Peripheral ghrelin deepens torpor bouts in mice through the arcuate nucleus neuropeptide Y signaling pathway

Abstract

Many small mammals have the ability to enter torpor, characterized by a controlled drop in body temperature (T_b). We hypothesized that ghrelin would modulate torpor bouts, because torpor is induced by fasting in mice coincident with elevated circulating ghrelin. Female National Institutes of Health (NIH) Swiss mice were implanted with a T_b telemeter and housed at an ambient temperature (T_a) of 18°C. On fasting, all mice entered a bout of torpor (minimum T_b: 23.8 ± 2.0°C). Peripheral ghrelin administration (100 μg) during fasting significantly deepened the bout of torpor (T_b minimum: 19.4 ± 0.5°C). When the arcuate nucleus (ARC) of the hypothalamus, a ghrelin receptor-rich region of the brain, was chemically ablated with monosodium glutamate (MSG), fasted mice failed to enter torpor (minimum T_b = 31.6 ± 0.6°C). Furthermore, ghrelin administration had no effect on the T_b minimum of ARC-ablated mice (31.8 ± 0.8°C). Two major pathways that regulate food intake reside in the ARC, the anorexigenic α-melanocyte stimulating hormone (α-MSH) pathway and the orexigenic neuropeptide Y (NPY) signaling pathway. Both A_y mice, which have the α-MSH pathway blocked, and Npy −/− mice exhibited shallow, aborted torpor bouts in response to fasting (T_b minimum: 29.1 ± 0.6°C and 29.9 ± 1.2°C, respectively). Ghrelin deepened torpor in A_y mice (T_b minimum: 22.8 ± 1.3°C), but had no effect in Npy −/− mice (T_b minimum: 29.5 ± 0.8°C). Collectively, these data suggest that ghrelin's actions on torpor are mediated via NPY neurons within the ARC.