Wellcome-MRC Institute of Metabolic Science
Our program of research explores the molecular mechanisms involved in controlling energy expenditure, fat deposition, and the mechanisms controlling the partition of energy towards oxidation or storage.
Techniques we use
We use a range of different models, with our two principle experimental systems being:
- genetically modified mouse models of insulin resistance and obesity and
- human ES and iPSC stem cells differentiated into brown and white adipocytes and macrophages.
We investigate these models using a range of advance phenotyping techniques including calorimetry, stable isotope analyses and -omics based approaches (RNAseq, lipidomics and proteomics).
Underpinning all the data generated is a key focus on data science and bioinformatics techniques that we both conduct internally and through a range of national and international collaborations.
Team achievements
Professor Vidal-Puig was awarded the 2019 Sir Philip Randle Lecture by the Biochemical Society.
Thanks to Agnes Lukasik from the TVP lab for organising an IMS-MRL summer party in June 2022.
IMS-MRL summer party 2022
Our highlight publications
Our latest paper identifies Peptidase D (PEPD) as an essential protein for the development of adipose tissue dysfunction, fibro-inflammation, and insulin resistance in obesity. Our results explain how changes in the expression and function of PEPD can explain the metabolically healthy obese and unhealthy non-obese paradox by providing a mechanism that uncouples fat mass expansion from its fibro-inflammatory complications.
This is a major effort by a broad set of international collaborators, including laboratories from Cambridge, Paris, Bielefeld, Nanjing, Girona, Valencia, Taiwan, Bari, Uppsala, London, New York and Copenhagen. We are very thankful for the funding bodies that have supported this global collaboration, particularly the MRC and British Heart Foundation supporting us here in Cambridge and the agencies supporting our collaborators.
Dysregulation of macrophage PEPD in obesity determines adipose tissue fibro-inflammation and insulin resistance. Pellegrinelli V, Rodriguez-Cuenca S, Rouault C, Figueroa-Juarez E, Schilbert H, Virtue S, Moreno-Navarrete JM, Bidault G, Vázquez-Borrego MC, Dias AR, Pucker B, Dale M, Campbell M, Carobbio S, Lin YH, Vacca M, Aron-Wisnewsky J, Mora S, Masiero MM, Emmanouilidou A, Mukhopadhyay S, Dougan G, den Hoed M, Loos RJF, Fernández-Real JM, Chiarugi D, Clément K, Vidal-Puig A. Nat Metab. 2022 Apr;4(4):476-494. doi: 10.1038/s42255-022-00561-5. Epub 2022 Apr 25.PMID: 35478031.
This is the most recent contribution to the Fatty Liver field led by the group of Lopa Mishra at George Washington University. We are happy to have contributed to this great piece of research enabled by a large group of collaborators bringing multidisciplinary approaches to a complex problem. The content of the paper is summarised as follows:
Liver diseases associated with lipid accumulation and fibrosis, such as nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), increase the risk of hepatocellular carcinoma (HCC). In this paper, Rao et al. focus on the role of β2-spectrin (SPTBN1), a protein that promotes TGF-β–SMAD3 signalling, in liver disease and tumour formation. SPTBN1, CASPASE-3, and SREBP1 were increased in liver tissue from patients with NASH. Liver-specific Sptbn1 KO mice were protected from diet-induced NASH, NAFLD, and HCC. siRNA targeting SPTBN1 reduced SREBP1 activation in HCC cells, altered fatty acid metabolism- and fibrosis-associated gene expression in a human cell culture model of NASH, and attenuated diet-induced NAFLD in mice. Results identify how SPTBN1 regulates SREBP activity and support therapeutic targeting of SPTBN1.
β2-spectrin (SPTBN1) as a therapeutic target for diet-induced liver disease and preventing cancer development. Rao S, Yang X, Ohshiro K, Zaidi S, Wang Z, Shetty K, Xiang X, Hassan MI, Mohammad T, Latham PS, Nguyen BN, Wong L, Yu H, Al-Abed Y, Mishra B, Vacca M, Guenigault G, Allison MED, Vidal-Puig A, Benhammou JN, Alvarez M, Pajukanta P, Pisegna JR, Mishra L.Sci Transl Med. 2021 Dec 15;13(624):eabk2267. doi: 10.1126/scitranslmed.abk2267. Epub 2021 Dec.
This collaborative (Cambridge, Heidelberg, Dublin, Aachen), research led by Guillaume Bidault, investigates the mechanisms of M2 polarisation in macrophages. Importantly, it identifies a new regulatory node for intracellular signalling, whereby fatty acid synthesis can cross talk to signalling pathways by depleting NADPH. This depletion of NADPH alters cellular redox balance by preventing GSH regeneration. While focussed on macrophages, the underlying mechanisms are likely to apply to many signalling pathways in many cell types.
SREBP1-induced fatty acid synthesis depletes macrophages antioxidant defences to promote their alternative activation. Guillaume Bidault, Samuel Virtue, Kasparas Petkevicius, Helen E. Jolin, Aurélien Dugourd, Anne-Claire Guénantin, Jennifer Leggat, Betania Mahler-Araujo, Brian Y. H. Lam, Marcella K. Ma, Martin Dale, Stefania Carobbio, Arthur Kaser, Padraic G. Fallon, Julio Saez-Rodriguez, Andrew N. J. McKenzie & Antonio Vidal-Puig. Nature Metabolism volume 3, pages1150–1162 (2021)C.
The TVPLab and our network of collaborators have identified the Bone Morphogenetic Protein 8B, an orphan member of the TGFβ/BMP family, as a new driver of Non-Alcoholic Steatohepatitis (NASH) promoting inflammation and disease progression. The molecular mechanisms promoting NASH are poorly understood and treatment options are limited. We found that Bone Morphogenetic Protein 8B (BMP8B), increases proportionally to disease stage in patients and animal models of NASH. BMP8B promotes hepatic stellate cells (HSC) activation and the hepatic wound healing responses causing #NASH progression. Due to the near absence of BMP8B in healthy livers, inhibition of BMP8B might represent a promising new therapeutic avenue for NASH treatment.
Bone morphogenetic protein 8B promotes the progression of non-alcoholic steatohepatitis. Michele Vacca, Jack Leslie, Samuel Virtue, Brian Y H Lam, Olivier Govaere, Dina Tiniakos, Sophie Snow, Susan Davies, Kasparas Petkevicius, Zhen Tong, Vivian Peirce, Mette Juul Nielsen, Zsuzsanna Ament, Wei Li, Tomasz Kostrzewski, Diana Julie Leeming, Vlad Ratziu, Michael E D Allison, Quentin M Anstee, Julian L Griffin, Fiona Oakley, Antonio Vidal-Puig. Nat Metab 2, 514–531 (2020) doi.org/10.1038/s42255-020-0214-9
