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

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

10.21203/rs.3.rs-538169/v1 ◽

2021 ◽

Author(s):

Maria Paula Cornejo ◽

Raphael Denis ◽

Guadalupe Garcia Romero ◽

Gimena Fernandez ◽

Mirta Reynaldo ◽

...

Keyword(s):

Food Intake ◽

Energy Homeostasis ◽

Arcuate Nucleus ◽

Peptide Hormone ◽

Heuristic Model ◽

Feeding Response ◽

Systemic Injection ◽

Biphasic Effect ◽

Nutrient Partitioning ◽

Hypothalamic Arcuate Nucleus

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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Peptide YY3–36 and Glucagon-Like Peptide-17–36 Inhibit Food Intake Additively

Endocrinology ◽

10.1210/en.2005-0237 ◽

2005 ◽

Vol 146 (12) ◽

pp. 5120-5127 ◽

Cited By ~ 226

Author(s):

Nicola M. Neary ◽

Caroline J. Small ◽

Maralyn R. Druce ◽

Adrian J. Park ◽

Sandra M. Ellis ◽

...

Keyword(s):

Food Intake ◽

Brain Stem ◽

Low Dose ◽

Arcuate Nucleus ◽

Peptide Yy ◽

High Dose ◽

Hypothalamic Arcuate Nucleus ◽

Inhibit Food Intake ◽

Glucagon Like Peptide ◽

The Brain

Peptide YY (PYY) and glucagon like peptide (GLP)-1 are cosecreted from intestinal L cells, and plasma levels of both hormones rise after a meal. Peripheral administration of PYY3–36 and GLP-17–36 inhibit food intake when administered alone. However, their combined effects on appetite are unknown. We studied the effects of peripheral coadministration of PYY3–36 with GLP-17–36 in rodents and man. Whereas high-dose PYY3–36 (100 nmol/kg) and high-dose GLP-17–36 (100 nmol/kg) inhibited feeding individually, their combination led to significantly greater feeding inhibition. Additive inhibition of feeding was also observed in the genetic obese models, ob/ob and db/db mice. At low doses of PYY3–36 (1 nmol/kg) and GLP-17–36 (10 nmol/kg), which alone had no effect on food intake, coadministration led to significant reduction in food intake. To investigate potential mechanisms, c-fos immunoreactivity was quantified in the hypothalamus and brain stem. In the hypothalamic arcuate nucleus, no changes were observed after low-dose PYY3–36 or GLP-17–36 individually, but there were significantly more fos-positive neurons after coadministration. In contrast, there was no evidence of additive fos-stimulation in the brain stem. Finally, we coadministered PYY3–36 and GLP-17–36 in man. Ten lean fasted volunteers received 120-min infusions of saline, GLP-17–36 (0.4 pmol/kg·min), PYY3–36 (0.4 pmol/kg·min), and PYY3–36 (0.4 pmol/kg·min) + GLP-17–36 (0.4 pmol/kg·min) on four separate days. Energy intake from a buffet meal after combined PYY3–36 + GLP-17–36 treatment was reduced by 27% and was significantly lower than that after either treatment alone. Thus, PYY3–36 and GLP-17–36, cosecreted after a meal, may inhibit food intake additively.

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Contribution of Neuroinflammation to the Pathogenesis of Cancer Cachexia

Mediators of Inflammation ◽

10.1155/2015/801685 ◽

2015 ◽

Vol 2015 ◽

pp. 1-7 ◽

Cited By ~ 11

Author(s):

Alessio Molfino ◽

Gianfranco Gioia ◽

Filippo Rossi Fanelli ◽

Alessandro Laviano

Keyword(s):

Adipose Tissue ◽

Food Intake ◽

Proinflammatory Cytokines ◽

Adaptive Response ◽

Energy Homeostasis ◽

Cancer Cachexia ◽

Behavioral Changes ◽

Brain Areas ◽

Functional Changes ◽

The Brain

Inflammation characterizes the course of acute and chronic diseases and is largely responsible for the metabolic and behavioral changes occurring during the clinical journey of patients. Robust data indicate that, during cancer, functional modifications within brain areas regulating energy homeostasis contribute to the onset of anorexia, reduced food intake, and increased catabolism of muscle mass and adipose tissue. In particular, functional changes are associated with increased hypothalamic concentration of proinflammatory cytokines, which suggests that neuroinflammation may represent the adaptive response of the brain to peripheral challenges, including tumor growth. Within this conceptual framework, the vagus nerve appears to be involved in conveying alert signals to the hypothalamus, whereas hypothalamic serotonin appears to contribute to triggering catabolic signals.

