We study the mechanisms that regulate energy homeostasis including the underlying cell signalling processes and neuronal circuits in the central nervous system with the aim of understanding how such processes are involved in the pathogenesis of metabolic and age-related disease.
“Can our nervous system influence our metabolism?”
Our brain plays a major role in how we eat. Multiple neuronal networks work together to shape our behaviour when it comes to deciding what to eat, when and how much. These networks are sensitive to a wide range of stimuli including nutrient levels, hormones, and or even just by how much we enjoy eating.
We are particularly focused on how the central nervous system may control metabolism, and how it can influence the development of diseases such as obesity and type 2 diabetes.
Our aim is to clearly identify the cellular and physiological mechanisms that work through these neural pathways to influence eating behaviour.
We also want to understand how these mechanisms and neural pathways are linked to metabolism, lifespan and overall health.
We use several methods to map brain circuits involved in feeding and related behaviours. We use optogenetic (controlling neural activity using light) and chemogenetic (control neuronal activity with designer receptors and drugs) approaches as well as techniques for monitoring neuronal activity in freely behaving mice. We combine these with a suite of experimental platforms for monitoring feeding behaviour and metabolism.
Developing a greater understanding of how neural activity influences eating and metabolism could pave the way for treatments for obesity and diabetes, or potential ways to prevent obesity and diabetes developing in the first place. Our work has also revealed common control mechanisms between metabolism and lifespan and this work could lead to treatments for the diseases of ageing.
“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 2 diabetes. We have shown that signalling pathways, such as those recruited by insulin, regulate both energy homeostasis and also lifespan 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.
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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*. (2021). Reproducing the dopamine pathophysiology of schizophrenia and approaches to ameliorate it: a translational imaging study with ketamine. Molecular Psychiatry 26:2562-2576.*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.
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.