Furthermore, non-surgical Y2RKO mice weight-matched to RYGB showed the same improvements in glycemic control as Y2RKO mice with RYGB that were similar to WT mice. CONCLUSIONS:PYY signaling through Y2R is not required for the normal appetite-suppressing and body weight-lowering effects of RYGB in this global knockout mouse model. Potential compensatory adaptations of PYY signaling through other receptor subtypes or other gut satiety hormones such as glucagon-like peptide-1 (GLP-1) remain to be investigated.

SUBMITTER: Boland B

PROVIDER: S-EPMC6471341 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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The PYY/Y2R-Deficient Mouse Responds Normally to High-Fat Diet and Gastric Bypass Surgery.

Boland Brandon B Mumphrey Michael B MB Hao Zheng Z Gill Benji B Townsend R Leigh RL Yu Sangho S Münzberg Heike H Morrison Christopher D CD Trevaskis James L JL Berthoud Hans-Rudolf HR

Nutrients 20190310 3

<h4>Background/goals</h4>The gut hormone peptide YY (PYY) secreted from intestinal L-cells has been implicated in the mechanisms of satiation via Y2-receptor (Y2R) signaling in the brain and periphery and is a major candidate for mediating the beneficial effects of bariatric surgery on appetite and body weight.<h4>Methods</h4>Here we assessed the role of Y2R signaling in the response to low- and high-fat diets and its role in the effects of Roux-en-Y gastric bypass (RYGB) surgery on body weight, ...[more]

PMID: 30857366

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Project description:ObjectivesDieting often fails because weight loss triggers strong counter-regulatory biological responses such as increased hunger and hypometabolism that are thought to be critically dependent on the master fuel sensor in the mediobasal hypothalamus (MBH). Because prolonged starvation has been shown to increase AgRP and NPY, the expression level of these two orexigenic genes has been taken as an experimental readout for the presence or absence of hunger. Roux-en-Y gastric bypass (RYGB) surgery leads to a significant weight loss without inducing the associated hunger, indicating possible changes in hypothalamic neuropeptides and/or signaling. Our goal was to assess key genes in the MBH involved in regulating body weight, appetite, and inflammation/oxidative stress after RYGB surgery in mice.MethodsObese mice on a high-fat diet were subjected to either sham or RYGB surgery, or caloric restriction to match the weight of RYGB group. Chow-fed mice without surgery served as an additional control group. After 2 or 12 weeks post-surgery, hypothalamic genes were analyzed by real-time qPCR.ResultsDuring the rapid weight loss phase at 2 weeks after RYGB surgery, hypothalamic AgRP and NPY gene expression was not increased compared to mice with sham surgery, indicating that the mice are not hungry. In contrast, the same weight loss induced by caloric restriction promptly triggered increased AgRP and NPY expression. This differential effect of RYGB and caloric restriction was no longer observed during the weight-maintenance phase at 12 weeks after surgery. A similar differential effect was observed for ObRb, but not for POMC and CART expression. Furthermore, RAGE and IBA-1, two markers for inflammation/oxidative stress, were significantly suppressed after RYGB compared to caloric restriction at 2 weeks post-surgery.ConclusionsThese findings suggest that RYGB prevents the biologically adaptive hunger response triggered by undernutrition and weight loss, and suppresses weight loss-induced hypothalamic inflammation markers.

Project description:Bone marrow fat is a unique fat depot that may regulate bone metabolism. Marrow fat is increased in states of low bone mass, severe underweight, and diabetes. However, longitudinal effects of weight loss and improved glucose homeostasis on marrow fat are unclear, as is the relationship between marrow fat and bone mineral density (BMD) changes. We hypothesized that after Roux-en-Y gastric bypass (RYGB) surgery, marrow fat changes are associated with BMD loss. We enrolled 30 obese women, stratified by diabetes status. Before and 6 months after RYGB, we measured BMD by dual-energy X-ray absorptiometry (DXA) and quantitative computed tomography (QCT) and vertebral marrow fat content by magnetic resonance spectroscopy. At baseline, those with higher marrow fat had lower BMD. Postoperatively, total body fat declined dramatically in all participants. Effects of RYGB on marrow fat differed by diabetes status (p = 0.03). Nondiabetic women showed no significant mean change in marrow fat (+1.8%, 95% confidence interval [CI] -1.8% to +5.4%, p = 0.29), although those who lost more total body fat were more likely to have marrow fat increases (r = -0.70, p = 0.01). In contrast, diabetic women demonstrated a mean marrow fat change of -6.5% (95% CI -13.1% to 0%, p = 0.05). Overall, those with greater improvements in hemoglobin A1c had decreases in marrow fat (r = 0.50, p = 0.01). Increases in IGF-1, a potential mediator of the marrow fat-bone relationship, were associated with marrow fat declines (r = -0.40, p = 0.05). Spinal volumetric BMD decreased by 6.4% ± 5.9% (p < 0.01), and femoral neck areal BMD decreased by 4.3% ± 4.1% (p < 0.01). Marrow fat and BMD changes were negatively associated, such that those with marrow fat increases had more BMD loss at both spine (r = -0.58, p < 0.01) and femoral neck (r = -0.49, p = 0.01), independent of age and menopause. Our findings suggest that glucose metabolism and weight loss may influence marrow fat behavior, and marrow fat may be a determinant of bone metabolism. © 2017 American Society for Bone and Mineral Research.

Project description:ObjectiveRoux-en-Y gastric surgery (RYGB) promotes a rapid and sustained weight loss and amelioration of glucose control in obese patients. A high number of molecular hypotheses were previously tested using duodenal-jejunal bypass (DJB) performed in various genetic models of mice with knockouts for various hormones or receptors. The data were globally negative or inconsistent. Therefore, the mechanisms remained elusive. Intestinal gluconeogenesis is a gut function that has been suggested to contribute to the metabolic benefits of RYGB in obese patients.MethodsWe studied the effects of DJB on body weight and glucose control in obese mice fed a high fat-high sucrose diet. Wild type mice and mice with a genetic suppression of intestinal gluconeogenesis were studied in parallel using glucose- and insulin-tolerance tests. Fecal losses, including excretion of lipids, were studied from the feces recovered in metabolic cages.ResultsDJB induced a dramatic decrease in body weight and improvement in glucose control (glucose- and insulin-tolerance) in obese wild type mice fed a high calorie diet, for 25 days after the surgery. The DJB-induced decrease in food intake was transient and resumed to normal in 7-8 days, suggesting that decreased food intake could not account for the benefits. Total fecal losses were about 5 times and lipid losses 7 times higher in DJB-mice than in control (sham-operated and pair-fed) mice, and could account for the weight loss of mice. The results were comparable in mice with suppression of intestinal gluconeogenesis. There was no effect of DJB on food intake, body weight or fecal loss in lean mice fed a normal chow diet.ConclusionsDJB in obese mice fed a high calorie diet promotes dramatic fecal loss, which could account for the dramatic weight loss and metabolic benefits observed. This could dominate the effects of the mouse genotype/phenotype. Thus, fecal energy loss should be considered as an essential process contributing to the metabolic benefits of DJB in obese mice.

Dataset Information

The PYY/Y2R-Deficient Mouse Responds Normally to High-Fat Diet and Gastric Bypass Surgery.

Publications

The PYY/Y2R-Deficient Mouse Responds Normally to High-Fat Diet and Gastric Bypass Surgery.

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