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Endocrine factors in the hypothalamic regulation of food intake in females: a review of the physiological roles and interactions of ghrelin, leptin, thyroid hormones, oestrogen and insulin

Nutrition Research Reviews ◽

10.1017/s0954422411000035 ◽

2011 ◽

Vol 24 (1) ◽

pp. 132-154 ◽

Cited By ~ 12

Author(s):

V. Somogyi ◽

A. Gyorffy ◽

T. J. Scalise ◽

D. S. Kiss ◽

G. Goszleth ◽

...

Keyword(s):

Food Intake ◽

Energy Expenditure ◽

Thyroid Hormones ◽

Energy Homeostasis ◽

The Body ◽

Feedback Information ◽

Hypothalamic Regulation ◽

The Individual ◽

Desire To Eat ◽

The Brain

Controlling energy homeostasis involves modulating the desire to eat and regulating energy expenditure. The controlling machinery includes a complex interplay of hormones secreted at various peripheral endocrine endpoints, such as the gastrointestinal tract, the adipose tissue, thyroid gland and thyroid hormone-exporting organs, the ovary and the pancreas, and, last but not least, the brain itself. The peripheral hormones that are the focus of the present review (ghrelin, leptin, thyroid hormones, oestrogen and insulin) play integrated regulatory roles in and provide feedback information on the nutritional and energetic status of the body. As peripheral signals, these hormones modulate central pathways in the brain, including the hypothalamus, to influence food intake, energy expenditure and to maintain energy homeostasis. Since the growth of the literature on the role of various hormones in the regulation of energy homeostasis shows a remarkable and dynamic expansion, it is now becoming increasingly difficult to understand the individual and interactive roles of hormonal mechanisms in their true complexity. Therefore, our goal is to review, in the context of general physiology, the roles of the five best-known peripheral trophic hormones (ghrelin, leptin, thyroid hormones, oestrogen and insulin, respectively) and discuss their interactions in the hypothalamic regulation of food intake.

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LGR4 and Its Ligands, R-Spondin 1 and R-Spondin 3, Regulate Food Intake in the Hypothalamus of Male Rats

Endocrinology ◽

10.1210/en.2013-1550 ◽

2014 ◽

Vol 155 (2) ◽

pp. 429-440 ◽

Cited By ~ 11

Author(s):

Ji-Yao Li ◽

Biaoxin Chai ◽

Weizhen Zhang ◽

Danielle M. Fritze ◽

Chao Zhang ◽

...

Keyword(s):

In Situ Hybridization ◽

Food Intake ◽

Neuropeptide Y ◽

Paraventricular Nucleus ◽

Median Eminence ◽

Energy Homeostasis ◽

Male Rats ◽

The Third ◽

The Brain

The hypothalamus plays a key role in the regulation of feeding behavior. Several hypothalamic nuclei, including the arcuate nucleus (ARC), paraventricular nucleus, and ventromedial nucleus of the hypothalamus (VMH), are involved in energy homeostasis. Analysis of microarray data derived from ARC revealed that leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4) is highly expressed. LGR4, LGR5, and LGR6 form a subfamily of closely related receptors. Recently, R-spondin (Rspo) family proteins were identified as ligands of the LGR4 subfamily. In the present study, we investigated the distribution and function of LGR4–LGR6 and Rspos (1–4) in the brain of male rat. In situ hybridization showed that LGR4 is expressed in the ARC, VMH, and median eminence of the hypothalamus. LGR4 colocalizes with neuropeptide Y, proopiomelanocortin, and brain-derived neurotrophic factor neurons. LGR5 is not detectable with in situ hybridization; LGR6 is only expressed in the epithelial lining of the lower portion of the third ventricle and median eminence. Rspo1 is expressed in the VMH and down-regulated with fasting. Rspo3 is expressed in the paraventricular nucleus and also down-regulated with fasting. Rspos 1 and 3 colocalize with the neuronal marker HuD, indicating that they are expressed by neurons. Injection of Rspo1 or Rspo3 into the third brain ventricle inhibited food intake. Rspo1 decreased neuropeptide Y and increased proopiomelanocortin expression in the ARC. Rspo1 and Rspo3 mRNA is up-regulated by insulin. These data indicate that Rspo1 and Rspo3 and their receptor LGR4 form novel circuits in the brain to regulate energy homeostasis.

