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The gut–brain axis maintains energy homeostasis through signaling of the membrane receptors for ghrelin, leptin, α-melanocyte-stimulating hormone (α-MSH), and cannabinoids. Signaling that emanates from these receptors in the stomach and the hypothalamus results in interregulation of the actions of these receptors and maintenance of physiological body weight, with imbalances leading to positive metabolism or obesity. The appetite-regulating ghrelin promotes food intake and fat storage, leptin inhibits appetite through its actions on α-MSH to reduce body weight, while signaling through the cannabinoid 1 receptor (CB1R) controls ghrelin secretion by the stomach and mediates the actions of both ghrelin and leptin in the hypothalamus. In rat obesity models, sleeve gastrectomy, a bariatric surgery performed in humans to manage obesity, imposes transcriptional reprogramming in the acyl–ghrelin–CB1R axis to lower body weight in the long term. Thus, peripheral intervention into this axis should be considered as a therapeutic target for human obesity.

Several studies have shown that ghrelin administration promotes wakefulness in rodents, while in human males it induces sleep but has no effect in women. Ghrelin also plays an important role in metabolism and appetite regulation, and as described in this review may participate in the energy balance during sleep. In this review, we summarize some of the effects induced by ghrelin administration on the sleep–wake cycle in relation to the effects of other hormones, such as growth hormone, leptin, and orexin. Finally we discuss the relationship between sleep deprivation, obesity and ghrelin secretion pattern. Fil: García García, Fabio. Universidad Veracruzana; México Fil: Juárez Aguilar, Enrique. Universidad Veracruzana; México Fil: Santiago García, Juan. Universidad Veracruzana; México Fil: Cardinali, Daniel Pedro. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Facultad de Ciencias Médicas. Departamento de Docencia e Investigación; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

Ghrelin is produced primarily in the stomach in response to hunger, and circulates in the blood. Plasma ghrelin levels increase during fasting and decrease after ingesting glucose and lipid, but not protein. The efferent vagus nerve contributes to the fasting-induced increase in ghrelin secretion. Ghrelin secreted by the stomach stimulates the afferent vagus nerve and promotes food intake. Ghrelin also stimulates pituitary gland secretion of growth hormone (GH) via the afferent vagus nerve. GH inhibits stomach ghrelin secretion. These findings indicate that the vagal circuit between the central nervous system and stomach has a crucial role in regulating plasma ghrelin levels. Moreover, body mass index modulates plasma ghrelin levels. In a lean state and anorexia nervosa, plasma ghrelin levels are increased, whereas in obesity, except in Prader-Willi syndrome, plasma ghrelin levels are decreased and the feeding- and sleeping-induced decline in plasma ghrelin levels is disrupted. There are two forms of ghrelin: active n-octanoyl-modified ghrelin and des-acyl ghrelin. Fasting increases both ghrelin types compared with the fed state. Hyperphagia and obesity are likely to decrease plasma des-acyl ghrelin, but not n-octanoyl-modified ghrelin levels. Hypothalamic serum and glucocorticoid-inducible kinase-1 and serotonin 5-HT2C/1B receptor gene expression levels are likely to be proportional to plasma des-acyl ghrelin levels during fasting, whereas they are likely to be inversely proportional to plasma des-acyl ghrelin levels in an increased energy storage state such as obesity. Thus, a dysfunction of the ghrelin feedback systems might contribute to the pathophysiology of obesity and eating disorders.

Ghrelin and its receptors are found in the reproductive organs and in the placenta, clearly indicating a role for ghrelin in reproduction. Circulating ghrelin levels peak at mid-gestation, then with advancing gestational age declining ghrelin levels are observed. At the same time the maternal organism increases its fat mass, becomes insulin resistant and the growth hormone (GH) axis is dominated by placental growth hormone circulating in concentrations comparable to GH levels observed in acromegaly. After delivery, normalization of ghrelin levels occurs before the maternal fat mass is restored at prepregnant levels. The physiological course of ghrelin during the three trimesters of human pregnancy is discussed, as are the physiological roles ghrelin may subserve. Regulation of maternal energy intake may be the prevailing effect of ghrelin in pregnancy and lactation, but several other effects of ghrelin may coexist, including local effects. Finally, ghrelin secretion in the fetus is briefly discussed.