My group’s aim is to understand the molecular mechanisms underlying the central control of food intake and body-weight.
The approaches we have taken include:
Understanding the physiological role of known genetic modifiers influencing food intake and body-weight
The first and most robust of the genes identified by GWAS is FTO (fat mass and obesity related transcript) and we have taken a number of different approaches to studying its biology. We have contributed to characterizing its enzymatic function as a demethylase (Gerken et al, Science 2007; Ma et al, Biochem J 2012), as well as identifying and characterizing loss-of-function human mutations (Boissel et al, AJHG 2009; Meyre et al, Diabetes 2010). Whatever the explanation for the effects of intronic polymorphism on human adiposity, studies of humans and mice indicate that FTO itself is an important regulator of body size and composition. We have demonstrated a role for FTO in the cellular sensing of amino acids, linking levels to mTOR signalling (Cheung et al, IJO 2013; Gulati et al, PNAS 2013), and that FTO links high-fat feeding to leptin resistance through activation of hypothalamic NFкB-related signalling pathways (Tung et al, Mol Met 2016).
However, as FTO has demonstrated, the speed of translating these obesity GWAS genes into insightful biological knowledge has been disappointing for two reasons: (1) the vast majority of the identified obesity susceptibility variants are located in intronic or integenic regions, making the identification of the ‘causative’ gene difficult to establish; and (2) the investigation of the involvement of the ‘proposed’ genes have so far been addressed in more complex model organisms such as mice. There is therefore an unmet need for validation of this GWAS data. Drosophila melanogaster, a key model for research in developmental biology, cell biology and neurobiology, has recently been demonstrated to be an excellent model for dissecting metabolic homeostasis and nutrient sensing pathways. We currently have a Wellcome Trust student developing a suite of assays in Drosophila to examine changes in the state of energy homoeostasis and changes in energy intake.
We are also currently interested the role of the non-coding RNAs Snord116 in the aetiology of Prader-Willi Syndrome (PWS). Patient reports have identified that microdeletions encompassing the SNORD116 cluster of non-coding RNAs (ncRNAs) on paternal chromosome 15q11.2 result in a phenotype that overlaps substantially with PWS. Profound hyperphagia is a major disabling feature of PWS. Understanding of its underlying mechanisms has been slowed by the paucity of animal models with increased food intake or obesity. Mice carrying a microdeletion encompassing the Snord116 cluster of non-coding RNAs, encoded within the Prader-Willi minimal deletion critical region, have previously been reported to show growth retardation and hyperphagia. We have shown that adult deletion of Snord116 in the mediobasal hypothalamus represents a hyperphagic murine model of PWS, with a subset of mice further developing obesity (Polex-Wolf et al, JCI 2018). Our work highlights that modulating the onset of Snord116 deletion in mouse can recapitulate differing phenotypes from the natural history of human PWS. This provides a unique model for further studies investigating the pathophysiology of PWS and as well as a platform for testing the efficacy of interventions aiming to prevent or reverse hyperphagia in PWS.
Identifying new players in the hypothalamic control of energy balance
Genetic studies point to the brain, and in particular the hypothalamus, as having a crucial role in modulating appetitive behaviour, which has limited the mechanistic insights achievable from human research. The inaccessibility of the human hypothalamus has, to date, meant our understanding of circuitry controlling food intake has emerged primarily from murine studies. For example, arcuate proopiomelanocortin (POMC) and NPY/AgRP neurons are critical nodes in the control of body weight. Often characterised simply as direct targets for leptin, recent data suggest a more complex architecture. Using single cell RNA sequencing, we have generated an atlas of gene expression in murine POMC and NPY/AgRP neurons. These data reveal murine arcuate POMC neurons to be a highly heterogeneous population (Lam et al, Mol Met 2017). However, is this necessarily going to be true in the human hypothalamus? A collaboration with the Cambridge Brain Bank allowing us access to fresh human donor brain samples, coupled with ‘dropseq’ single-cell sequencing technologies and single-molecule fluorescent in-situ hybridization (smFISH), provides us a timely opportunity to map the functional architecture of the human hypothalamus underlying appetitive behaviour.
