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.

Keywords: body composition; body weight; diabetes; energy expenditure; glucose tolerance; incretin; insulin tolerance; obesity.

Figure 1

Body weight, body composition, fasting glucose and insulin and glucose tolerance of male wildtype (WT) and Y2R-deficient (Y2RKO) mice on either low-fat (10%; LF) or high-fat (60%; HF) diet. Absolute (a) and percent change (b) in body weight; total fat mass (c) and lean mass (d); fasting blood glucose (e) and plasma insulin (f) and intraperitoneal glucose tolerance test (1.5 g/kg) (g) with associated area under the curve analysis (h). n = 10/group. ^a p ≤ 0.05 LF WT vs. HF WT, ^b p ≤ 0.05 LF Y2RKO vs. HF Y2RKO, ^c p ≤ 0.05 HF WT vs. LF Y2RKO, ^d p ≤ 0.05 LF WT vs. HF Y2RKO, ^e p ≤ 0.05 HF WT vs. HF Y2RKO, ^f p ≤ 0.05 LF WT vs. LF Y2RKO.

Figure 2

Effect of RYGB or sham surgery, or weight matching to RYGB by caloric restriction (WM) on body weight, body composition, and leptin levels of Y2RKO and WT mice. (a,b): Effect on absolute body weight and percent body weight change over the 18-week observation period. Body weight of WM mice was, by design, similar to RYGB and is not shown. Timing of glucose tolerance test (GTT), insulin tolerance test (ITT), and metabolic chamber exposure (M, gray bar) are shown in A. (c–e): Effect on fat mass (c), lean mass (d), and adiposity index (e) over the 18-week observation period. (f): Plasma leptin levels at termination of the study. Data in a-e are shown as means ± SEM. Data in f are presented as individual data points over a box showing means ± SEM. Groups that do not share the same letters are significantly different from each other (p < 0.05, pairwise t-tests with Benjamini–Hochberg correction, false discovery rate (FDR) = 0.05).

Figure 3

Effect of RYGB, sham surgery, or weight matching to RYGB by caloric restriction (WM) on food intake and diet preference in Y2RKO and WT mice. All mice were on a two-choice diet consisting of high-fat and regular (low-fat) chow. (a): Daily food intake before and for 15 days after surgery. (b): Average daily food intake over three distinct periods: pre-surgical (5 days before surgery), recovery (days 1–10 after surgery), and stable period (days 11–15 after surgery). (c): Daily chow preference before and for 15 days after surgery. Preference is expressed as percent calories obtained from chow diet. WM mice were given a fixed percent of calories from chow so their data is not shown. (d): Average daily chow preference over the same periods as in b. Data in a and c are presented as means ± SEM. Data in b and d are presented as individual data points over a box showing means ± SEM. Groups that do not share the same letters are significantly different from each other (p < 0.05, pairwise t-tests with Benjamini–Hochberg correction, FDR = 0.05).

Figure 4

Effect of RYGB, sham surgery, or weight matching to RYGB by caloric restriction (WM) on ANCOVA adjusted energy expenditure using body weight as a covariate (a), respiratory exchange ratio (b), and locomotor activity (c) in Y2RKO and WT mice. Measurements were taken both at room temperature (23 °C) and at thermoneutrality (29 °C) at about 7–8 weeks after surgery. Data are expressed as individual data points over a box showing means ± SEM. Data that do not share the same letters are significantly different from each other (p < 0.05, pairwise t-tests with Benjamini–Hochberg correction, FDR = 0.05).

Figure 5

Effect of RYGB, sham surgery, or weight matching to RYGB by caloric restriction (WM) on glucose tolerance (a) and Insulin tolerance (b) in Y2RKO and WT mice. Data are presented as means ± SEM, or as individual data points over a box showing means ± SEM. Data that do not share the same letters are significantly different from each other (p < 0.05, pairwise t-tests with Benjamini–Hochberg correction, FDR = 0.05).

Figure 6

Effect of RYGB, sham surgery, or weight matching to RYGB by caloric restriction (WM) on fasting plasma glucose (a), fasting plasma insulin (b), and HOMA-IR (c), in Y2R-KO and WT mice, as measured at termination of the experiment. Data are presented as individual data points over a box showing means ± SEM. Data that do not share the same letters are significantly different from each other (p < 0.05, pairwise t-tests with Benjamini–Hochberg correction, FDR = 0.05).