Meal-induced hormone responses in a rat model of Roux-en-Y gastric bypass surgery

Abstract

Roux-en-Y gastric bypass (RYGB) surgery is the most effective treatment for morbid obesity and remission of associated type 2 diabetes, but the mechanisms involved are poorly understood. The aim of the present study was to develop and validate a rat model for RYGB surgery that allows repeated measurement of meal-induced changes in gut and pancreatic hormones via chronic venous catheters. Male Sprague Dawley rats made obese on a palatable high-fat diet were subjected to RYGB or sham surgery and compared with chow-fed, lean controls. Hormonal responses to a mixed-liquid test meal were examined by frequent blood sampling through chronically implanted jugular catheters in freely behaving rats, 3-4 months after surgery, when RYGB rats had significantly reduced body weight and fat mass compared with sham-operated rats. Hyperleptinemia, basal hyperinsulinemia, and hyperglycemia as well as postprandial glucose intolerance seen in sham-operated, obese rats were completely reversed by RYGB and no longer different from lean controls. Postprandial increases in glucagon-like peptide-1, peptide YY, and amylin as well as suppression of ghrelin levels were all significantly augmented in RYGB rats compared with both sham-operated obese and lean control rats. Thus, our rat model replicates most of the salient hormonal and glycemic changes reported in obese patients after RYGB, with the addition of amylin to the list of potential candidate hormones involved in hypophagia, weight loss, and remission of diabetes. The model will be useful for elucidating the specific peripheral and central mechanisms involved in the suppression of appetite, loss of body weight, and remission of type 2 diabetes.

Figure 1

Body weight of high-fat exposed RYGB (filled circles, n = 5) and sham-operated (open circles, n = 6) as well as chow-fed control rats (open triangles, n = 6). Availability of high-fat diet (HF), Ensure (E), and regular chow (chow) is indicated on top. The period of blood sampling and hormone tests is indicated by the gray bar.

Figure 2

Body composition as assessed by whole-body magnetic resonance relaxometry, showing absolute (upper panels) and relative (lower panels) fat mass (left panels) and lean mass (right panels). The left two bars in each panel show values before exposure to high-fat diet (white bars) and before surgery (light gray bars). Obese rats were then matched for body weight and adiposity and assigned for RYGB or sham surgery. The right three bars in each panel show values 9–12 wk after surgery for RYGB rats (dark gray bars), sham-operated (obese) rats (light gray bars), and nonoperated, age-matched, chow-fed lean rats (white bars). Bars that do not share a common letter are significantly different from each other (P < 0.05; based on ANOVA followed by Fisher’s LSD post hoc test).

Figure 3

Left panel, Fasting plasma leptin levels in RYGB (dark gray bars), sham-operated obese rats (light gray bars), and age-matched chow-fed, lean controls (white bars) at 3 months after surgery. Right panel, HOMA-IR calculated from fasting insulin and glucose levels in Fig. 5. Bars that do not share a common letter are significantly (P < 0.05) different from each other (based on ANOVA followed by Fisher’s LSD post hoc test).

Figure 4

GLP-1, PYY, and GIP responses to a mixed meal in RYGB (filled circles), sham-operated, obese rats (open circles), and chow-fed lean controls (open triangles). Overnight food-deprived rats consumed 5 ml (∼5 kcal) of Ensure delivered at 1 ml/min, and jugular vein blood was sampled remotely at the times indicated. *, RYGB significantly (P < 0.05) different compared with both sham-operated/obese and lean controls; #, RYGB significantly (P < 0.05) different compared with lean controls. Areas under the curve (AUC) are shown in the bar graphs at the right, with bars that do not share a common letter significantly (P < 0.05) different from each other.

Figure 5

Insulin, glucose, and amylin responses to a mixed meal in RYGB (filled circles), sham-operated/obese rats (open circles), and chow-fed, lean controls (open triangles). Overnight food-deprived rats consumed 5 ml (∼5 kcal) of Ensure delivered at 1 ml/min, and jugular vein blood was sampled remotely at the times indicated. *, P < 0.05 between sham and RYGB rats; #, P < 0.05 between sham and lean control rats; +, P < 0.05 between RYGB and both other groups. Areas under the curve (AUC) are shown in the bar graphs at the right, with bars that do not share a common letter significantly (P < 0.05) different from each other.

Figure 6

Ghrelin responses to a mixed meal in RYGB (filled circles), sham-operated (obese) rats (open circles), and nonoperated, chow-fed lean controls (open triangles). Overnight food-deprived rats consumed 5 ml (∼5 kcal) of Ensure delivered at 1 ml/min, and jugular vein blood was sampled remotely at the times indicated. *, RYGB significantly (P < 0.05) different compared with sham-operated rats. Areas under the curve (AUC) are shown in the bar graph at the right, with bars that do not share a common letter significantly (P < 0.05) different from each other.

Figure 7

Linear regression analysis of relationships between body weight or weight loss with various circulating hormones or postprandial hormone responses. Correlations included either all treatment groups (lean controls, open triangles; sham-operated obese, open circles; RYGB, filled circles; full regression lines) or only RYGB rats (dotted regression lines), and only significant correlations are shown. A and B, Leptin levels are positively correlated to body weight and negatively to body weight loss using all treatment groups. C and D, Areas under the curve (AUC) for GLP-1 and PYY are negatively correlated to body weight across all treatment groups and for RYGB rats only. E and F, AUC for amylin and percent suppression of acylated ghrelin are positively correlated with body weight loss. G, GLP-1 and PYY AUCs are positively correlated. H, Twenty-minute peaks of GLP-1 and insulin are positively correlated. I, Basal insulin is positively correlated with body weight. J, HOMA-IR is negatively correlated with body weight loss.