Metabolism

About the research

Complex obesity research addresses both complications of obesity as well as complex causes of obesity utilising integrated in vitro, ex vivo, and human in vivo physiology and experimental medicine approaches as well as interventional clinical trials, cohort and population health studies. Major programmes of research target Polycystic Ovary Syndrome and the impact of androgen excess on metabolic dysfunction (Arlt, Wellcome Investigator Award), synergistically interacting with NIHR-funded research led by Thangaratinam (Gestational Diabetes, Obesity in Pregnancy) and Tahrani (Sleep-related disorders and metabolic health, obesity management including bariatric surgery; diabetes-related neuropathy), with public health input by Nirantharakumar.

Manolopoulos spearheads the IMSR human metabolic in vivo physiology hub, a dedicated set-up integrated into the Birmingham NIHR Clinical Research Facility, focussing on adipose tissue physiology. Another major asset of the Complex Obesity theme is the Metabolic Neurology Group with a principal research focus on Idiopathic Intracranial Hypertension (IIH), a condition of raised intracranial pressure driven by obesity and primarily affecting women of reproductive age (Sinclair, Sir Jules Thorne Award). Recent achievements include a recently licensed spin-out company (Invex Therapeutics), and a collaboration with NASA to address space flight-induced intracranial hypertension affecting astronauts.

Publications

Association Between Idiopathic Intracranial Hypertension and Risk of Cardiovascular Diseases in Women in the United Kingdom. Adderley NJ, Subramanian A, Nirantharakumar K, Yiangou A, Gokhale KM, Mollan SP, Sinclair AJ. JAMA Neurol. 2019 Jul 8. doi: 10.1001/jamaneurol.2019.1812. [Epub ahead of print]

Mediterranean-style diet in pregnant women with metabolic risk factors (ESTEEM): A pragmatic multicentre randomised trial. H Al Wattar B, Dodds J, Placzek A, Beresford L, Spyreli E, Moore A, Gonzalez Carreras FJ, Austin F, Murugesu N, Roseboom TJ, Bes-Rastrollo M, Hitman GA, Hooper R, Khan KS, Thangaratinam S; ESTEEM study group. PLoS Med. 2019 Jul 23;16(7):e1002857.

About the research

The Diabetes and Energy Metabolism theme employs molecular, cellular and in vivo physiology approaches to define mechanisms relating to the control of metabolism in disease. The IMSR Mouse Metabolic Phenotyping core enables deep metabolic phenotyping of animal models to understand how energy-sensors in muscle, liver and brain influence glucose homeostasis (da Silva Xavier), how NAD+ biology influences muscle ageing (Lavery) and how nutrients partition in islet beta and alpha cells to influence insulin and glucagon secretion (Hodson). Hodson (ERC Starter) uses advanced imaging, chemical biology and CRISPR-Cas9 genome-editing to understand how different cell subpopulations contribute to islet function. Gorvin (AMS Starter Grant) investigates the regulation of GPCRs involved in food intake and obesity using novel screening approaches. Akerman (Diabetes UK RD Lawrence Fellow) uses genomics and bioinformatics to identify new diabetes susceptibility regions of the human genome. Prete (Diabetes UK Sir George Alberti Fellow) investigates the mechanisms underlying the increased type 2 diabetes risk in patients with mild autonomous cortisol excess due to adrenal adenomas. Arlt (Wellcome Trust Investigator) studies how lipid metabolism and diabetes risk is influenced by androgen excess in women with polycystic ovarian syndrome. Thangaratinam (NIHR) investigates how maternal obesity and diabetes impacts lifelong metabolic health of the offspring. IMSR-affiliated investigators from Sports, Exercise and Rehabilitation Sciences collaborate on exercise metabolism and nutrition (Breen, Lai, Wallis, Whitham).

Publications

Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD+ Metabolome and Induces Transcriptomic and Anti-inflammatory Signatures. Elhassan YS, Kluckova K, Fletcher RS, Schmidt MS, Garten A, Doig CL, Cartwright DM, Oakey L, Burley CV, Jenkinson N, Wilson M, Lucas SJE, Akerman I, Seabright A, Lai YC, Tennant DA, Nightingale P, Wallis GA, Manolopoulos KN, Brenner C, Philp A, Lavery GG. Cell Rep. 2019 Aug 13;28(7):1717-1728.e6.

Neuronatin regulates pancreatic β cell insulin content and secretion. Millership SJ, Da Silva Xavier G, Choudhury AI, Bertazzo S, Chabosseau P, Pedroni SM, Irvine EE, Montoya A, Faull P, Taylor WR, Kerr-Conte J, Pattou F, Ferrer J, Christian M, John RM, Latreille M, Liu M, Rutter GA, Scott J, Withers DJ. J Clin Invest. 2018 Aug 1;128(8):3369-3381.

Glucocorticoids Reprogram β-Cell Signaling to Preserve Insulin Secretion Fine NHF, Doig CL, Elhassan YS, Vierra NC, Marchetti P, Bugliani M, Nano R, Piemonti L, Rutter GA, Jacobson DA, Lavery GG Hodson DJ. Diabetes. 2018 Feb;67(2):278-290. doi: 10.2337/db16-1356. Epub 2017 Dec 4.

