Physiology - Research Publications

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    A Neural basis for Octanoic acid regulation of energy balance
    Haynes, VR ; Michael, NJ ; van den Top, M ; Zhao, F-Y ; Brown, RD ; De Souza, D ; Dodd, GT ; Spanswick, D ; Watt, MJ (ELSEVIER, 2020-04-01)
    OBJECTIVES: Nutrient sensing by hypothalamic neurons is critical for the regulation of food intake and energy expenditure. We aimed to identify long- and medium-chain fatty acid species transported into the brain, their effects on energy balance, and the mechanisms by which they regulate activity of hypothalamic neurons. METHODS: Simultaneous blood and cerebrospinal fluid (CSF) sampling was undertaken in rats and metabolic analyses using radiolabeled fatty acid tracers were performed on mice. Electrophysiological recording techniques were used to investigate signaling mechanisms underlying fatty acid-induced changes in activity of pro-opiomelanocortin (POMC) neurons. RESULTS: Medium-chain fatty acid (MCFA) octanoic acid (C8:0), unlike long-chain fatty acids, was rapidly transported into the hypothalamus of mice and almost exclusively oxidized, causing rapid, transient reductions in food intake and increased energy expenditure. Octanoic acid differentially regulates the excitability of POMC neurons, activating these neurons directly via GPR40 and inducing inhibition via an indirect non-synaptic, purine, and adenosine receptor-dependent mechanism. CONCLUSIONS: MCFA octanoic acid is a central signaling nutrient that targets POMC neurons via distinct direct and indirect signal transduction pathways to instigate changes in energy status. These results could explain the beneficial health effects that accompany MCFA consumption.
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    The cytokine GDF15 signals through a population of brainstem cholecystokinin neurons to mediate anorectic signalling
    Worth, AA ; Shoop, R ; Tye, K ; Feetham, CH ; D'Agostino, G ; Dodd, GT ; Reimann, F ; Gribble, FM ; Beebe, EC ; Dunbar, JD ; Alexander-Chacko, JT ; Sindelar, DK ; Coskun, T ; Emmerson, PJ ; Luckman, SM (ELIFE SCIENCES PUBLICATIONS LTD, 2020-07-29)
    The cytokine, GDF15, is produced in pathological states which cause cellular stress, including cancer. When over expressed, it causes dramatic weight reduction, suggesting a role in disease-related anorexia. Here, we demonstrate that the GDF15 receptor, GFRAL, is located in a subset of cholecystokinin neurons which span the area postrema and the nucleus of the tractus solitarius of the mouse. GDF15 activates GFRALAP/NTS neurons and supports conditioned taste and place aversions, while the anorexia it causes can be blocked by a monoclonal antibody directed at GFRAL or by disrupting CCK neuronal signalling. The cancer-therapeutic drug, cisplatin, induces the release of GDF15 and activates GFRALAP/NTS neurons, as well as causing significant reductions in food intake and body weight in mice. These metabolic effects of cisplatin are abolished by pre-treatment with the GFRAL monoclonal antibody. Our results suggest that GFRAL neutralising antibodies or antagonists may provide a co-treatment opportunity for patients undergoing chemotherapy.