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      Voluntary exercise is motivated by ghrelin, possibly related to the central reward circuit

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          Abstract

          We previously reported that voluntary exercise contributed to the amelioration of abnormal feeding behavior with a concomitant restoration of ghrelin production in a rat model of obesity, suggesting a possible relationship between exercise and appetite-regulating hormones. Ghrelin is known to be involved in the brain reward circuits via dopamine neurons related to motivational properties. We investigated the relevance of ghrelin as an initiator of voluntary exercise as well as feeding behavior. The plasma ghrelin concentration fluctuates throughout the day with its peak at the beginning of the dark period in the wild-type (WT) mice with voluntary exercise. Although predominant increases in wheel running activity were observed accordant to the peak of plasma ghrelin concentration in the WT mice, those were severely attenuated in the ghrelin-knockout (GKO) mice under either ad libitum or time-restricted feeding. A single injection of ghrelin receptor agonist brought about and reproduced a marked enhancement of wheel running activity, in contrast to no effect by the continuous administration of the same drug. Brain dopamine levels (DAs) were enhanced after food consumption in the WT mice under voluntary exercise. Although the acceleration of DAs were apparently blunted in the GKO mice, they were dramatically revived after the administration of ghrelin receptor agonist, suggesting the relevance of ghrelin in the reward circuit under voluntary exercise. These findings emphasize that the surge of ghrelin plays a crucial role in the formation of motivation for the initiation of voluntary exercise possibly related to the central dopamine system.

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          Most cited references30

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          Ghrelin octanoylation mediated by an orphan lipid transferase.

          The peptide hormone ghrelin is the only known protein modified with an O-linked octanoyl side group, which occurs on its third serine residue. This modification is crucial for ghrelin's physiological effects including regulation of feeding, adiposity, and insulin secretion. Despite the crucial role for octanoylation in the physiology of ghrelin, the lipid transferase that mediates this novel modification has remained unknown. Here we report the identification and characterization of human GOAT, the ghrelin O-acyl transferase. GOAT is a conserved orphan membrane-bound O-acyl transferase (MBOAT) that specifically octanoylates serine-3 of the ghrelin peptide. Transcripts for both GOAT and ghrelin occur predominantly in stomach and pancreas. GOAT is conserved across vertebrates, and genetic disruption of the GOAT gene in mice leads to complete absence of acylated ghrelin in circulation. The occurrence of ghrelin and GOAT in stomach and pancreas tissues demonstrates the relevance of GOAT in the acylation of ghrelin and further implicates acylated ghrelin in pancreatic function.
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            Ghrelin and des-acyl ghrelin: two major forms of rat ghrelin peptide in gastrointestinal tissue.

            Ghrelin, a novel peptide purified from stomach, is the endogenous ligand for the growth hormone secretagogue receptor and has potent growth hormone-releasing activity. The Ser3 residue of ghrelin is modified by n-octanoic acid, a modification necessary for hormonal activity. We established two ghrelin-specific radioimmunoassays; one recognizes the octanoyl-modified portion and another the C-terminal portion of ghrelin. Using these radioimmunoassay systems, we found that two major molecular forms exist-ghrelin and des-n-octanoyl ghrelin. While ghrelin activates growth-hormone secretagogue (GHS) receptor-expressing cells, the nonmodified des-n-octanyl form of ghrelin, designated as des-acyl ghrelin, does not. In addition to these findings, our radioimmunoassay systems also revealed high concentrations of ghrelin in the stomach and small intestine.
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              Ghrelin administration into tegmental areas stimulates locomotor activity and increases extracellular concentration of dopamine in the nucleus accumbens.

              Ghrelin stimulates appetite, increases food intake and causes adiposity by mechanisms that include direct actions on the brain. Previously, we showed that intracerebroventricular administration of ghrelin has stimulatory and dopamine-enhancing properties. These effects of ghrelin are mediated via central nicotine receptors, suggesting that ghrelin can activate the acetylcholine-dopamine reward link. This reward link consists of cholinergic input from the laterodorsal tegmental area (LDTg) to the mesolimbic dopamine system that originates in the ventral tegmental area (VTA) and projects to the nucleus accumbens. Given that growth hormone secretagogue receptors (GHSR-1A) are expressed in the VTA and LDTg, brain areas involved in reward, the present series of experiments were undertaken to examine the hypothesis that these regions may mediate the stimulatory and dopamine-enhancing effects of ghrelin, by means of locomotor activity and in vivo microdialysis in freely moving mice. We found that local administration of ghrelin into the VTA (1 microg in 1 microl) induced an increase in locomotor activity and in the extracellular concentration of accumbal dopamine. In addition, local administration of ghrelin into the LDTg (1 microg in 1 microl) caused a locomotor stimulation and an increase in the extracellular levels of accumbal dopamine. Taken together, this indicates that ghrelin might, via activation of GHSR-1A in the VTA and LDTg, stimulate the acetylcholine-dopamine reward link, implicating that ghrelin is a part of the neurochemical overlap between the reward systems and those that regulate energy balance.

                Author and article information

                Journal
                J Endocrinol
                J. Endocrinol
                JOE
                The Journal of Endocrinology
                Bioscientifica Ltd (Bristol )
                0022-0795
                1479-6805
                January 2020
                08 October 2019
                : 244
                : 1
                : 123-132
                Affiliations
                [1 ]Institute of Animal Experimentation , Kurume University School of Medicine, Kurume, Japan
                [2 ]Division of Endocrinology and Metabolism , Kurume University School of Medicine, Kurume, Japan
                [3 ]Department of Pharmacology , Kurume University School of Medicine, Kurume, Japan
                [4 ]Molecular Genetics , Life Science Institute, Kurume University, Kurume, Japan
                [5 ]Department of Physiology , Kurume University School of Medicine, Kurume, Japan
                [6 ]Department of Exercise Physiology , Institute of Health and Sports Science, Kurume University, Kurume, Japan
                [7 ]Bostatistics Center , Kurume University, Kurume, Japan
                Author notes
                Correspondence should be addressed to Y Tajiri: tajiriy@ 123456med.kurume-u.ac.jp
                Article
                JOE-19-0213
                10.1530/JOE-19-0213
                6859445
                31629323
                163234d4-8afe-4c09-a2b8-cd363f77e7c9
                © 2020 The authors

                This work is licensed under a Creative Commons Attribution 4.0 International License.

                History
                : 03 October 2019
                : 08 October 2019
                Categories
                Research

                Endocrinology & Diabetes
                exercise,ghrelin,motivation,reward circuit,dopamine
                Endocrinology & Diabetes
                exercise, ghrelin, motivation, reward circuit, dopamine

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