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Thesis Title Molecular characterisation of the adiponectin receptors, AdipoR1 and AdipoR2 Sahar Keshvari MSc, Honours A thesis submitted for the degree of Doctor of Philosophy at The University of Queensland in 2016 School of Medicine Abstract The increasing global prevalence of cardiovascular and metabolic diseases necessitates the development of more effective therapeutic strategies that, in turn, require a greater understanding of the regulatory networks involved. Research over the last decade has increased our appreciation of the key role of the adiponectin axis as a major regulator of metabolic, cardiovascular and inflammatory tone, thereby establishing it as a province of therapeutic opportunity. The receptors for adiponectin, AdipoR1 and AdipoR2, are distant relatives of the largest single class of drug targets, the G-protein coupled receptor (GPCR) family. However, unlike GPCRs they have intracellular N-termini and extracellular C-termini and signal via atypical pathways. Our current understanding of AdipoR1 and AdipoR2 is rudimentary, constraining our ability to target these receptors effectively. The aim of this thesis was to characterise molecular features of AdipoR1 and AdipoR2 that facilitate adiponectin signal transduction to advance our understanding and identify strategies to enhance adiponectin’s beneficial effects. We have begun to characterise basic properties of AdipoR1 and AdipoR2, focusing on molecular factors that drive cell-surface expression (CSE) of the receptors using a range of C-terminal, epitope-tagged AdipoR1 and AdipoR2 constructs. Surprisingly, under steady-state conditions (no serum starvation) only AdipoR1 was readily detected on the cell-surface (cell-surface ratio of AdipoR1 vs AdipoR2 is 0.6±0.1 vs 0.15±0.1, p<0.05). Generation and characterisation of a series of chimeric and truncated constructs demonstrated that a non-conserved, intracellular, N-terminal region of AdipoR2 (R2(1-81)) restricted its CSE whilst the same region in AdipoR1 (R1(1-70)) promoted its CSE. We also confirmed that AdipoR1 and AdipoR2 form heterodimer and that co- expression of these receptors increase the CSE of AdipoR2. Subsequently, we provided evidence that the subcellular localisation of AdipoR1 and AdipoR2 is governed by multiple motifs across their non-conserved and conserved cytoplasmic domains. For instance, two highly conserved motifs, an ER exit motif (FxxxFxxxF) and Di-Leucine motif (DxxxLL), in the conserved N- terminal domain are required for the proper CSE of both AdipoR1 and AdipoR2, whilst different parts of the non-conserved domain of AdipoR2 inhibits its CSE. Moreover, we demonstrated that in HEK-293 cells over-expressing AdipoR1 adiponectin activated downstream signalling networks (AMPK, AKT, ERK & P38MAPK) acutely (peaking at 15 min) whereas signal transduction via AdipoR2 was relatively chronic (peaking at 24 h). This difference was also underpinned by the non-conserved N-terminal domains of AdipoR1 and AdipoR2. We also demonstrated that a number of conserved and non-conserved cysteines in the N-terminal domain of ii AdipoR1 and AdipoR2 are subject to palmitoylation and that palmitoylation of a conserved cysteine, situated in the juxta-membrane region of the N-termini of AdipoR1 and AdipoR2 in a position analogous to that observed in GPCRs, plays a key role in the CSE of both receptors. Mutation of these sites inhibits CSE and signal transduction of full-length receptors in vitro and in vivo. Furthermore, palmitoylation of these ‘canonical cysteines’ promotes enrichment of N- terminal, cytoplasmic AdipoR1(R1(1-127)) and AdipoR2 (R2(1-138)) constructs under the PM. Our further investigation revealed the differential effects of electrotransfer-mediated overexpression of AdipoR1 or AdipoR2 in the Tibialis Anterior (TA) muscle of lean (chow) or obese (10 wk HFD) mice (n=6/group). In lean mice, overexpression of AdipoR1 or AdipoR2 increased phosphorylation of downstream effectors AMPK, Akt and ERK (all p<0.05), but not p38MAPK. The magnitude of these effects was reduced in obese mice; consistent with the development of adiponectin resistance (circulating adiponectin was not reduced after 10 wk HFD). Both AdipoR1 and AdipoR2 increased glut-4 mRNA (2-fold, p<0.05) and this was also affected by obesity. In contrast, only AdipoR2 increased pparα and a downstream target gene Acox1 (all p<0.05) and this effect was blunted by obesity. Surprisingly, exclusive overexpression of AdipoR2 in TA muscle of obese mice resulted in marked systemic effects which included increased circulating adiponectin levels, decreased body weight gain and reduced epididymal fat mass and markers of adipose tissue inflammation (all p<0.05). Collectively these results indicate that there are (i) fundamental differences between