Polex-Wolf J, Lam BYH, Larder R, Tadross J, Rimmington D, Bosch F, Cenzano VJ, Eduard Ayuso E, Ma MKL, Rainbow K, Coll AP, O’Rahilly S, Yeo GSH. Hypothalamic loss of Snord116 recapitulates the hyperphagia of Prader-Willi Syndrome. (2018) J. Clin. Invest. 128(3):960-969. doi: 10.1172/JCI97007. Epub 2018 Jan 29 PMID: 29376887
Lam BYH, Cimino I, Polex-Wolf J, Kohnke SN, Rimmington D, Iyemere V, Heeley N, Cossetti C, Schulte R, Saraiva LR, Logan DW, Blouet C, O’Rahilly S, Coll AP & Yeo GSH. Heterogeneity of hypothalamic Pro-opiomelanocortin-expressing neurons revealed by single-cell RNA sequencing. (2017) Molecular Metabolism 6(5):383-392. PMID: 28462073
Raffan E, Dennis RJ, O’Donovan CJ, Becker JM, Scott RA, Smith SP, Withers DJ, Wood CJ, Conci E, Clements DN, Summers KM, German AJ, Mellersh CS, Arendt ML, Iyemere VP, Withers E, Söder J, Wernersson S, Andersson G, Lindblad-Toh K, Yeo GSH†, O’Rahilly S†. A deletion in the canine POMC gene is associated with weight and appetite in obesity prone Labrador retriever dogs. 2016 Cell Metabolism 10;23(5):893-900. († co-senior author). PMID: 27157046. PMCID: PMC4873617.
Tung YCL, Gulati P, Liu CH, Rimmington D, Dennis R, Ma M, Saudek V, O’Rahilly S, Coll AP, Yeo GSH. FTO is necessary for the induction of leptin resistance by high-fat feeding. Molecular Metabolism (2015) 4(4):287-98. PMID: 25830092. PMCID: PMC4354923.
Gulati P, Cheung MK, Antrobus R, Church C, Harding H, Tung TCL, Rimmington D, Ma M, Ron D, Lehner PJ, Ashcroft F, Cox RD, Coll AP, O’Rahilly S and Yeo GSH. (2013). A role for the obesity-related FTO gene in the cellular sensing of amino acids. Proc. Natl. Acad. Sci. U.S.A. www.pnas.org/cgi/doi/10.1073/pnas. 1222796110. PMID: 22614055.
Yeo GSH and Heisler LH. (2012). Unravelling the brain regulation of appetite: Lessons from genetics. Nat Neurosci, 15(10):1343-9. PMID: 23007189.
Ma M, Harding HP, O’Rahilly S, Ron D and Yeo GSH. (2012). Kinetic analysis of FTO (Fat mass and obesity related) reveals that it is unlikely to function as a sensor for 2-oxoglutarate. Biochem J, 2012 Mar 21. PMID: 22435707.
Meyre D, Proulx K, Kawagoe-Takaki H, Vatin V, Gutiérrez-Aguilar R, Lyon D, Ma M, Choquet H, Horber F, Van Hul W, Van Gaal L, Balkau B, Visvikis-Siest S, Pattou F, Farooqi IS, Saudek V, O’Rahilly S, Froguel P, Sedgwick B, Yeo GSH. (2010). Prevalence of loss-of-function FTO mutations in lean and obese individuals. Diabetes, 59(1):311-8. PMID: 19833892. PMCID: PMC2797938.
Tung YCL, Ma M, Piper S, Coll AP, O´Rahilly S and Yeo GSH. (2008). Novel leptin-regulated genes revealed by transcriptional profiling of the hypothalamic paraventricular nucleus. J Neuroscience, 28(47):12419-26. PMID: 19020034. PMCID: PMC2650686.
Yeo GSH, Hung C.C, Rochford J, Keogh J.M, Gray J, Sivaramakrishnan S, O’Rahilly S and Farooqi I.S. (2004). A de novo mutation affecting human TrkB associated with severe obesity and developmental delay. Nature Neuroscience, 7(11):1187-9. PMID: 15494731.
Yeo GSH, Farooqi I.S, Aminian S, Halsall D.J, Stanhope R.G and O’Rahilly. (1998). A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nature Genetics, 20(2):111-2. PMID: 9771698.