The adaptive response to cold exposure includes matched increases of both energy expenditure (to support thermogenesis) and energy intake, enabling core temperature to be maintained with no change of body fat stores. To investigate whether activation of agouti-related peptide (AgRP) neurons plays a role in this cold-induced hyperphagic response, we first determined whether this neuronal population is activated during cold exposure by employing AgRP-Cre/GFP marker mice and found that acute cold exposure rapidly induces cFos (a marker of neuronal activation) in these neurons. Further, relative to chow-fed controls housed at room temperature, mice subjected to chronic, mild cold exposure (14°C for 5 days) exhibited both the expected increase of food intake (28%) and a 117% increase of Agrp mRNA (p<0.01 for both). Having established that AgRP neurons are activated by cold exposure, we next sought to determine whether this response is required for the associated hyperphagia. To this end, we used a DREADD-based pharmacogenetic approach using AgRP-IRES-Cre mice. Here, we found that cold-induced hyperphagia was blocked by inhibition of AgRP neurons (2h food intake upon acute housing at 14C: 0.26±0.06 g for Sal. vs. 0.10±0.04 g for CNO; p<0.05). We next focused on the fidelity of this system in mice exposed to a high fat diet (HFD). We found that although HFD-fed mice exhibit intact thermogenic responses to cold and maintain normal core body temperature, they fail to increase energy intake (12.43±0.48 for 22C vs. 13.49±1.54 kcal for 14C; p=ns) and consequently experience weight loss not observed in lean, chow-fed controls (body weight change: 0.16±0.15g for chow vs. -0.49±0.23g for HFD; p=0.05). Since the absence of cold-induced hyperphagia in HFD-fed mice is accompanied by failure to increase hypothalamic Agrp mRNA (22C vs. 14C; 0.19±0.07 vs. 0.24±0.09; p=ns), these data demonstrate that 1) AgRP neuron activation is required for cold-induced hyperphagia, and 2) this response is impaired in HFD-fed mice.


J.D. Deem: None. K. Ogimoto: None. J. Nelson: None. B.N. Phan: None. K.R. Velasco: None. V. Damian: None. M.W. Schwartz: Consultant; Self; Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S. G.J. Morton: None.


University of Washington Diabetes Research Center

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