AdipoR1 and AdipoR2 and demonstrate that (ii) there are specific motifs in the intracellular N-terminal region of both AdipoR1 and AdipoR2 regulating the subcellular trafficking, (iii) both receptors need palmitoylation for efficient cell-surface expression and signal transduction. Also (iiii) Muscle- specific overexpression of AdipoR1 or AdipoR2 gives rise to differential local and systemic effects. Further studies are required to extend these novel observations and elaborate the complex mechanisms governing AdipoR trafficking and signalling to determine whether alterations in these processes contribute to the aetiology of human disease and or can be targeted therapeutically. iii Declaration by author This thesis is composed of my original work, and contains no material previously published or written by another person except where due reference has been made in the text. I have clearly stated the contribution by others to jointly-authored works that I have included in my thesis. I have clearly stated the contribution of others to my thesis as a whole, including statistical assistance, survey design, data analysis, significant technical procedures, professional editorial advice, and any other original research work used or reported in my thesis. The content of my thesis is the result of work I have carried out since the commencement of my research higher degree candidature and does not include a substantial part of work that has been submitted to qualify for the award of any other degree or diploma in any university or other tertiary institution. I have clearly stated which parts of my thesis, if any, have been submitted to qualify for another award. I acknowledge that an electronic copy of my thesis must be lodged with the University Library and, subject to the policy and procedures of The University of Queensland, the thesis be made available for research and study in accordance with the Copyright Act 1968 unless a period of embargo has been approved by the Dean of the Graduate School. I acknowledge that copyright of all material contained in my thesis resides with the copyright holder(s) of that material. Where appropriate I have obtained copyright permission from the copyright holder to reproduce material in this thesis. iv Publications during candidature Peer-reviewed papers: 1- Kim, Y.H. *, Barclay J.L. *, He J., Luo X., O'Neill H.M., Keshvari S., Webster J.A., Ng C., Hutley L.J., Prins J.B., and Whitehead J.P., Identification of carboxypeptidase X (CPX)-1 as a positive regulator of adipogenesis. FASEB J,2016. 2- Barclay J.L.*, Keshvari, S.*, Whitehead J.P., Inder W.J., ANNALS EXPRESS: Development of an enzyme-linked immunosorbent assay for thrombospondin-1 and comparison of human plasma and serum concentrations. Ann Clin Biochem, 2016. 3- Barclay J.L., Petersons C.J., Keshvari S, Sorbello J., Mangelsdorf B.L., Thompson C.H., Prins J.B., Burt M.G., Whitehead J.P., Inder W.J., Thrombospondin-1 is a glucocorticoid responsive protein in humans. Eur J Endocrinol, 2015. EJE-15-0964. 4- Keshvari, S. and Whitehead J.P., Characterisation of the adiponectin receptors: Differential cell-surface expression and temporal signaling profiles of AdipoR1 and AdipoR2 are regulated by the non-conserved N-terminal trunks. Mol Cell Endocrinol, 2015. 409: p. 121-9 (Incorporated as Chapter 2) 5- Yang, M., Kimura, M., Ng, C., He, J., Keshvari, S., Rose, F. J., Barclay, J. L., Whitehead, J. P., Induction of heme-oxygenase-1 (HO-1) does not enhance adiponectin production in human adipocytes: Evidence against a direct HO-1 - Adiponectin axis. Mol Cell Endocrinol, 2015. 413: p. 209-216 6- Keshvari, S., Rose, F. J., Charlton, H. K., Scheiber, N. L., Webster, J., Kim, Y. H., Ng, C. Parton, R. G., Whitehead, J. P., Characterisation of the adiponectin receptors: The non- conserved N-terminal region of AdipoR2 prevents its expression at the cell-surface. Biochem Biophys Res Commun, 2013. 432(1): p. 28-33. (Incorporated as Chapter 3) v Conference abstracts: 1- Keshvari, S., Adams, M.N., Hooper, J.D., Whitehead J.P., New insights into the Adiponectin Receptors: AdipoR1 and AdipoR2 show different cell surface expression and temporal signalling profiles and both are dependent on palmitoylation. Australian & New Zealand Obesity Society, Melbourne, 2015. 2- Keshvari, S., Henstridge, D.C., Febbraio, M.A., Whitehead J.P., Muscle-specific overexpression of AdipoR1 or AdipoR2 gives rise to differential local and systemic effects. Australian Diabetes Society, Melbourne, 2015. 3- Keshvari, S. and Whitehead J.P., Characterisation of the Adiponectin Receptors: Palmitoylation of AdipoR1 and AdipoR2 is required for Efficient Cell-Surface Expression and Down-Stream Signalling. Australian Diabetes Society, Melbourne, 2014. 4- Keshvari, S. and Whitehead J.P.,
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