Metabolic Signalling

“Our research focuses on the roles of hormone and nutrient-regulated signalling pathways in obesity, type 2 diabetes and age-related diseases”

Our work investigates the signalling processes and neuronal populations in the central nervous system that regulate energy homeostasis and their contribution to diseases such as obesity and type II diabetes. We have shown that signalling pathways, such as those recruited by insulin, regulate both energy homeostasis and longevity and healthspan. We also use optogenetic, chemogenetic and in vivo imaging approaches to map the brain circuits involved in feeding and other related behaviours. These studies have revealed that the dynamic activities of defined neuronal populations integrate food intake, metabolism and complex motivated behaviours. Our goal is to identify the cellular and physiological mechanisms that control energy balance and understand how such processes are involved in the pathogenesis of metabolic and age-related disease.

Metabolic Signalling

A coronal section through the arcuate nucleus of the hypothalamus showing pro-opiomelanocortin (POMC) neurons expressing green fluorescent protein transduced with an adenovirus expressing channelrhodopsin and mCherry (red). POMC neurons co-expressing the virus appear yellow.

Selected Publications

Kokkinou M, Irvine EE, Bonsall DR, Natesan S, Wells LA, Smith M, Glegola J, Paul EJ, Tossell K, Veronese M, Khadayate S, Dedic N, Hopkins SC, Ungless MA, Withers DJ*, Howes OD*. (2020). Reproducing the dopamine pathophysiology of schizophrenia and approaches to ameliorate it: a translational imaging study with ketamine.  Molecular Psychiatry doi: 10.1038/s41380-020-0740-6 *joint communicating authors.

Smith MA, Choudhury AI, Glegola JA, Viskaitis P, Irvine EE, Custodio de Campos Silva PC, Khadayate S, Zeilhofer HU, Withers, DJ. (2020). Extrahypothalamic GABAergic nociceptin-expressing neurons regulate AgRP neuron activity to control feeding behaviour. The Journal of Clinical Investigation 130, 126-142.

Guerrero A, Herranz N, Sun B, Wagner V, Gallage S, Guiho R, Wolter K, Pombo J, Irvine EE, Innes AJ, Birch J, Glegola J, Manshaei S, Heide D, Dharmalingam G, Harbig J, Olona A, Behmoaras J, Dauch D, Uren AG, Zender L, Vernia S, Martínez-Barbera JP, Heikenwalder M, Withers DJ, Gil J. (2019). Cardiac glycosides are broad-spectrum senolytics. Nature Metabolism 1, 1074-1088.

Rached M-T, Millership SJ, Pedroni SMA, Choudhury AI, Costa ASH, Hardy DG, Glegola JA, Irvine EE, Selman C, Woodberry MC, Yadav VK, Khadayte S, Vidal-Puig A, Virtue S, Frezza C, Withers DJ. (2019). Deletion of myeloid IRS2 enhances adipose tissue sympathetic nerve function and limits obesity. Molecular Metabolism 20, 38-50.

Smith MA, Katsouri L, Virtue S, Chouhury AI, Vidal-Puig A, Ashford MLJ, Wither DJ. (2018). Calcium channel Ca(v)2.3 subunits regulate hepatic glucose production by modulating leptin-induced excitation of arcuate pro-opiomelanocortin neurons. Cell Reports 25(2), 278-287.

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 M1 Rutter GA, Scott J, Withers DJ. (2018). Neuronatin regulates pancreatic β cell insulin content and secretion. The Journal of Clinical Investigation 1, 128(8), 3369-3381. doi: 10.1172/JCI120115.

Viskaitis P, Irvine EE, Smith MA, Choudhury AI, Alvarez-Curto E, Glegola JA, Hardy DG, Pedroni SMA, Paiva Pessoa MR, Fernando ABP, Katsouri L, Sardini A, Ungless MA, Milligan G, Withers DJ. (2017). Modulation of SF1 Neuron Activity Coordinately Regulates Both Feeding Behavior and Associated Emotional States. Cell Reports 21(12), 3559-3572.

Smith MA, Katsouri L, Irvine EE, Hankir MK, Pedroni SM, Voshol PJ, Gordon MW, Choudhury AI, Woods A, Vidal-Puig A, Carling D, Withers DJ. (2015). Ribosomal S6K1 in POMC and AgRP Neurons Regulates Glucose Homeostasis but Not Feeding Behavior in Mice. Cell Reports 11(3), 335-343.

Selman C, Tullet JM, Wieser D, Irvine E, Lingard SJ, Choudhury AI, Claret M, Al-Qassab H, Carmignac D, Ramadani F, Woods A, Robinson IC, Schuster E, Batterham RL, Kozma SC, Thomas G, Carling D, Okkenhaug K, Thornton JM, Partridge L, Gems D, Withers DJ. (2009). Ribosomal protein s6 kinase 1 signaling regulates mammalian life span. Science 326(5949), 140–144.