Ghrelin Treatment Induces Rapid and Delayed Increments of Food Intake: A Heuristic Model to Explain Ghrelin’s Orexigenic Effects

Abstract Ghrelin is a stomach-derived peptide hormone with salient roles in the regulation of energy balance and metabolism. Notably, ghrelin is recognized as the most powerful known circulating orexigenic hormone. Here, we systematically investigated the effects of ghrelin on energy homeostasis and found that ghrelin primarily induces a biphasic effect on food intake that has indirect consequences on energy expenditure and nutrient partitioning. We also found that ghrelin-induced biphasic effect on food intake requires the integrity of Agouti-related peptide/neuropeptide Y-producing neurons of the hypothalamic arcuate nucleus (ARH), which seem to display a long-lasting activation after a single systemic injection of ghrelin. Finally, we found that different autonomic, hormonal and metabolic satiation signals transiently counteract ghrelin-induced food intake. Based on our observations, we propose a heuristic model to describe how the orexigenic effect of ghrelin and the anorectic food intake-induced rebound sculpt a timely constrain feeding response to ghrelin.

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Astaxanthin Exerts Anabolic Effects via Pleiotropic Modulation of the Excitable Tissue

International Journal of Molecular Sciences ◽

10.3390/ijms23020917 ◽

2022 ◽

Vol 23 (2) ◽

pp. 917

Author(s):

Mónika Gönczi ◽

Andrea Csemer ◽

László Szabó ◽

Mónika Sztretye ◽

János Fodor ◽

...

Keyword(s):

Skeletal Muscle ◽

Food Intake ◽

Energy Homeostasis ◽

Arcuate Nucleus ◽

Fatty Acid Biosynthesis ◽

Synaptic Activity ◽

Systematic Analysis ◽

Protein Levels ◽

General Metabolism ◽

Hypothalamic Arcuate Nucleus

Astaxanthin is a lipid-soluble carotenoid influencing lipid metabolism, body weight, and insulin sensitivity. We provide a systematic analysis of acute and chronic effects of astaxanthin on different organs. Changes by chronic astaxanthin feeding were analyzed on general metabolism, expression of regulatory proteins in the skeletal muscle, as well as changes of excitation and synaptic activity in the hypothalamic arcuate nucleus of mice. Acute responses were also tested on canine cardiac muscle and different neuronal populations of the hypothalamic arcuate nucleus in mice. Dietary astaxanthin significantly increased food intake. It also increased protein levels affecting glucose metabolism and fatty acid biosynthesis in skeletal muscle. Inhibitory inputs innervating neurons of the arcuate nucleus regulating metabolism and food intake were strengthened by both acute and chronic astaxanthin treatment. Astaxanthin moderately shortened cardiac action potentials, depressed their plateau potential, and reduced the maximal rate of depolarization. Based on its complex actions on metabolism and food intake, our data support the previous findings that astaxanthin is suitable for supplementing the diet of patients with disturbances in energy homeostasis.

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Appetite Regulation: Hormones, Peptides, and Neurotransmitters and Their Role in Obesity

American Journal of Lifestyle Medicine ◽

10.1177/1559827617716376 ◽

2017 ◽

Vol 13 (6) ◽

pp. 586-601 ◽

Cited By ~ 6

Author(s):

Gary D. Miller

Keyword(s):

