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Principal investigator

Research interests

1) POMC derived peptides and melanocortin receptor signalling

The physiological responses to pro-opiomelanocortin (POMC)-derived peptides include pigmentation, adrenal development and corticosteroid synthesis, food intake and feed efficiency, metabolism, body weight, insulin secretion, immune and cardiovascular regulation. Melanocortin peptides derived from POMC are ligands for a family of 5 G-protein coupled receptors known as melanocortin receptors 1-5 (MC1R – MC5R).

POMC and MC4R have been shown to be pivotal in the regulation of energy homeostasis. POMC, produced primarily in the pituitary and hypothalamus, is processed through a coordinated, tissue-specific, series of proteolytic cleavages and post-translational modifications which influence the activity of the peptides. We are interested in how N-terminal acetylation of the POMC peptide, ACTH 1-13NH 2, enhances some activities (pigmentation; inhibition of food intake) of this peptide and virtually eliminates others. Research projects include studying:

• Signal transduction induced by these peptides in vivo (hypothalamus) and in vitro (hypothalamic and other cells)
• MC4R trafficking
• MC4R gene regulation
• Regulation and measurement of the levels of these peptides.

These studies involve the use of mutant and transgenic mice, and cell lines either overexpressing, or endogenously expressing, melanocortin receptors and their accessory proteins.

2) Pigmentation gene loci and body weight

NZG/Kgm mice arose during a breeding programme at Ruakura, NZ in the 1970s and were gifted to researchers at The University of Auckland. Ginger coat colour, rapid growth and large body size are all striking characteristics that make NZG/Kgm mice stand out from other mice. We have determined that NZG/Kgm mice are lean and have an unusual pattern of fat distribution compared with other mouse strains; they have disproportionately larger amounts of subcutaneous fat (good fat) and a lower amount of visceral fat (bad fat). To understand the genes responsible for this unique phenotype, we bred NZG/Kgm mice with black CAST/Ei mice. Three coat colours were produced in the N2 generation leading to the identification of two recessive pigmentation variant genes in NZG/Kgm mice: tyrp1b and pink-eyed dilution (oca2p). Mendelian geneticists documented in the early 1900s that pigmentation gene loci associated with either increased or decreased body weight in mice, rats and rabbits; the exact genes and their mechanism of action have never been resolved, except for agouti. Research projects include breeding NZG/Kgm mice to develop congenic mouse lines for identifying genes and gene interactions which may be fundamental to the large lean body size phenotype of NZG/Kgm mice.

Personnel

Graduate students: Emma Kay, Abhishek Tiwari and Rikus Botha

Research technicians: Sarah Rynbeck

Research projects

• Melanocortin peptide signal transduction in vitro and in vivo
• Measurement of melanocortin peptides
• Mapping gene expression for melanocortin receptors and melanocortin receptor accessory proteins
• Melanocortin-4 receptor gene regulation
• NZG /Kgm mice: Understanding pigmentation gene loci associated with body weight
• Understanding mechanism of action of a novel weight reducing drug

Active research collaborations

• Dr Johanna Montgomery, Department of Physiology, The University of Auckland
• Dr Deborah Young, Department of Molecular Medicine and Pathology, The University of Auckland
• Professor Margaret Brimble, School of Chemical Sciences, The University of Auckland
• Professor Peter Hunter, Bioengineering Institute, The University of Auckland

Facilities, technology and special equipment

• Molecular biology
• Cell Culture
• Cell signaling assays
• ELISA assays
• Radioimmunoassays
• In situ hybridisation
• Immunohistochemistry
• Mouse physiology
• Mouse genetics

