Roux-en-Y gastric bypass enhances energy expenditure and extends lifespan in diet-induced obese rats

Abstract

Gastrointestinal weight-loss surgery (GIWLS) is currently the most effective treatment for severe obesity, with Roux en-Y gastric bypass (RYGB) among the best of the available surgical options. Despite its widespread clinical use, the mechanisms by which RYGB induces its profound weight loss remain largely unknown. This procedure effects weight loss by altering the physiology of weight regulation and eating behavior rather than by simple mechanical restriction and/or malabsorption as previously thought. To study how RYGB affects the physiology of energy balance, we developed a rat model of this procedure. In this report, we demonstrate that RYGB in diet-induced obese (DIO) rats induces a 25% weight loss, prolongs mean survival by 45%, and normalizes glucose homeostasis and lipid metabolism. RYGB induced a 19% increase in total and a 31% increase in resting energy expenditure (REE). These effects, along with a 17% decrease in food intake and a 4% decrease in nutrient absorption account for the normalization of body weight after this procedure. These effects indicate that surgery acts by altering the physiology of weight regulation and help to explain the effectiveness of RYGB in comparison to restrictive dieting and other forms of dietary and pharmacological therapies for obesity. The clinical effectiveness of RYGB and its physiological effects on body weight regulation and energy expenditure (EE) suggest that this operation provides a unique opportunity to explore the mechanisms of energy homeostasis and to identify novel therapies for obesity and related metabolic diseases.

Figures

Figure 1

Roux-en-Y gastric bypass (RYGB) in the rat. (a) Schematic diagram of the procedure and normal rat stomach anatomy (inset) showing the fore stomach (white area), which is separated from the glandular stomach (gray area) by a visible ridge. (b,c) Intraoperative photographs showing the creation of the gastric pouch (GP) using a laparoscopic stapler (S), the distal stomach (DS), Roux limb (RL), biliopancreatic limb (BP), common limb (CL), gastrojejunostomy (GJ) and jejunojejunostomy (JJ). (d) Upper GI contrast study with Gastrograffin after RYGB. (e) Long-term weight changes after RYGB and sham operation in diet-induced obese Sprague-Dawley (DIO SD) rats. Data plotted as mean ± s.e.m.; RYGB, N = 15; sham-operated, N = 10.

Figure 2

Roux-en-Y gastric bypass (RYGB) increases lifespan and improves glucose homeostasis and lipid metabolism in diet-induced obese Levin Sprague-Dawley (DIO Levin-SD) rats. (a) Kaplan–Meier survival curve showing the increase in survival after RYGB. The dotted line highlights median survival. (b) Fasting blood glucose levels after RYGB and in control rats. (c) Oral and (d) intraperitoneal glucose tolerance in RYGB-treated and control rats. The areas under the glucose excursion curves (AUCs) are shown in the insets. AUC was calculated using the trapezoid rule (20,24). Data plotted as mean ± s.e.m.; RYGB, N = 10; sham-operated, N = 10. *P < 0.05. **P < 0.001.

Figure 3

Effects of Roux-en-Y gastric bypass (RYGB) on food intake, diet cycling and calorie absorption. (a) Over a period of 5 months, RYGB-diet-induced obese Sprague-Dawley (DIO SD) rats consumed an average of 16.8% fewer calories than sham-DIO rats. (b) The response to sequential dietary manipulation in RYGB and sham-operated SD rats. Body weight of sham-operated rats increased during the periods when a high-fat diet (HFD) was available and decreased on a low-fat diet (normal chow, NC). Body weights of RYGB-treated animals remained stable irrespective of diet. (c) Nutrient absorption in RYGB-treated and sham-operated SD rats. Nutrient absorption was measured 12 weeks after surgery. Normal values for nutrient absorption in rodents are >75–80% (ref. 35). (d) Daily fat and protein excretion increased slightly after RYGB. Data plotted as mean ± s.e.m.; RYGB, N = 15; sham-operated, N = 10. *P < 0.05.

Figure 4

Roux-en-Y gastric bypass (RYGB) induces a substantial increase in energy expenditure. (a) Body weight changes in RYGB-treated, sham-operated controls, and control, pair-fed diet-induced obese Sprague-Dawley (DIO SD) rats fed ad libitum with an high-fat diet (HFD). RYGB, N = 15; sham-operated, N = 10; pair-fed, N = 12. (b) Total and (c) resting oxygen consumption during ad libitum feeding of DIO Osborne Mendel (OM) rats on an HFD. VO2 measurements are controlled for BW0.75. RYGB, N = 8; sham-operated, N = 7; food-restricted, weight-matched (FRWM), N = 5; normal chow-fed (NC) controls, N = 5. (d) Oxygen consumption by individual rats in the three groups without normalization. (e) Respiratory quotient (RQ) during feeding, fasting and refeeding. RYGB-treated rats had a lower RQ suggesting increased fat utilization during ad libitum feeding. The inset shows the change in RQ in RYGB- and sham-operated, fasted rats after the reintroduction of food (RYGB, N = 8; sham-operated, N = 7). RYGB-treated rats increase their RQ faster, suggesting that their ability to utilize glucose after a meal is significantly improved. Data plotted as mean ± s.e.m. *P < 0.001.

Figure 5

Roux-en-Y gastric bypass (RYGB)-stimulated increases in energy expenditure are dependent on food ingestion. (a) Oxygen consumption during a 48-h period of fasting followed by refeeding ad libitum for 48 h. Resting VO2 was higher in RYGB-treated animals only during the 48-h period of ad libitum refeeding and not during the preceding 48-h fasting period. Upon refeeding, resting VO2 in RYGB-treated diet-induced obese Osborne Mendel (DIO OM) rats increased more than twice as much as in sham-DIO animals. (b) Core body temperature in RYGB-treated and sham-operated control DIO rats. RYGB was associated with an average 0.33 °C increase in core body temperature. Data plotted as mean ± s.e.m.; RYGB, N = 8; sham-operated, N = 7. *P < 0.001.