SURGICAL FORUM Neurobiologic Changes in the Hypothalamus Associated with Weight Loss after Gastric Bypass Irina V Romanova, PhD, Eduardo JB Ramos, MD, Yuan Xu, MD, Robert Quinn, DVM, Chung Chen, PhD, Zachariah M George, BSc, Akio Inui, MD, PhD, Undurti Das, MD, Michael M Meguid, MD, PhD, FACS BACKGROUND: Effects of Roux-en-Y gastric bypass (RYGB) on hypothalamic food intake regulation have not been investigated. The hypothalamic arcuate nucleus (ARC) and the magnocellular (m) and parvocellular (p) parts of the paraventricular nucleus (PVN) regulate hunger and satiety, and are under control of the orexigenic neuropeptide Y (NPY), and the anorexigenic -melanocyte stimulating hormone (-MSH) and serotonin (5-HT). We hypothesized that after RYGB, weight loss is associated with hypothalamic down regulation of NPY and up regulation of 5-HT and -MSH. STUDY DESIGN: Obesity was induced in 12 Sprague Dawley rats using a high-energy diet for 7 weeks, and then the rats were divided into three groups (n = 4/group): RYGB, sham-operated pair-fed (PF), and sham- operated ad libitum (obese control). Ten days after operation, immunohistochemical quantification of NPY, -MSH, and 5-HT 1B -receptors in ARC and PVN was performed. Data were analyzed using ANOVA andTukey’s test. RESULTS: Body weight decreased in RYGB (417  21g; mean  SE) and in PF (436  14g) rats 10 days after operation compared with obese control rats (484  15g; p  0.05 for each comparison). NPY in ARC, pPVN, and mPVN decreased by 43%, 43%, and 61%, respectively in RYGB and by 55%, 42%, and 71% in PF, respectively, compared with obese controls (p  0.05 for each pairwise comparison). RYGB versus PF did not show differences. -MSH in ARC, pPVN and mPVN increased by 35%, 175%, and 67%, respectively in RYGB and by 29%, 162%, and 116% in PF, respectively, compared with obese controls (each p  0.05). In mPVN, -MSH significantly de- creased by 23% in RYGB versus PF (p  0.05). 5-HT- 1B -receptor in pPVN increased by 58% in RYGB and by 26% in PF, compared with obese controls (p  0.05). Compared with obese controls, 5HT- 1B -receptor in mPVN increased by 39% in RYGB (p  0.05) and by 9% in PF (p  0.05). An increase of 5-HT- 1B -receptor in pPVN and mPVN occurred in RYGB versus PF (p  0.05). CONCLUSIONS: Obese rats that undergo weight loss after RYGB demonstrate changes in hypothalamic down regu- lation of NPY and up regulation of -MSH and serotonin. (J Am Coll Surg 2004;199:887–895. © 2004 by the American College of Surgeons) Using body mass index (BMI), defined as a person’s body weight in kg divided by their height in meters squared, as the criterion for obesity, it is estimated that 25% to 33% of people in the US have a BMI of 25 to 30 kg/m 2 and are considered overweight; another 30% have a BMI  30 kg/m 2 and are considered obese. Approximately 8 million people are morbidly obese. Obesity increases the incidence of type 2 diabetes mellitus, hypertension, hypercholesterol- emia, and stroke, and decreases life expectancy. 1,2 Obesity has been treated by diet, behavior modification, and through pharmacologic approaches with limited success. In morbid obesity, the most effective method to achieve a sus- tained weight loss is by surgical intervention. 3 Besides weight loss, Roux-en-Y gastric bypass and biliopancreatic diversion effectively control type 2 diabetes mellitus in morbidly obese individuals by unknown mechanisms. It has been postulated that exclusion of the proximal gut con- tributes to improvement of diabetes. 4 Obesity occurs as a result of biochemical changes in No competing interests declared. This work was supported in part by the Hendrick’s Fund #130230-30, by the Scientist Exchange Program of the Office of the International Affairs, NCI award to IVR (2002–2003), by an NIH/NCI Grant Ca-70239 to MMM, and by an Educational Grant from the Department of Surgery, University Hospital. Presented at the American College of Surgeons 89th Annual Clinical Con- gress, Surgical Forum, Chicago, IL, October 2003. Received December 17, 2003; Revised June 28, 2004; Accepted July 12, 2004. From the Surgical Metabolism and Nutrition Laboratory, Neuroscience Program, Department of Surgery, University Hospital, SUNY Upstate Medical University (Romanova, Ramos, Xu, Quinn, George, Das, Meguid), Syracuse, NY; the De- partment of Management Information and Decision, Whitman School of Man- agement, Syracuse University (Chen), Syracuse, NY; and the Division of Diabe- tes, Digestive and Kidney Diseases, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan (Inui). Correspondence address: Michael M Meguid MD, PhD, Department of Surgery, University Hospital, 750 Adams St, Syracuse, NY 13210. 887 © 2004 by the American College of Surgeons ISSN 1072-7515/04/$30.00 Published by Elsevier Inc. doi:10.1016/j.jamcollsurg.2004.07.013