The preproghrelin gene is required for the normal integration of thermoregulation and sleep in mice

Abstract

Peptidergic mechanisms controlling feeding, metabolism, thermoregulation, and sleep overlap in the hypothalamus. Low ambient temperatures and food restriction induce hypothermic (torpor) bouts and characteristic metabolic and sleep changes in mice. We report that mice lacking the preproghrelin gene, but not those lacking the ghrelin receptor, have impaired abilities to manifest and integrate normal sleep and thermoregulatory responses to metabolic challenges. In response to fasting at 17°C (a subthermoneutral ambient temperature), preproghrelin knockout mice enter hypothermic bouts associated with reduced sleep, culminating in a marked drop in body temperature to near-ambient levels. Prior treatment with obestatin, another preproghrelin gene product, attenuates the hypothermic response of preproghrelin knockout mice. Results suggest that obestatin is a component in the coordinated regulation of metabolism and sleep during torpor.EEG ͉ ghrelin ͉ metabolism ͉ obestatin ͉ torpor N atural shortages of food and low environmental temperature are commonly encountered in the wild. Small rodents tolerate these conditions by exhibiting torpor, a regulated drop in body temperature associated with behavioral hyporesponsiveness. Hormones and neuropeptides, including ghrelin and obestatin, play an integral role in the regulation of metabolism and energy balance (1, 2). Ghrelin promotes positive energy balance by stimulating feeding and suppressing energy expenditure (3). The role of obestatin, a distinct product of the preproghrelin gene, in the regulation of feeding and metabolism is less clear. Several (2, 4-6) but not all (7, 8) studies suggest that obestatin suppresses appetite and enhances energy expenditure.Ghrelin and obestatin may also regulate sleep. Sleep deprivation induces increases in hypothalamic and plasma ghrelin levels (9). In rats, administration of ghrelin facilitates wakefulness (10, 11), whereas injection of obestatin facilitates sleep (12). Wakefulness and feeding may be parallel outputs of a hypothalamic circuitry that involves neuropeptide Y-, orexin-, and ghrelinergic neurons (10, 11, 13). Sleep-wake activity (14) and metabolism (15) of preproghrelin knockout (KO) mice (originally named ghrelin Ϫ/Ϫ mice) are, however, relatively normal if the animals are kept at thermoneutral ambient temperature (30°C Ϯ 1°C) with food provided ad libitum. Under nonstressed conditions, redundant regulatory systems likely compensate for the lack of the preproghrelin gene product(s). We hypothesized that in a negative metabolic state, such as torpor, preproghrelin gene products might be involved in the coordinated regulation of energy sources and vigilance.In the present experiments we studied sleep and thermoregulatory responses to 3 days of cold exposure (17°C) and to the combined challenge of cold environmental temperature and fasting in preproghrelin KO and ghrelin receptor KO mice. We report that the ability to mount normal body temperature and sleep response to a metabolic challenge is greatly impaired in preproghr...

Ghrelin gene products, receptors, and GOAT enzyme: biological and pathophysiological insight

“…However, these data are in contrast with other studies showing that, under extreme thermic conditions, both GHSR-KO (Szentirmai et al 2009) and GOAT-KO mice (Heppner et al 2013) can control core body temperature, and with those showing that AG administration does not alter body temperature in mice, rats, and humans (Wiedmer et al 2011). In this scenario, the actions of alternative ghrelin gene-derived peptides could shed some light on this controversy, in that, for example, obestatin has been shown to attenuate the hypothermic response of ghrelin gene KO mice (Szentirmai et al 2009), thereby suggesting a complex regulation of body temperature by the ghrelin system. Gastric motility and acid secretion AG is a potent accelerator of gastric emptying and a stimulator of GI motility in humans (Tack et al 2006), rats (Trudel et al 2002, and mice (Masuda et al 2000, Fujino et al 2003, Ariga et al 2007, Zheng et al 2009); while this effect was not observed in dogs (Ohno et al 2010).…”

“…This idea is supported by the fact that ghrelin gene KO mice cannot control body temperature under extreme thermic conditions (Szentirmai et al 2009), and because areas of the hypothalamus located in the vicinity of cold-sensitive neurons exhibit ghrelin-binding sites (Wiedmer et al 2011). However, these data are in contrast with other studies showing that, under extreme thermic conditions, both GHSR-KO (Szentirmai et al 2009) and GOAT-KO mice (Heppner et al 2013) can control core body temperature, and with those showing that AG administration does not alter body temperature in mice, rats, and humans (Wiedmer et al 2011). In this scenario, the actions of alternative ghrelin gene-derived peptides could shed some light on this controversy, in that, for example, obestatin has been shown to attenuate the hypothermic response of ghrelin gene KO mice (Szentirmai et al 2009), thereby suggesting a complex regulation of body temperature by the ghrelin system.…”

“…Initial studies suggested a biphasic action of AG on thermogenesis, in that low doses of AG could reduce body temperature (Lawrence et al 2002), while high doses could increase it (Jaszberenyi et al 2006), probably through a hypothalamic action (Tokizawa et al 2012). This idea is supported by the fact that ghrelin gene KO mice cannot control body temperature under extreme thermic conditions (Szentirmai et al 2009), and because areas of the hypothalamus located in the vicinity of cold-sensitive neurons exhibit ghrelin-binding sites (Wiedmer et al 2011). However, these data are in contrast with other studies showing that, under extreme thermic conditions, both GHSR-KO (Szentirmai et al 2009) and GOAT-KO mice (Heppner et al 2013) can control core body temperature, and with those showing that AG administration does not alter body temperature in mice, rats, and humans (Wiedmer et al 2011).…”

Ghrelin in mental health, sleep, memory

“…Prior to treatment with obestatin, which is like a preproghrelin gene product, attenuated this hypothermic response of the preproghrelin knockout mice (Szentirmai et al, 2009) Previous studies suggest the occurrence of peaks of ghrelin around sleep onset (Cummings et al, 2001;Dzaja et al, 2004). This issue was not supported in a study with a more frequent sampling of blood specimens .…”

Ghrelin Regulation in Epilepsy

“…In according to a sleep-promoting effect of ghrelin, knockout mice for ghrelin had impaired physiologic sleep regulation and thermoregulatory responses too. Thus, in response to fasting at 17 °C, these knockout mice presented hypothermic bousts associated with a reduced sleep (Szentirmai et al, 2009). Furthermore, also previous studies in humans suggested a sleep-promoting effect of ghrelin, with the evidence of its peaks around the sleep onset (Dzaja et al, 2004).…”