Food Intake ◽

Energy Homeostasis ◽

Arcuate Nucleus ◽

Feeding Behaviors ◽

New Agents ◽

Brainstem Nucleus ◽

Hypothalamic Arcuate Nucleus ◽

Efferent Pathways ◽

The Brain ◽

New Strategies

Understanding body weight regulation will aid in the development of new strategies to combat obesity. This review examines energy homeostasis and food intake behaviors, specifically with regards to hormones, peptides, and neurotransmitters in the periphery and central nervous system, and their potential role in obesity. Dysfunction in feeding signals by the brain is a factor in obesity. The hypothalamic (arcuate nucleus) and brainstem (nucleus tractus solitaris) areas integrate behavioral, endocrine, and autonomic responses via afferent and efferent pathways from and to the brainstem and peripheral organs. Neurons present in the arcuate nucleus express pro-opiomelanocortin, Neuropeptide Y, and Agouti Related Peptide, with the former involved in lowering food intake, and the latter two acutely increasing feeding behaviors. Action of peripheral hormones from the gut, pancreas, adipose, and liver are also involved in energy homeostasis. Vagal afferent neurons are also important in regulating energy homeostasis. Peripheral signals respond to the level of stored and currently available fuel. By studying their actions, new agents maybe developed that disable orexigenic responses and enhance anorexigenic signals. Although there are relatively few medications currently available for obesity treatment, a number of agents are in development that work through these pathways.

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Lateral ventricular ghrelin and fourth ventricular ghrelin induce similar increases in food intake and patterns of hypothalamic gene expression

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00785.2005 ◽

2006 ◽

Vol 290 (6) ◽

pp. R1565-R1569 ◽

Cited By ~ 17

Author(s):

Kimberly P. Kinzig ◽

Karen A. Scott ◽

Jayson Hyun ◽

Sheng Bi ◽

Timothy H. Moran

Keyword(s):

Gene Expression ◽

Food Intake ◽

Fourth Ventricle ◽

Time Course ◽

Arcuate Nucleus ◽

Central Administration ◽

Stimulatory Action ◽

Hypothalamic Arcuate Nucleus ◽

Ghrelin Receptors ◽

The Brain

The gut peptide ghrelin has been shown to stimulate food intake after both peripheral and central administration, and the hypothalamic arcuate nucleus has been proposed to be the major site for mediating this feeding stimulatory action. Ghrelin receptors are widely distributed in the brain, and hindbrain ghrelin administration has been shown to potently stimulate feeding, suggesting that there may be other sites for ghrelin action. In the present study, we have further assessed potential sites for ghrelin action by comparing the ability of lateral and fourth ventricular ghrelin administration to stimulate food intake and alter patterns of hypothalamic gene expression. Ghrelin (0.32, 1, or 3.2 nmol) in the lateral or fourth ventricle significantly increased food intake in the first 4 h after injection, with no ventricle-dependent differences in degree or time course of hyperphagia. One nanomole of ghrelin into either the lateral or fourth ventricle resulted in similar increases in arcuate nucleus neuropeptide Y mRNA expression. Expression levels of agouti-related peptide or proopiomelanocortin mRNA were not affected by ghrelin administration. These data demonstrate that ghrelin can affect food intake and hypothalamic gene expression through interactions at multiple brain sites.

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Changes in mRNA expression of arcuate nucleus appetite-regulating peptides during lactation in rats

Journal of Molecular Endocrinology ◽

10.1530/jme-13-0015 ◽

2013 ◽

Vol 52 (2) ◽

pp. 97-109 ◽

Cited By ~ 10

Author(s):

Yoshihiro Suzuki ◽

Keiko Nakahara ◽

Keisuke Maruyama ◽

Rieko Okame ◽

Takuya Ensho ◽

...

Keyword(s):

