In homeothermic species, maintenance of euthermia in the face of a wide range of ambient temperatures is critical for survival. In small homeotherms, countering cold stress requires not only that adaptive adjustments of heat production occur rapidly and potently, but also that they are achieved without depleting body fuel stored in the form of fat (Gordon, 1993). Thus, when animals are housed in a cool environment, energy expenditure swiftly increases to generate the heat needed to maintain core body temperature (Cannon and Nedergaard, 2011) and, so long as a food is readily available, a compensatory hyperphagia prevents changes to body fat mass (Kaiyala et al., 2012). While much is known regarding the neurocircuitry underlying cold-induced thermogenesis (Madden and Morrison, 2019; Nakamura and Morrison, 2011; Tan and Knight, 2018), the origins of cold-induced hyperphagia remain poorly understood.
One potential explanation for cold-induced hyperphagia is that it is mounted as a secondary response to the negative energy balance state that results from cold-induced thermogenesis, analogous to what occurs in other states of negative energy balance. During caloric restriction, for example, the imposed negative energy balance and the associated reduction of body fat stores drives adaptive homeostatic responses aimed at returning body fat stores to pre-intervention values. Reduced energy expenditure and increased hunger drive are major components of this adaptive response, and both are thought to be primarily driven by humoral signals indicative of energy deficiency (e.g., reductions of leptin and insulin) (Schwartz et al., 2000). It has, therefore, been reasonably assumed that the hyperphagic response to cold requires the same signals of energy deficiency, and this hypothesis is supported by studies that have been conducted over time periods sufficient to induce hormonal changes (Bing et al., 1998; Hardie et al., 1996; Puerta et al., 2002).
Among central targets of these humoral feedback signals are neurons located in the hypothalamic arcuate nucleus (ARC) that express agouti-related peptide (AgRP) (Hahn et al., 1998) which, when activated, potently stimulate feeding (Aponte et al., 2011; Atasoy et al., 2012; Krashes et al., 2011). However, recent evidence suggests that, although AgRP neurons are regulated by humoral signals (Hahn et al., 1998; Schwartz et al., 2000), they may also be under feed-forward control (Chen and Knight, 2016; Lowell, 2019) such that they can be activated by neurocircuits that integrate sensory cues from the environment (Betley et al., 2015; Chen et al., 2015; Mandelblat-Cerf et al., 2015; Zimmer et al., 2019) and thereby avert a negative energy state. Based on these observations, we hypothesized a role for AgRP neuron activation in the adaptive increase in food intake induced by cold exposure, and that this effect is not secondary to the associated increase in energy expenditure or a state of negative energy balance.
