OR45-2 Neuronal Proopiomelanocortin Deficiency Activates the Hypothalamic-Pituitary-Adrenal Stress Axis in Male Mice

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR45-HPA Axis
Tuesday, June 18, 2013: 9:15 AM-10:45 AM
Presentation Start Time: 9:30 AM
Room 135 (Moscone Center)
Jessica M. Adams*, Veronica Otero-Corchon and Malcolm James Low
University of Michigan, Ann Arbor, MI
Our understanding of central nervous system control of the hypothalamic-pituitary-adrenal (HPA) axis is incomplete. The paraventricular nucleus of the hypothalamus (PVH) receives and integrates stressor signals from many brain regions, including the hypothalamic arcuate nucleus (ARC), which contains a set of neurons expressing proopiomelanocortin (Pomc). POMC is cleaved into several peptides that are critical for feeding and energy balance regulation. To test our hypothesis that hypothalamic POMC physiologically modulates the HPA axis, we generated ARC-specific POMC knockout mice (ArcPOMC-KO) by insertion of a neomycin cassette into the upstream neural enhancer region of Pomc, which completely abolishes expression of the gene in the ARC. At age 4-wk, male ArcPOMC-KO mice exhibited elevated basal diurnal levels of corticosterone, and at 8-wk their evening corticosterone peak was 1.9-fold higher than wild-type (WT) controls (160 ± 14 ng/ml vs 85 ± 17 ng/ml; p=0.003). Male ArcPOMC-KO mice at this age also had larger adrenal glands (4.60 ± 0.13 mg vs 3.04 ± 0.12 mg; p<0.001) than WTs. Although no changes from WT were observed in the hormone response of ArcPOMC-KO to acute restraint stress at age 8-wk, by 20-wk, ArcPOMC-KOs exhibited a blunted ACTH response (164 ± 71 pg/mL vs 525 ± 77 pg/mL; p=0.006) coupled with an exaggerated corticosterone response (208 ± 21 ng/mL vs 88 ± 5 ng/mL; p<0.001). ArcPOMC-KO mice exhibited normal levels of corticotropin releasing hormone (Crh) mRNA in the PVH as measured by quantitative  in situ hybridization. However, arginine vasopressin (Avp) mRNA in the PVH was elevated 2-fold in ArcPOMC-KOs versus WTs at age 8-wk, and by 20-wk, the intensity of AVP immunofluorescence was elevated 3-fold (p<0.001). In the anterior pituitary, levels of Avpr1b mRNA as measured by reverse transcription qPCR were elevated by 30% at age 8–wk in ArcPOMC-KO mice (p<0.001). Taken together, these data suggest that central POMC deficiency leads to chronic activation of the HPA axis in male mice, which could be due to a shift in the ACTH secretagogue burden away from CRH and towards AVP, a phenomenon that has been described in several models of chronic stress in rodents. This shift appears to become more pronounced with age, in parallel with worsening obesity. Future studies are needed to confirm the role of AVP in the HPA activation of ArcPOMC-KO mice and to dissociate primary from secondary phenotypic effects possibly related to obesity in these mice.

Nothing to Disclose: JMA, VO, MJL

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: NIH grant DK066604 awarded to MJL