期刊
JOURNAL OF THE ENDOCRINE SOCIETY
卷 1, 期 10, 页码 1235-1246出版社
ENDOCRINE SOC
DOI: 10.1210/js.2017-00289
关键词
agouti-related protein; beta-endorphin; cerebrospinal fluid; cortisol; proopiomelanocortin; naltrexone
资金
- National Institutes of Health (NIH) [RO1-DK093920]
- National Center for Advancing Translational Sciences NIH Grants [UL1 TR000040, T32DK065522]
- Russell Berrie Foundation Naomi Berrie Fellowship
- Atkins Foundation
Context: Hypothalamic proopiomelanocortin (POMC) is processed to alpha-melanocyte-stimulating hormone, which interacts with the melanocortin antagonist agouti-related protein (AgRP), to regulate energy balance. The POMC-derived opioid peptide beta-endorphin (beta-EP) also affects feeding behavior via interactions with brain pi-opioid receptors (MORs), including autoinhibitory interactions with MOR expressed by POMC neurons. The opioid antagonist naltrexone (NTX) stimulates POMC neurons in rodents and decreases food intake. Objective and Design: The effect of NTX on brain POMC in humans was assessed by measuring POMC peptide concentrations in lumbar cerebrospinal fluid (CSF). AgRP and cortisol levels were also measured because both are inhibited by opioids. In a double-blinded crossover study, 14 healthy subjects were given NTX (50 mg daily) or placebo for either 2 or 7 days. Results: CSF beta-EP levels increased after 2 and 7 days of NTX treatment; CSF POMC levels did not change, but the beta-EP-to-POMC ratio increased. CSF AgRP levels did not change, but plasma AgRP levels tended to increase after NTX (P = 0.06). Cortisol increased in plasma and CSF after NTX treatment; these changes correlated positively with changes in AgRP levels. Conclusion: Opioid antagonism stimulates POMC peptide release into CSF in humans. The increase in the CSF beta-EP-to-POMC ratio could indicate selective release of processed peptides or an effect on POMC processing. Furthermore, AgRP and cortisol stimulation by NTX may mitigate POMC-induced decrease in food intake. It remains to be determined if biomarkers in CSF and plasma could be used to predict responses to pharmacotherapy targeting the melanocortin system. Copyright (c) 2017 Endocrine Society.
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