Research publications

1. Mountjoy, K.G. 'Functions for pro-opiomelanocortin-derived peptides in obesity and diabetes', Review in Biochem J, 428, p305-324, 2010
2. Mountjoy, K.G. 'Distribution and Function of Melanocortin Receptors within the Brain', ADV EXP MED BIOL, 681, p29-48, 2010
3. Joseph, C.G; Yao, H; Scott, J.W; Sorensen, N.B; Marnane, R.N; Mountjoy, K.G; Haskell-Luevano, C. 'γ2-Melanocyte stimulation hormone (γ2- MSH) truncation studies results in the cautionary note that γ2- MSH is not selective for the mouse MC3R over the mouse MC5R', Peptides, 31, (12), p2304-2313, 2010
4. Duchesnes, C.E., Naggert, J.K., Tatnell, M.A., Beckman, N., Marnane, R.N., Rodrigues, J.A., Halim, A., Pontre, B., Stewart, A., Wolff, G.L., Elliott, R., Mountjoy, K.G. New Zealand Ginger Mouse: Novel model that associates the tyrp1b pigmentation gene locus with regulation of lean body mass. Physiological Genomics 37; 164-174, 2009
5. Wong, J., Nock, N.L., Xu, Z., Kyle, C.V., Daniels, A., White, M., Yue, D.K., Elston, R.C., Mountjoy, K.G 'A polymorphism (D20S32e) close to the human melanocortin receptor 3 is associated with insulin resistance but not the metabolic syndrome.', Diabetes Research and Clinical Practice, 80, 203-207, 2008
6. Heisler, L.K., Jobst, E.E., Sutton, G.M., Zhou, L., Borok, E., Thornton-Jones, Z., Liu, H.Y., Zigman, J.M., Balthasar, N., Kishi, T., Lee, C.E., Aschkenasi, C.J., Zhang, C.Y., Yu, J., Boss, O., Mountjoy, K.G., Clifton, P.G., Lowell, B.B., Friedman, J.M., Horvath, T., Butler, A.A., Elmquist, J.K., Cowley, M.A. Serotonin reciprocally regulates melanocortin neurons to modulate food intake. Neuron, 51; 239-249, 2006
7. Wu, C.J.,Greenwood, D.R.,Cooney, J.M.,Jensen, D.J.,Tatnell, M.A.,Cooper, G.J.S., Mountjoy, K.G. Peripherally administered desacetyl-a-MSH and a-MSH both influence post-natal rat growth and associated rat hypothalamic protein expression.', American Journal of Physiology-Endocrinology and Metabolism 291: E1372-1380, 2006
8. Balthasar, N., Dalgaard, L.T., Lee, C.E., Yu, L., Funahashi, H., Williams, T., Ferreira, M., Tang, V., McGovern, R.A., Kenny, C.D., Christiansen, L.M., Edelstein, E., Choi, B., Boss, O., Aschkenasi, C., Zhang, C., Mountjoy, K., Kishi, T., Elmquist, J.K., Lowell, B.B. Divergence of melanocortin pathways in the control of food intake and energy expenditure. Cell 123; 493-505, 2005
9. Daniel, P.B., Fernando, C., Wu, C-S., Marnane, R., Broadhurst, R., Mountjoy, K.G. 1kb of 5’ flanking sequence from mouse MC4R gene is sufficient for tissue specific expression in a transgenic mouse. Mol Cell Endocrinol 239; 63-71, 2005
10. Dumont, L.M., Wu, C.-S.J., Tatnell, M.A., Cornish, J., Mountjoy, K.G. Evidence for direct actions of melanocortin peptides on bone metabolism. Peptides 26; 1929-1935, 2005
11. Mountjoy KG, Wu C-S J, Dumont LM, Wild JM Melanocortin-4 receptor mRNA expression in rat cardiorespiratory, musculoskeletal, and integumentary systems. Endocrinology 144; 5488-5496, 2003
12. Mountjoy KG, Wu C.-S, Cornish J, Callon K Alpha-MSH and desacetyl-alpha-MSH signalling through melanocortin receptors. Annals New York Acad Sciences 994, 58-65,2003
13. Cornish J, Callon KE, Mountjoy KG, Bava U, Lin, JM, Myers DE, Naot D, Reid IR Alpha-melanocyte-stimulating hormone is a novel regulator of bone. American Journal of Physiological Endocrinology and Metabolism 284; E1181-E1190, 2003
14. Kishi T, Aschkenasi CJ, Lee CE, Mountjoy KG, Saper CB, Elmquist JK Expression of melanocortin 4 receptor mRNA in the central nervous system of the rat. Journal of Comparative Neurology. 457; 213-235, 2003
15. Wong J., Love, DR, Kyle C, Daniels A, White M, Stewart AW, Schnell AH, Elston RC, Holdaway IM, Mountjoy KG Melanocortin-3 receptor gene variants in a Maori kindred with obesity and early onset type 2 diabetes. Diabetes Research and Clinical Practice 58; 61-71, 2002
16. Henry, B.A., Rao, A., Ikenasio, B.A., Mountjoy, K.G., Tilbrook, A.J., Clarke, I.J. Differential expression of cocaine- and amphetamine-regulated transcript and agouti related-protein in chronically food-restricted sheep. Brain Research 918, 40-50, 2001
17. Dumont, L.M., Wu, C.-S., Aschkenasi, C.J., Elmquist, J.K., Lowell, B.B., Mountjoy, K.G. The 5’-Flanking region of the mouse melanocortin-4 receptor (MC4-R) geneimparts cell specific expression in vitro. Molecular and Cellular Endocrinology 184,173-185, 2001
18. Iqbal, J., Pompolo, S., Dumont , L.M., Wu, C.-S., Mountjoy, K.G., Henry, B.A., Clarke, I.J. Long-term alterations in body weight do not affect the expression of melanocortin receptor-3 and -4 mRNA in the ovine hypothalamus. Neuroscience 105, 931-939, 2001
19. Mountjoy, K.G., Kong, P.L., Tayor, J.A., Willard, D.H., Wilkison, W.O. Melanocortin receptor-mediated mobilization of intracellular free calcium in HEK293 cells. Physiological Genomics 5, 11-19, 2001
20. Mountjoy, K.G. Cloning of the melanocortin receptors. In “The Melanocortin Receptors”. Chapter 7, 209-235, 2000 R.D.Cone (ed) Humana Press

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