Endocrine Abstracts (2002) 3 OC44

MSH precursor peptides in rat cerebrospinal fluid: Evidence that pro-opiomelanocortin (POMC) processing is regulated with respect to energy balance

LE Pritchard1,3, RL Oliver2, JD McLoughlin2, S Birtles3, AV Turnbull3 & A White1,3

1School of Biological Sciences and Faculty of Medicine, University of Manchester, Manchester, UK; 2Diabetes and Endocrinology, University of Manchester, Hope Hospital, Salford, UK; 3AstraZeneca, Mereside, Alderley Park, UK.

Pro-opiomelanocortin (POMC) derived peptides coordinate energy balance via central melanocortin receptors. In order to monitor central POMC expression and processing in-vivo, we have quantified the POMC derived peptides ACTH, alpha-MSH and the high molecular weight precursors POMC/proACTH in rat cerebrospinal fluid (csf). POMC/proACTH levels were significantly lower in csf samples from fasted versus fed rats (65.2 ± 4.5 pmol/l versus 112 ± 10.1 pmol/l; p = 0.0015) and obese (fa/fa) versus lean (+/+, +/fa) Zucker rats (28 ± 12.7 pmol/l versus 68.5 ± 12 pmol/l; p = 0.008). Similarly ACTH levels were lower in fasted rats (4.6 ± 0.7 pmol/l versus 8.6 ± 1 pmol\/l; p = 0.0025) and obese Zucker rats (<1.1 pmol\/l versus 9.7 ± 1.5 pmol/l) versus control animals. alphaMSH could not be detected. In obese Zucker rats, the ratio of POMC/proACTH to ACTH was elevated compared to lean animals, indicating reduced processing of the precursors.

We have also tested relative potency of alpha-MSH and beta-MSH along with their precursors desacetyl alpha-MSH, ACTH and beta-lipotrophic hormone (beta-LPH) at cloned human melanocortin-4 receptor (MC4-R) in-vitro. The relative potencies of peptides were: Nleu4dPhe7alpha-MSH (0.2nM) > desacetyl alpha-MSH (4.5nM) > beta-MSH (5.6nM) > ACTH (9.6nM) > alpha-MSH (12.3nM) > beta-LPH (62.4nM)(EC50 values).

Overall, this study demonstrates that a) POMC processing in the hypothalamus is incomplete and high molecular weight MSH precursors are secreted. b) the levels of POMC/proACTH and ACTH in rat csf correlate with hypothalamic POMC gene expression c) POMC processing may be downregulated in-vivo in the absence of leptin signalling d) precursors of alpha-MSH and beta-MSH can also bind and activate the MC4R. Based on these observations, we propose that POMC neurons secrete a complex 'soup' of MSH peptides and precursors and the relative abundance of these peptides may be controlled with respect to energy requirement.

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