neuropeptide y (npy) has long been known to play a major role in mediating energy balance. Intracerebral ventricular injection of NPY results in a vigorous feeding response and is perhaps the most orexigenic compound studied to date (3). NPY expression is robustly elevated within the hypothalamus of calorically restricted animals, as well as in most genetic models of rodent obesity (i.e., ob/ob mouse and the Zucker fa/fa rat), and it is thought that this elevation is responsible for the ravenous appetite of these animals (20). NPY is coexpressed in neurons with another important modulator of feeding, agouti-related protein (AgRP) (14). These neurons reside alongside the anorexigenic proopiomelanocortin (POMC) neurons within the arcuate nucleus of the hypothalamus, where NPY/AgRP neurons inhibit activity of POMC neurons, but not vice versa (4). Importantly, ablation of the NPY/AgRP neuron in the adult mouse results in a lack of food intake with subsequent death from starvation (13). NPY-containing neurons send projections to various regions throughout the brain known to be involved with hunger, metabolism, growth, and endocrine function (14). When released at the synapse, NPY interacts with one of six flavors of NPY receptors, named Y1-Y6. The NPY Y1 and Y5 receptors are the primary mediators for the feeding response to NPY or fasting (11). To date, most studies defining the orexigenic role of NPY have been performed in mouse and rat models. However, NPY's effects on food behavior can vary across species. For example, Siberian hamsters respond to both food deprivation and intracerebroventricular administration of NPY with only a moderate increase in food intake if food becomes available. Rather, the primary responses of these hamsters involve other behaviors associated with food, namely foraging and storage of food (1, 6). Hoarding and foraging appear to be mediated by the NPY Y1 receptor, whereas hunger is mediated through the NPY Y5 receptor in the Siberian hamster (7).
In addition to food consumption, the other component of energetic balance is caloric expenditure. Many organisms throughout the animal kingdom, including Siberian hamsters, can experience a well-orchestrated decline in metabolic rate and core body temperature (Tb) in response to, or in anticipation of, a lack of sufficient caloric intake (8). The energy savings gained during this hypometabolic state are substantial and vary with the depth and duration of the torpor bout. Torpor in Siberian hamsters is considered “daily,” as the depth of the bout is shallow (a fall in Tb of ∼17°C) and the duration is short (∼6 h) (10). In contrast, the core Tb of hibernating Arctic squirrels can be near 0°C for weeks at a time (8). Recent studies by John Dark's group at University of California, Berkeley, have demonstrated that intracerebroventricular administration of NPY or a Y1 receptor agonist can induce a significant bout of hypothermia (16, 17). In the current issue of American Journal of Physiology—Regulatory, Integrative and Comparative Physiology, Dark and Pelz have continued this line of work and have convincingly shown that the hypothermia in Siberian hamsters induced from intracerebroventricular administration of NPY is mediated through the NPY Y1 receptor (5). A straightforward experimental design was implemented to inject either NPY or vehicle alongside an NPY Y1 antagonist, NPY Y5 antagonist, or vehicle. Coadministration of the Y1 receptor antagonist with NPY prevented the bout of hypothermia in all but one animal tested. However, coadministration of the Y5 receptor antagonist with NPY had no impact on the number of hamsters that experienced hypothermia, although the duration and depth of hypothermia were slightly less in hamsters that received NPY alone. These data clearly identify the NPY Y1 receptor as both necessary (5) and sufficient (17) for NPY-induced hypothermia. It should be noted, however, that ambient temperature is likely a critical determinant as to whether these hamsters experience hypothermia with intracerebroventricular delivery of NPY. The hamsters tested in the current study (5) were housed at 10°C and entered hypothermia when administered NPY, whereas hamsters housed at 21°C injected with NPY only alter foraging and hoarding behavior (7, 12). Importantly, experiments in mice, which also can undergo shallow daily bouts of torpor when calorically restricted in a cool environment, also suggest a role for NPY in torpor bouts. Mice deficient in neuropeptide Y (Npy−/−), which have a remarkably normal feeding phenotype (15), are unable to sustain torpor bouts when fasted (9).
The “elephant in the room” is whether injection of NPY truly evokes a torpor response or merely causes a brief bout of hypothermia in hamsters. Dark and Pelz (5) describe the hypothermia induced by NPY as “torporlike” hypothermia, and appropriately so. Given the relatively high surface area to volume ratio of the hamster, the core Tb of this animal is particularly susceptible to any metabolic inhibition, be it from either a metabolic poison or activating an as-of-yet unidentified pathway(s) for induction of torpor. From a functional point of view, both a natural torpor bout and intracerebroventricular administration of NPY into hamsters evoke a hypothermic state, although the depth of a natural bout of torpor in the Siberian hamster, at 20°C (10), is 7–8°C cooler than that of NPY-induced hypothermia (5, 16). Rats that do not enter torpor bouts as adults respond to NPY delivery with a fall in core Tb of only 1–3°C (19), offering some correlation between depth of NPY-induced hypothermia and the ability to enter a “natural” torpid state. Dark and Pelz suggest that body position is similar in hamsters that receive NPY with those in a natural torpor state (5). It would be instructive to know whether administration of an NPY Y1 receptor antagonist prevents or blunts a naturally occurring bout of torpor. Short of this evidence, additional physiological parameters obtained can help differentiate between true torpor and an unregulated hypothermia bout. For example, hamsters enter a daily torpor bout typically at the beginning of the light cycle (10). Does NPY-induced hypothermia vary with the circadian clock of the hamster? In addition, animals entering torpor substantially lower metabolic rate and alter the fuel source utilized during torpor to the oxidation of primarily fats, as assessed by respiratory quotient values (8). Does intracerebroventricular delivery of NPY mimic the metabolic changes that occur during a natural torpor bout? Further, does NPY evoke similar cardiovascular and respiratory changes that occur during a natural torpor bout, (e.g., 18)? Other perturbations that substantially lower the core Tb of a small animal like a hamster or mouse, e.g., breathing H2S (2), should similarly be scrutinized to determine whether the fall in metabolic rate and core Tb are simply a function of nonspecific metabolic inhibition or the activation of torpor-inducing pathways.
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