Biomarkers of hypothalamic melanocortin activity in human energy balance.

The hypothalamic melanocortin system, comprised of proopiomelanocortin (POMC) and agouti-related protein (AgRP) neurons, regulates energy balance but studies in humans are limited by lack of biomarkers to assess brain melanocortin activity. Previous studies evaluated POMC concentrations in human CSF in relation to BMI and leptin and to weight loss, including pharmacotherapy with lorcaserin which targets POMC neurons, showing that lower baseline POMC predicted a better weight loss response to lorcaserin. We performed a retrospective analysis of baseline CSF POMC levels in 139 healthy weight-stable individuals without diabetes or neurologic disease who participated in previous studies, including a subgroup analysis of 70 subjects spread equally across the BMI spectrum (19.2-57.3) and in 97 subjects with obesity. POMC was measured in CSF and AgRP was measured in CSF and plasma by sensitive 2-site ELISAs. Mean CSF POMC was lower in individuals with elevated versus normal BMI (200 vs. 269 fmol/mL; p = .0003) and strong negative correlations between CSF POMC and both BMI and leptin were found in 70 subjects across the BMI spectrum (p < .0001); this remained significant in all 139 subjects but not in 97 with obesity. The cohort with obesity included some very low CSF POMC levels (bottom 10%) that do not overlap with non-obese subjects. Strong positive correlations were noted between CSF POMC and AgRP in both CSF and plasma in all groups, including the subgroup with obesity, providing evidence that activities of both sets of neurons may be linked independently of leptin and BMI. Importantly CSF POMC levels remained remarkably constant when nine weight-stable subjects were studied twice over several years. In summary, CSF POMC was lower in individuals with elevated BMI and correlated negatively with BMI and leptin across the BMI spectrum but not within a cohort with obesity. However, the cohort with obesity contained subjects with very low CSF POMC levels that may indicate POMC deficiency and predict treatment response to melanocortin agonists. It remains to be determined if alternative biomarkers associated with low CSF POMC can be identified for use in the clinical setting.