MON-667 Effects of Weight Loss After Diet Versus Bariatric Surgery on Beta-MSH Levels in Human CSF

Abstract Disclosure: D.M. Berger: None. S.K. Panigrahi: None. J. Arriaza: None. R.M. Smiley: None. J. Korner: None. S.L. Wardlaw: None. The hypothalamic melanocortin system, consisting of proopiomelanocortin (POMC) neurons (which produce MSH peptides) and AgRP neurons, plays a key role in regulating energy balance. Suppression of melanocortin activity after diet-induced weight loss (WL) can contribute to weight regain; why WL is maintained after bariatric surgery remains unclear. ß-MSH is a major POMC processing product in humans but not in rodents and has potent effects on food intake and body weight; POMC mutations that impact ß-MSH are associated with obesity. In this study we measured ß-MSH levels in human CSF as a reflection of hypothalamic activity and characterized the detected ß-MSH immunoactivity by gel filtration. We then examined changes in ß-MSH and the POMC prohormone in CSF before and after WL achieved after 3 months of low calorie diet (n=14) vs bariatric surgery (n=15),(Roux-en-Y gastric bypass n=4; Sleeve Gastrectomy n=11). Seven surgery subjects were again studied one year after surgery. ß-MSH was measured by radioimmunoassay that crossreacts 10% with POMC. POMC was measured by two-site ELISA that has no crossreactivity with ß-MSH. Leptin and AgRP were measured by ELISA. Mean BMI was 41.3 kg/m2 (diet group) and 45.5 (surgery group). Mean WL was 12.5% (range:5.5-18.2%) after diet and 14.9% (10.8-22.6%) after surgery. WL 1 yr after surgery was 29.1% (19.4-45.2%). Mean plasma leptin decreased by 57.3% (71.2 to 30.4 ng/ml) after diet vs 58.2% (71.0 to 29.7 ng/ml) after surgery. CSF leptin decreased by 27.7 % (0.48 to 0.35 ng/ml) after diet vs 29.3% (0.51 to 0.36 ng/ml) after surgery. Thus groups were well matched with respect to baseline plasma and CSF leptin and had equivalent declines in leptin after WL. After diet-induced WL, CSF ß-MSH decreased by 27.9% (34.1 to 24.6 fmol/ml, p=0.0002). There was a 4.5% nonsignificant fall in CSF POMC but the ß-MSH/POMC ratio decreased by 25.2% (p=0.0004) consistent with a relative fall in levels of the processed peptide vs the POMC prohormone after WL. AgRP increased by 17.8% (p=0.0008). ß-MSH/AgRP ratio, a combined measure of melanocortin activity, decreased by 37.8%(p<0.0001). After surgical WL, CSF ß-MSH decreased by 20% (36.4 to 29.1 fmol/ml, p=0.0003). CSF POMC decreased by 6.9% (p=0.045) but ß-MSH/POMC ratio decreased by 13.9% (p=0.029). AgRP increased by 9.4% (p=0.05) and ß-MSH/AgRP ratio decreased by 27.5% (p=0.0002). These changes did not differ significantly from changes after diet. One year after surgery CSF ß-MSH remained suppressed by 25.1% (p=0.0001), ß-MSH/POMC by 26.7%(p=0.0008) and ß-MSH/AgRP by 28.7% (p=0.013). In conclusion, we were able to demonstrate for the first time that CSF ß-MSH declines after weight loss, irrespective of the method of WL, and remains suppressed one year after WL in bariatric surgery subjects. Thus WL after surgery is maintained despite the counterregulatory changes in melanocortin activity that would be expected to stimulate weight regain. Presentation: Monday, July 14, 2025