Research Interests
We aim to identify new molecules and pathways that play a role in the brain control of energy homeostasis, and thus reveal new potential therapeutic targets to tackle obesity.
The approaches we have taken include:
Mapping the appetitive control circuits in the mammalian brain using single nucleus RNA sequencing (NucSeq) and spatial transcriptomics approaches. 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. We were one of the pioneers in single cell profiling of mouse hypothalami (Lam et al, Molecular Metabolism 2017) and more recently, using single nucleus sequencing (NucSeq), the mouse hindbrain (Dowsett et al, Molecular Metabolism 2021). We integrated 18 separate single-cell datasets of the murine hypothalamus to create the 'HypoMap' reference atlas (Steuernagel, Lam et al, Nature Metabolism 2022). We have now combined both single-cell and spatial transcriptomic approaches to create a high resolution ‘spatio-cellular’ map of the human hypothalamus (Tadross, Steuernagel, Dowsett et al, Nature In press; BioRXiv 2023).
I co-lead an MRC-MDU research programme (with O’Rahilly and Coll) on ‘Mechanisms in disorders of energy balance and body composition’. Highlights include identifying that a deletion in POMC is a key driver of obesity in Labradors (Raffan et al, Cell Metabolism 2016); generating the first mouse model recapitulating the hyperphagia seen in Prader Willi Syndrome (Polex-Wolf et al, JCI 2018); establishing that the frequency of MC4R mutations in a UK birth cohort is 0.3%, far more common than previously thought (Wade et al, Nature Medicine 2021); and uncovering that MC3R links nutritional state to childhood growth and timing of puberty (Lam et al, Nature 2021). Most recently, with my close colleague John Perry, we have identified new genes linked to adult onset obesity at the population level (Zhao et al, Nature Genetics 2024).
Molecularly characterizing, in human neurons, genes associated with changes in bodyweight identified from consanguineous pedigrees. 10% of severe human obesity currently has a monogenic cause. Thus, much of the genetic aetiology of severe obesity remains unknown. In an MRC funded collaborative project grant with Philippe Froguel (Imperial/Lille), we are studying the disease in consanguineous pedigrees. Froguel has recruited a cohort of >400 severely obese children from consanguineous families in Pakistan, in which homozygous mutations in the leptin-melanocortin pathway, identified by whole exome sequencing, explain ~30% of cases. We are currently molecularly characterizing emerging candidate genes that emerge from the screen in human neurons and mapping their expression in the human hypothalamus. In addition, we plan to explore the functional consequences of mutations in these candidate genes in hypothalamic neurons derived from human stem cells.
Group members
Ms Lucy Bedwell, DTP-MR PhD Student (Yeo) - lab203 at medschl.cam.ac.uk
Dr Irene Cimino, Research Associate, (Coll, O’Rahilly, Yeo) - ic326 at medschl.cam.ac.uk
Dr Brian Lam, Senior Research Associate (Coll, O’Rahilly, Yeo) - yhbl2 at cam.ac.uk
Dr Sheridan Littleton, Research Associate (Yeo) - sl2225 at medschl.cam.ac.uk
Mrs Kara Rainbow, Research Manager (Coll, O’Rahilly, Yeo) - kh271 at medschl.cam.ac.uk
Dr John Tadross, Affiliated Assistant Professor (Coll, O’Rahilly, Yeo) - jt636 at medschl.cam.ac.uk
Dr Loraine Tung, Senior Research Associate (Coll, O’Rahilly, Yeo) - lyct2 at cam.ac.uk
Genomics Facility
Dr Marcella Ma, Research Associate and Facility Manager - mkm32 at medschl.cam.ac.uk
Ms Hannah Rosekilly, Research Technician - hfr29 at cam.ac.uk