Food Intake ◽

Mrna Expression ◽

Arcuate Nucleus ◽

Peptide Yy ◽

Weaning Food ◽

Hypothalamic Arcuate Nucleus ◽

Pregnancy And Lactation ◽

Acyl Ghrelin ◽

Plasma Leptin ◽

Agouti Related Protein

The contribution of hypothalamic appetite-regulating peptides to further hyperphagia accompanying the course of lactation in rats was investigated by using PCR array and real-time PCR. Furthermore, changes in the mRNA expression for appetite-regulating peptides in the hypothalamic arcuate nucleus (ARC) were analyzed at all stages of pregnancy and lactation, and also after weaning. Food intake was significantly higher during pregnancy, lactation, and after weaning than during non-lactation periods. During lactation, ARC expression of mRNAs for agouti-related protein (AgRP) and peptide YY was increased, whereas that of mRNAs for proopiomelanocortin (POMC) and cholecystokinin (CCK) was decreased, in comparison with non-lactation periods. The increase in AgRP mRNA expression during lactation was especially marked. The plasma level of leptin was significantly decreased during the course of lactation, whereas that of acyl-ghrelin was unchanged. In addition, food intake was negatively correlated with the plasma leptin level during lactation. This study has clarified synchronous changes in the expression of many appetite-regulating peptides in ARC of rats during lactation. Our results suggest that hyperphagia during lactation in rats is caused by decreases in POMC and CCK expression and increases in AgRP expression in ARC, the latter being most notable. Together with the decrease in the blood leptin level, such changes in mRNA expression may explain the further hyperphagia accompanying the course of lactation.

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Obesity, food intake and exercise: Relationship with ghrelin

Biomedical Human Kinetics ◽

10.1515/bhk-2015-0018 ◽

2015 ◽

Vol 7 (1) ◽

Cited By ~ 2

Author(s):

Gul Tiryaki-Sonmez ◽

Serife Vatansever ◽

Burcin Olcucu ◽

Brad Schoenfeld

Keyword(s):

Food Intake ◽

Energy Homeostasis ◽

Adult Population ◽

Peptide Hormone ◽

Adverse Health Outcomes ◽

General Adult Population ◽

Orexigenic Peptide ◽

Term Energy ◽

Short And Long Term

SummaryObesity, a disorder of body composition, is defined by a relative or absolute excess of body fat. In general adult population, obesity has been associated with a diverse array of adverse health outcomes, including major causes of death such as cancer, diabetes, cardiovascular disease, as well as functional impairment from problems such as osteoarthritis and sleep apnea. Ghrelin is a newly discovered peptide hormone which plays an important role in obesity. It is a powerful, endogenous orexigenic peptide and has a crucial function in appetite regulation, as well as short – and long-term energy homeostasis. In the presence of increased obesity, decreased physical activity, and high food consumption, the relationship between exercise, appetite, food intake and ghrelin levels has important implications. In this review, we discuss the effect of acute and chronic exercise performance on appetite, food intake and ghrelin and their relationships.

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Hypothalamic arcuate nucleus tyrosine hydroxylase neurons play orexigenic role in energy homeostasis

Nature Neuroscience ◽

10.1038/nn.4372 ◽

2016 ◽

Vol 19 (10) ◽

pp. 1341-1347 ◽

Cited By ~ 74

Author(s):

Xiaobing Zhang ◽

Anthony N van den Pol

Keyword(s):

Tyrosine Hydroxylase ◽

Energy Homeostasis ◽

Arcuate Nucleus ◽

Hypothalamic Arcuate Nucleus

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Involvement of the Acyl-CoA binding domain containing 7 in the control of food intake and energy expenditure in mice

eLife ◽

10.7554/elife.11742 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 12

Author(s):

Damien Lanfray ◽

Alexandre Caron ◽

Marie-Claude Roy ◽

Mathieu Laplante ◽

Fabrice Morin ◽

...

Keyword(s):

Food Intake ◽

Energy Expenditure ◽

Arcuate Nucleus ◽

Binding Domain ◽

Nucleotide Polymorphism ◽

Melanocortin System ◽

Single Nucleotide ◽

Hypothalamic Arcuate Nucleus ◽

Paralog Gene ◽

G Protein Coupled

Acyl-CoA binding domain-containing 7 (Acbd7) is a paralog gene of the diazepam-binding inhibitor/Acyl-CoA binding protein in which single nucleotide polymorphism has recently been associated with obesity in humans. In this report, we provide converging evidence indicating that a splice variant isoform of the Acbd7 mRNA is expressed and translated by some POMC and GABAergic-neurons in the hypothalamic arcuate nucleus (ARC). We have demonstrated that the ARC ACBD7 isoform was produced and processed into a bioactive peptide referred to as nonadecaneuropeptide (NDN) in response to catabolic signals. We have characterized NDN as a potent anorexigenic signal acting through an uncharacterized endozepine G protein-coupled receptor and subsequently via the melanocortin system. Our results suggest that ACBD7-producing neurons participate in the hypothalamic leptin signalling pathway. Taken together, these data suggest that ACBD7-producing neurons are involved in the hypothalamic control exerted on food intake and energy expenditure by the leptin-melanocortin pathway.

