Although hyperphagic feeding during cold exposure is widely viewed as a response to the negative energy state that results from increased thermogenesis, the underlying mechanisms are unknown. We investigated an alternative hypothesis, that during cold exposure, hyperphagia is mounted in anticipation of homeostatic need, rather than as a compensatory response. In support of this hypothesis, we report that in chow-fed mice acutely housed at 14°C, increases of food intake and thermogenesis occur both rapidly and simultaneously, implying hyperphagia is not mounted as a compensatory response. We next asked whether this cold-induced feeding response involves activation of agouti-related peptide (Agrp) neurons, which are implicated in other forms of hyperphagic feeding. Consistent with this hypothesis, we report that Agrp neurons are activated within 1-2 min of cold exposure and prior to the onset of hyperphagia, as judged by in vivo fiber photometry and confirmed by cFos induction (Agrp+/cFos+, 22°C: 5.3±4.5% vs. 14°C: 20.2±6.1%; p<0.01). To test whether Agrp neuron activation is required for cold-induced hyperphagia, we employed a chemogenetic strategy to silence Agrp neurons. As predicted, their silencing prevented hyperphagic feeding (2h food intake after housing at 14°C: 0.26±0.06 g vs. 0.10±0.04 g; p<0.05), but not the associated thermogenic response (0.63 vs. 0.62 kcal/hr; p=ns) during cold exposure. Interestingly, cold-induced hyperphagia is absent in mice with diet-induced obesity (DIO). Consequently, unlike chow-fed mice, these animals lose weight during cold exposure. These observations suggest that 1) Agrp neurons lie downstream of thermoregulatory neurocircuits, 2) during cold exposure, increased Agrp neuronal firing occurs rapidly as part of a homeostatic response that preserves body temperature and energy stores, and 3) this response appears to be impaired in mice with DIO. Future studies will map the neurocircuitry underlying these responses and clarify how DIO impairs their activation.


J.D. Deem: None. C.L. Faber: None. C. Pedersen: None. B.N. Phan: None. K. Ogimoto: None. S.A. Larsen: None. M.A. Tran: None. V. Damian: None. K. Kaiyala: None. J. Scarlett: None. M.R. Bruchas: None. M.W. Schwartz: Research Support; Self; Novo Nordisk A/S. G.J. Morton: Research Support; Self; Novo Nordisk A/S.


American Diabetes Association (1-19-PDF-103 to J.D.D.); Dick and Julia McAbee Foundation; National Institutes of Health (T32-HL007028-39, R01DK089056, R01DK101997, R01DK124238, R01DK089056, P30DK017047, P30DK035816)

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