LICAMM Brown adipose tissue-derived small molecule interorgan signalling in cardiometabolic disease

Brown adipose tissue (BAT) functions to regulate body temperature through non-shivering thermogenesis; the dissipation of chemical energy to produce heat [1,2].Beige adipocytes are interspersed within the white adipose tissue (WAT) of rodents and humans, and can be induced to switch from a white-adipocyte-like phenotype to a brown-adipocyte-like phenotype; a process known as browning [3]. Brown and beige adipose tissue are emerging as distinct endocrine organs [4]. These tissues are functionally associated with skeletal muscle, adipose tissue metabolism and systemic energy expenditure, suggesting an interorgan signaling network [5-7]. Using metabolomics, we have identified 3-methyl-2-oxovaleric acid, 5-oxoproline, and β-hydroxyisobutyric acid as small molecule metabokines synthesized in browning adipocytes and secreted via monocarboxylate transporters [8]. 3-methyl-2-oxovaleric acid (MOVA), 5-oxoproline (5OP) and β-hydroxyisobutyric acid (BHIBA) induce a brown adipocyte-specific phenotype in white adipocytes and mitochondrial oxidative energy metabolism in skeletal myocytes both in vitro and in vivo [8]. MOVA and 5OP signal through cAMP-PKA-p38 MAPK and BHIBA via mTOR8. In humans, plasma and adipose tissue MOVA, 5OP and BHIBA concentrations correlate with markers of adipose browning and inversely associate with body mass index [8]. These metabolites reduce adiposity, increase energy expenditure and improve glucose and insulin homeostasis in mouse models of obesity and diabetes [8]. Our findings identify beige adipose-brown adipose-muscle physiological metabokine crosstalk. However, increased BAT thermogenic activity or BAT transplant are also known to improve cardiac function [9]. Moreover, thermogenic activation and transplantation of BAT increases hepatic lipid oxidation, inhibits liver de novo lipogenesis and reduces oxidative stress and fibrosis through batokine and secreted factor-implicated interorgan mechanisms [10-13].

<p style="margin-bottom:13px; text-align:justify">This project will investigate the role of the brown adipose metabokine signals (MOVA, 5OP and BHIBA) in organ crosstalk to protect against the deleterious metabolic effects of obesity and diabetes. This research will focus on the effects of the metabokines on cardiac metabolism and function and liver metabolism in preclinical and human tissue culture models of obesity and diabetes. The student will use an array of molecular biology techniques (rt-qPCR, immunoblotting) [8,14,15], metabolic techniques (high-resolution respirometry [8,16]; Whole-body indirect calorimetry [8,16,17]; metabolomics [8,14,17]), and imaging techniques (PET-CT8,18; Echocardiography).</p> <h5>References</h5> <ol> <li>Lowell, B.B. & Spiegelman, B.M. Towards a molecular understanding of adaptive thermogenesis. Nature 404, 652-60 (2000).</li> <li>Wu, Z. et al. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98, 115-24 (1999).</li> <li>Wu, J. et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 150, 366-76 (2012).</li> <li>Keipert, S. et al. Endogenous FGF21-signaling controls paradoxical obesity resistance of UCP1-deficient mice. Nat Commun 11, 624 (2020).</li> <li>Tran, T.T., Yamamoto, Y., Gesta, S. & Kahn, C.R. Beneficial effects of subcutaneous fat transplantation on metabolism. Cell Metab 7, 410-20 (2008).</li> <li>Kong, X. et al. Brown Adipose Tissue Controls Skeletal Muscle Function via the Secretion of Myostatin. Cell Metab (2018).</li> <li>Liu, X. et al. Brown adipose tissue transplantation improves whole-body energy metabolism. Cell Res 23, 851-4 (2013).</li> <li>Whitehead, A. et al. Brown and beige adipose tissue regulate systemic metabolism through a metabolite interorgan signaling axis. Nat Commun 12, 1905 (2021).</li> <li>Pinckard, K.M. et al. A Novel Endocrine Role for the BAT-Released Lipokine 12,13-diHOME to Mediate Cardiac Function. Circulation 143, 145-159 (2021).</li> <li>Li, P. et al. Transplantation of brown adipose tissue up-regulates miR-99a to ameliorate liver metabolic disorders in diabetic mice by targeting NOX4. Adipocyte 9, 57-67 (2020).</li> <li>Yang, F.T. & Stanford, K.I. Batokines: Mediators of Inter-Tissue Communication (a Mini-Review). Curr Obes Rep (2022).</li> <li>Chen, Z. et al. Nrg4 promotes fuel oxidation and a healthy adipokine profile to ameliorate diet-induced metabolic disorders. Mol Metab 6, 863-872 (2017).</li> <li>Wang, G.X. et al. The brown fat-enriched secreted factor Nrg4 preserves metabolic homeostasis through attenuation of hepatic lipogenesis. Nat Med 20, 1436-1443 (2014).</li> <li>McNally, B.D. et al. Long-chain ceramides are cell non-autonomous signals linking lipotoxicity to endoplasmic reticulum stress in skeletal muscle. Nat Commun 13, 1748 (2022).</li> <li>Roberts, L.D. et al. Inorganic nitrate promotes the browning of white adipose tissue through the nitrate-nitrite-nitric oxide pathway. Diabetes 64, 471-84 (2015).</li> <li>MacCannell, A.D.V. et al. Sexual dimorphism in adipose tissue mitochondrial function and metabolic flexibility in obesity. Int J Obes (Lond) (2021).</li> <li>Roberts, L.D. et al. beta-Aminoisobutyric Acid Induces Browning of White Fat and Hepatic beta-Oxidation and Is Inversely Correlated with Cardiometabolic Risk Factors. Cell Metab 19, 96-108 (2014).</li> <li>MacCannell, A.D.V., Wright, J., Schneider, J.E. & Roberts, L.D. Multi-modal Functional Imaging of Brown Adipose Tissue. J Lipid Res (2020).</li> </ol>

<p>Please note these are not standalone projects and applicants must apply to the PhD academy directly.</p> <p>Applications can be made at any time. You should complete an <a href="https://medicinehealth.leeds.ac.uk/faculty-graduate-school/doc/apply-2">online application form</a> and attach the following documentation to support your application. </p> <ul> <li>a full academic CV</li> <li>degree certificate and transcripts of marks (or marks so far if still studying)</li> <li>Evidence that you meet the programme’s minimum English language requirements (if applicable, see requirement below)</li> <li>Evidence of funding to support your studies</li> </ul> <p>To help us identify that you are applying for this project please ensure you provide the following information on your application form;</p> <ul> <li>Select PhD in Medicine, Health & Human Disease as your planned programme of study</li> <li>Give the full project title and name the supervisors listed in this advert</li> </ul>

Applicants to research degree programmes should normally have at least a first class or an upper second class British Bachelors Honours degree (or equivalent) in an appropriate discipline. A Master degree is desirable, but not essential..

Applicants whose first language is not English must provide evidence that their English language is sufficient to meet the specific demands of their study. The minimum requirements for this programme in IELTS and TOEFL tests are: • British Council IELTS - score of 7.0 overall, with no element less than 6.5 • TOEFL iBT - overall score of 100 with the listening and reading element no less than 22, writing element no less than 23 and the speaking element no less than 24.

<p>For further information please contact the Faculty Graduate School<br /> e:<a href="mailto:fmhpgradmissions@leeds.ac.uk">fmhpgradmissions@leeds.ac.uk</a></p>