Cerebrospinal Fluid Biomarkers in Bariatric Surgery

The goal of this project is to understand why bariatric surgery is such an effective treatment for obesity with a focus on brain mechanisms. Cerebrospinal fluid (CSF) neuropeptide, hormone and protein levels will be measured as a surrogate for changes in brain activity in participants before and after bariatric surgery as compared with participants before and after diet-induced weight loss. The investigators are studying neuropeptides and hormones that are know to be involved with the regulation of appetite and body weight to determine if some of the changes that are expected to occur after diet-induced weight loss do not occur after bariatric surgery. In addition, proteomic analysis will be used to uncover new protein biomarkers that are unique to surgical weight loss. The results of these studies will help explain why bariatric surgery is so effective in achieving long-term weight loss. Understanding how the central nervous system responds to bariatric surgery could help the development of alternative nonsurgical therapies for obesity and its metabolic complications.

Peripheral metabolic signals communicate levels of energy stores to the brain and elicit a host of neuronal responses that maintain energy balance; such regulatory mechanisms make it difficult to maintain diet-induced weight loss. The goal is to understand how these central regulatory mechanisms are circumvented following surgical alterations in the gut in subjects after Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (SG) compared to carefully matched diet- induced weight loss controls who achieve weight loss on a low calorie liquid diet. Surgery participants will be patients who have already chosen to have a bariatric surgery procedure with their doctor. Diet participants will be provided with the low calorie liquid diet for approximately 3 months and will be monitored weekly throughout the study. Surgery participants will be studied at 3 time-points: Before the intervention After surgery at 10-15% weight loss At 12 months after surgery Low calorie diet participants will be studied at 2 time-points: Before intervention At 10-15% weight loss (approximately 12 weeks on the diet) At each time-point subjects will have a lumbar puncture (spinal tap) for cerebrospinal fluid (CSF) sampling and blood will be collected in the fasting state and in response to a liquid meal challenge. Body weight, waist and hip circumference will be measured.

This surgery is often called gastric bypass. It is a weight-loss surgery that involves creating a small stomach pouch and bypassing part of the small intestine. If you decide with your doctor to have gastric bypass, you can be enrolled on this arm of the study. A surgery date should be pending before the investigators screen you for the study. The study does not cover the cost of the Roux-en-Y gastric bypass.

Sleeve gastrectomy, is a weight-loss surgery that involves removing about 80% of the stomach. If you decide with your doctor to have sleeve gastrectomy, you can be enrolled on this arm of the study. A surgery date should be pending before the investigators screen you for the study. The study does not cover the cost of the sleeve gastrectomy.

Weight loss with calorie restricted liquid diet. Participants will be placed on a 800 kcal/day diet for meal replacement (Optifast) provided by the investigator for 12 weeks. Participants will be monitored weekly by the study dietician and medical staff.

Change in the levels of cerebrospinal fluid (CSF) proopiomelanocortin (POMC) derived peptides (fmol/ml) that occur in subjects after diet induced weight loss compared to RYGB and SG.

POMC plays a critical role in regulating energy balance and levels decrease in the hypothalamus after diet-induced weight loss; this may lead to weight regain after dieting.

Comparison of changes in the CSF proteome that occur after diet-induced weight-loss compared to RYGB and SG using unbiased proteomic analysis.

Comparison of the changes in Agouti-related protein (AgRP) concentrations (fmol/ml) in CSF and plasma that occur in subjects after diet induced weight loss compared to RYGB and SG.

Comparison of changes in CSF cortisol (ng/mL) that occur in subjects after diet induced weight loss compared to RYGB and SG.

Inclusion Criteria: 18-65 years old BMI 35-55 Exclusion Criteria: No clinically significant medical conditions No use of tobacco No alcohol or drug abuse No recent weight change (+/-5%) within prior 6 months No medications that may affect body weight or blood glucose No diabetes medications, beta-blockers, opiates or glucocorticoids No pregnancy, breastfeeding, or planning to become pregnant during the study (diet group only) No lactose intolerance