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The gut hormone Allatostatin C regulates food intake and metabolic homeostasis under nutrient stress

10.1101/2020.12.05.412874 ◽

2020 ◽

Author(s):

Olga Kubrak ◽

Line Jensen ◽

Nadja Ahrentløv ◽

Takashi Koyama ◽

Alina Malita ◽

...

Keyword(s):

Food Intake ◽

Energy Homeostasis ◽

Somatostatin Receptors ◽

Gut Hormones ◽

Peptide Hormone ◽

Nutrient Stress ◽

Metabolic Homeostasis ◽

Adipokinetic Hormone ◽

Energy Mobilization ◽

Gut Hormone

AbstractThe intestine is a central regulator of metabolic homeostasis. Dietary inputs are absorbed through the gut, which senses their nutritional value and relays hormonal information to other organs to coordinate systemic energy balance. However, the specific gut hormones that communicate energy availability to target organs to induce appropriate metabolic and behavioral responses are poorly defined. Here we show that the enteroendocrine cells (EECs) of the Drosophila gut sense nutrient stress via the intracellular TOR pathway, and in response secrete the peptide hormone allatostatin C (AstC). Gut-derived AstC induces secretion of glucagon-like adipokinetic hormone (AKH) via its receptor AstC-R2, a homolog of mammalian somatostatin receptors, to coordinate food intake and energy mobilization. Loss of gut AstC or its receptor in the AKH-producing cells impairs lipid and sugar mobilization during fasting, leading to hypoglycemia. Our findings illustrate a nutrient-responsive endocrine mechanism that maintains energy homeostasis under nutrient-stress conditions, a function that is essential to health and whose failure can lead to metabolic disorders.

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Arcuate NPY neurons and energy homeostasis in diet-induced obese and resistant rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1999.276.2.r382 ◽

1999 ◽

Vol 276 (2) ◽

pp. R382-R387 ◽

Cited By ~ 26

Author(s):

Barry E. Levin

Keyword(s):

Metabolic Regulation ◽

Energy Homeostasis ◽

Arcuate Nucleus ◽

Inbred Strains ◽

Energy Restriction ◽

Short Term ◽

Diet Induced Obesity ◽

Body Weights ◽

Hypothalamic Arcuate Nucleus

The neuropeptide Y (NPY) neurons in the hypothalamic arcuate nucleus regulate and are regulated by short-term changes in energy homeostasis. Both outbred and inbred strains of rats that develop diet-induced obesity (DIO) or are diet resistant (DR) when fed a diet relatively high in energy, fat, and sucrose content (HE diet) were used to study arcuate NPY mRNA expression during long-term changes in energy balance. Outbred, chow-fed obesity-prone rats had 59% higher NPY levels than obesity-resistant rats. After 14 wk on HE diet, DIO rats had 17% lower NPY levels than DR rats made comparably obese on a highly palatable diet. When switched to chow, obese DR rats spontaneously reduced their intake and their body weights fell to control levels in association with a 10% decrease in NPY levels. DIO rats lost weight only with energy restriction associated with a 21% increase in their NPY levels. When again fed ad libitum, the weight and NPY levels in the rats returned to those of unrestricted DIO rats. Chow-fed, inbred DIO rats weigh more and are fatter than age-matched inbred DR rats. As with outbred DIO rats fed the HE diet, inbred DIO rats had 20% lower NPY levels than DR rats. Thus preobese, outbred DIO rats have high levels of NPY message that are not susceptible to metabolic regulation. When obesity develops in both inbred and outbred rats, the levels of NPY mRNA fall but become responsive to alterations in energy availability.

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