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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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The Antiobesity Effects of Centrally Administered Neuromedin U and Neuromedin S Are Mediated Predominantly by the Neuromedin U Receptor 2 (NMUR2)

Endocrinology ◽

10.1210/en.2008-1772 ◽

2009 ◽

Vol 150 (7) ◽

pp. 3101-3109 ◽

Cited By ~ 47

Author(s):

Andrea Peier ◽

Jennifer Kosinski ◽

Kimberly Cox-York ◽

Ying Qian ◽

Kunal Desai ◽

...

Keyword(s):

Food Intake ◽

Energy Homeostasis ◽

Central Administration ◽

Diet Induced Obesity ◽

Inhibit Food Intake ◽

Selective Agonists ◽

Treatment Of Obesity ◽

The Brain ◽

Deficient Mice

Neuromedin U (NMU) and neuromedin S (NMS) are structurally related neuropeptides that have been reported to modulate energy homeostasis. Pharmacological data have shown that NMU and NMS inhibit food intake when administered centrally and that NMU increases energy expenditure. Additionally, NMU-deficient mice develop obesity, whereas transgenic mice overexpressing NMU are lean and hypophagic. Two high-affinity NMU/NMS receptors, NMUR1 and NMUR2, have been identified. NMUR1 is predominantly expressed in the periphery, whereas NMUR2 is predominantly expressed in the brain, suggesting that the effects of centrally administered NMU and NMS are mediated by NMUR2. To evaluate the role of NMUR2 in the regulation of energy homeostasis, we characterized NMUR2-deficient (Nmur2−/−) mice. Nmur2−/− mice exhibited a modest resistance to diet-induced obesity that was at least in part due to reduced food intake. Acute central administration of NMU and NMS reduced food intake in wild-type but not in Nmur2−/− mice. The effects on activity and core temperature induced by centrally administered NMU were also absent in Nmur2−/− mice. Moreover, chronic central administration of NMU and NMS evoked significant reductions in body weight and sustained reductions in food intake in mice. In contrast, Nmur2−/− mice were largely resistant to these effects. Collectively, these data demonstrate that the anorectic and weight-reducing actions of centrally administered NMU and NMS are mediated predominantly by NMUR2, suggesting that NMUR2-selective agonists may be useful for the treatment of obesity.

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Inconsistencies in the assessment of food intake

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00415.2012 ◽

2012 ◽

Vol 303 (12) ◽

pp. E1408-E1418 ◽

Cited By ~ 26

Author(s):

Stephen C. Woods ◽

Wolfgang Langhans

Keyword(s):

Food Intake ◽

Energy Intake ◽

Body Fat ◽

Energy Homeostasis ◽

Behavioral Responses ◽

Normal Function ◽

Direct Proportion ◽

Heated Debate ◽

The Brain ◽

Reducing Energy

Many peptides and other compounds that influence metabolism also influence food intake, and numerous hypotheses explaining the observed effects in terms of energy homeostasis have been suggested over the years. For example, cholecystokinin (CCK), a duodenal peptide secreted during meals that aids in digestion, also reduces ongoing food intake, thereby contributing to satiation; and insulin and leptin, hormones secreted in direct proportion to body fat, act in the brain to help control adiposity by reducing energy intake. These behavioral actions are often considered to be hard-wired, such that negative experiments, in which an administered compound fails to have its purported effect, are generally disregarded. In point of fact, failures to replicate the effects of compounds on food intake are commonplace, and this occurs both between and within laboratories. Failures to replicate have historically fueled heated debate about the efficacy and/or normal function of one or another compound, leading to confusion and ambiguity in the literature. We review these phenomena and their implications and argue that, rather than eliciting hard-wired behavioral responses in the maintenance of homeostasis, compounds that alter food intake are subjected to numerous influences that can render them completely ineffective at times and that a major reason for this variance is that food intake is not under stringent homeostatic control.

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