About the research

The Metabolic Receptor Biology theme aims to investigate the fundamental mechanisms of G protein-coupled receptor (GPCR) signalling and their alterations in metabolic and endocrine disease (Calebiro, Hodson, Gorvin). A key focus of the theme is the development of innovative microscopy methods (such as FRET and single-molecule microscopy), in combination with new biosensors, to monitor receptor signalling directly in living cells and tissues with unprecedented spatiotemporal resolution (Calebiro, Wellcome SRF). This is combined with novel mathematical and computational approaches to extract information from complex imaging data and model receptor signalling at both molecular and cellular level. Using this multi-disciplinary approach, we have redefined fundamental mechanisms of GPCR signalling, including the discovery that GPCRs are not only active at the plasma membrane, but also at intracellular sites such as endosomes and the Golgi complex. We have identified genetic alterations in GPCR signalling as drivers of endocrine and metabolic disease and aim to develop innovative therapeutic strategies for metabolic diseases (Gorvin, AMS Springboard Award).

Publications

Super-resolution microscopy compatible fluorescent probes reveal endogenous glucogon-like peptide-1 receptor distribution and dynamics. Ast J, Arvaniti A, Fine NHF, Nasteska D, Ashford FB, Stamataki Z, Koszegi Z, Bacon A, Jones BJ, Lucey MA, Sasaki S, Brierley DI, Hastoy B, Tomas A, D’Agostino A, Reimann F, Lynn FC, Reissaus CA, Linnemann AK, D’Este E, Calebiro D, Trapp S, Johnsson K, Podwin T, Broichhagen, Hodson DJ. Nat Commun. 2020 (accepted for publication 17 Dec 2019)

Single-molecule imaging reveals receptor-G protein interactions at cell surface hot spots. Sungkaworn T, Jobin ML, Burnecki K, Weron A, Lohse MJ, Calebiro D. Nature. 2017 Oct 26;550(7677):543-547.

A calcium-sensing receptor mutation causing hypocalcemia disrupts a transmembrane salt bridge to activate β-arrestin-biased signaling. Gorvin CM, Babinsky VN, Malinauskas T, Nissen PH, Schou AJ, Hanyaloglu AC, Siebold C, Jones EY, Hannan FM, Thakker RV. Sci Signal. 2018 Feb 20;11(518). pii: eaan3714.

About the research

Cancer metabolism research in the IMSR aims to understand the role of the cellular and biochemical tumour microenvironment. Studies in tumours arising from mutations in central metabolic enzymes have furthered our understanding of similar vulnerabilities observed in hypoxic regions of all tumours (Tennant CRUK Programme Foundation grant, focusing on glioma, breast cancer and multiple myeloma). We use multi-cellular systems to understand the complex whole tumour metabolism, culturing cancer cells alongside fibroblasts or adipocytes (Tennant). We have developed a further programme to investigate how the malignant microenvironment can subvert the anti-tumour immune response (Dimeloe, Marie Curie & Leuka Fellow), studying both the role of specific metabolites on T cell function, and the metabolism of primary T cells isolated from patient samples. Our research goes further towards altering the growth and treatment outcomes of tumours by subverting their microenvironment.

Maslowski (CRUK Career Establishment Fellow) is investigating how attenuated Salmonella alters the metabolic microenvironment of colon cancer, using cutting-edge animal models and innovative analytical approaches. The research is underpinned by the development of innovative tools and acquisition methods (Ludwig) that permit resolution of complex datasets arising from incubating cells and tissues and infusing animals and patients with stable isotope enriched nutrients.

Publications

Tumor-derived TGF-β inhibits mitochondrial respiration to suppress IFN-γ production by human CD4+T cells. Dimeloe S, Gubser P, Loeliger J, Frick C, Develioglu L, Fischer M, Marquardsen F, Bantug GR, Thommen D, Lecoultre Y, Zippelius A, Langenkamp A, Hess C. Sci Signal. 2019 Sep 17;12(599). pii: eaav3334.

A transcriptionally and functionally distinct PD-1+ CD8+ T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade. Thommen DS, Koelzer VH, Herzig P, Roller A, Trefny M, Dimeloe S, Kiialainen A, Hanhart J, Schill C, Hess C, Savic Prince S, Wiese M, Lardinois D, Ho PC, Klein C, Karanikas V, Mertz KD, Schumacher TN, Zippelius A. Nat Med. 2018 Jul;24(7):994-1004.

About the research

IMSR Immunometabolism researchers investigate the role of metabolism in immune cell function and associated inflammatory and infectious disease. Studies of steroid metabolism (Hewison, Hardy, Tamblyn and Jenkinson) have defined the pivotal importance of glucocorticoid and vitamin D metabolic pathways in regulating the innate immune response. More recent work has characterised the steroid metabolome in monocytes and T cells, with analysis of human and animal models for rheumatoid arthritis, inflammatory bowel disease and pregnancy, also establishing novel steroid and vitamin D mass spectrometry profiling methods.

IMSR immunometabolism research also incorporates studies of the role of cell metabolism (oxidative phosphorylation, electron transport and the TCA cycle) in innate and adaptive immunity (Tennant, Mauro, Dimeloe and Maslowski). Recent studies have established the interplay of vitamin D and antigen-presenting cell fatty acid synthesis, and a role for NAD metabolism in T cells.

Publications

Lactate Buildup at the Site of Chronic Inflammation Promotes Disease by Inducing CD4+ T Cell Metabolic Rewiring. Pucino V, Certo M, Bulusu V, Cucchi D, Goldmann K, Pontarini E, Haas R, Smith J, Headland SE, Blighe K, Ruscica M, Humby F, Lewis MJ, Kamphorst JJ, Bombardieri M, Pitzalis C, Mauro C. Cell Metab. 2019 Dec 3;30(6):1055-1074.e8.

11 Beta-hydroxysteroid dehydrogenase type 1 regulates synovitis, joint destruction, and systemic bone loss in chronic polyarthritis. Hardy RS, Fenton C, Croft AP, Naylor AJ, Begum R, Desanti G, Buckley CD, Lavery G, Cooper MS, Raza K. J Autoimmun. 2018 Aug;92:104-113.