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Molecular Mechanisms of Appetite Regulation
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Molecular Mechanisms of Appetite Regulation

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Endocrinology & Metabolism".

Deadline for manuscript submissions: closed (25 November 2021) | Viewed by 22667

Special Issue Editors

Dr. James Ernie Blevins

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Guest Editor
Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington, VA Puget Sound Health Care System, 1660 South Columbian Way, Research-151, Seattle, WA 98108, USA
Interests: neural circuits that contribute to the effects of leptin signaling on food intake and energy expenditure; role of oxytocin receptor signaling in the pathogenesis underlying diet-induced obesity; role of brown adipose tissue thermogenesis in mediating oxytocin-elicited weight loss in diet-induced obese rodents and nonhuman primates
Dr. Pawel K. Olszewski

E-Mail Website
Guest Editor
1. FSEN, University of Waikato, Hamilton, New Zealand
2. Department of Food Science and Nutrition, CFANS, and Integrative Biology and Physiology, Medical School, University of Minnesota, St. Paul, MN, USA
Interests: neural and neuroendocrine control of satiation; interplay between reward- and energy-related signaling in the regulation of food intake; oxytocin as a molecule that ties feeding behavior to a broad physiological state of the organism
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Obesity and its associated complications have reached epidemic proportions in the US and worldwide. This is due, in part, to increased dietary intake of fat and high-fructose corn syrup and sugar, which is linked with the development of metabolic abnormalities characteristic of metabolic syndrome (e.g., dyslipidemia, weight gain, visceral fat) in both humans and diet-induced obese (DIO) nonhuman primates (NHPs). However, current weight loss therapies are largely unsuccessful, highlighting the urgent need to develop new and effective strategies to treat the growing obesity epidemic. The failure of therapies to induce sustained weight loss in obese humans is thought to occur, in part, by activation of potent orexigenic mechanisms in the CNS that drive hunger and energy conservation mechanisms that reduce energy expenditure (EE), thus preventing further weight loss and promoting weight regain. Multi-drug therapies aimed at both suppressing food intake and/or increasing EE are therefore likely required as successful weight loss strategies.

In this Special Issue on Molecular Mechanisms of Appetite Regulation, we present new and historical data pertaining to factors that contribute to the obesity epidemic, with particular focus on molecular processes whose dysregulation leads to abnormal appetite and/or energy expenditure. We also identify pharmacological strategies that can potentially contribute to restoring a proper energy balance. We conclude by describing ongoing challenges that remain in order for therapeutics to be used as a long-term strategy to treat obesity in humans.

Dr. James Ernie Blevins
Dr. Pawel K. Olszewski
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • obesity
  • appetite
  • energy expenditure
  • leptin resistance
  • macronutrients
  • peptides
  • amino acids

Published Papers (7 papers)

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Research

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41 pages, 83518 KiB  
Article
Glycemic Challenge Is Associated with the Rapid Cellular Activation of the Locus Ceruleus and Nucleus of Solitary Tract: Circumscribed Spatial Analysis of Phosphorylated MAP Kinase Immunoreactivity
by Geronimo P. Tapia, Lindsay J. Agostinelli, Sarah D. Chenausky, Jessica V. Salcido Padilla, Vanessa I. Navarro, Amy Alagh, Gabriel Si, Richard H. Thompson, Sivasai Balivada and Arshad M. Khan
J. Clin. Med. 2023, 12(7), 2483; https://doi.org/10.3390/jcm12072483 - 24 Mar 2023
Viewed by 6393
Abstract
Rodent studies indicate that impaired glucose utilization or hypoglycemia is associated with the cellular activation of neurons in the medulla (Winslow, 1733) (MY), believed to control feeding behavior and glucose counterregulation. However, such activation has been tracked primarily within hours of the challenge, [...] Read more.
Rodent studies indicate that impaired glucose utilization or hypoglycemia is associated with the cellular activation of neurons in the medulla (Winslow, 1733) (MY), believed to control feeding behavior and glucose counterregulation. However, such activation has been tracked primarily within hours of the challenge, rather than sooner, and has been poorly mapped within standardized brain atlases. Here, we report that, within 15 min of receiving 2-deoxy-d-glucose (2-DG; 250 mg/kg, i.v.), which can trigger glucoprivic feeding behavior, marked elevations were observed in the numbers of rhombic brain (His, 1893) (RB) neuronal cell profiles immunoreactive for the cellular activation marker(s), phosphorylated p44/42 MAP kinases (phospho-ERK1/2), and that some of these profiles were also catecholaminergic. We mapped their distributions within an open-access rat brain atlas and found that 2-DG-treated rats (compared to their saline-treated controls) displayed greater numbers of phospho-ERK1/2+ neurons in the locus ceruleus (Wenzel and Wenzel, 1812) (LC) and the nucleus of solitary tract (>1840) (NTS). Thus, the 2-DG-activation of certain RB neurons is more rapid than perhaps previously realized, engaging neurons that serve multiple functional systems and which are of varying cellular phenotypes. Mapping these populations within standardized brain atlas maps streamlines their targeting and/or comparable mapping in preclinical rodent models of disease. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Appetite Regulation)
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20 pages, 1390 KiB  
Article
Anatabine, Nornicotine, and Anabasine Reduce Weight Gain and Body Fat through Decreases in Food Intake and Increases in Physical Activity
by Patricia E. Grebenstein, Paige Erickson, Martha Grace and Catherine M. Kotz
J. Clin. Med. 2022, 11(3), 481; https://doi.org/10.3390/jcm11030481 - 18 Jan 2022
Cited by 3 | Viewed by 1991
Abstract
Obesity is a leading cause of preventable death in the United States. Currently approved pharmacotherapies for the treatment of obesity are associated with rebound weight gain, negative side effects, and the potential for abuse. There is a need for new treatments with fewer [...] Read more.
Obesity is a leading cause of preventable death in the United States. Currently approved pharmacotherapies for the treatment of obesity are associated with rebound weight gain, negative side effects, and the potential for abuse. There is a need for new treatments with fewer side effects. Minor tobacco alkaloids (MTAs) are potential candidates for novel obesity pharmacotherapies. These alkaloids are structurally related to nicotine, which can help reduce body weight, but without the same addictive potential. The purpose of the current study was to examine the effects of three MTAs (nornicotine, anatabine, and anabasine) and nicotine on weight gain, body composition, chow intake, and physical activity. We hypothesized that the MTAs and nicotine would reduce weight gain through reductions in chow intake and increases in physical activity. To test this, male Sprague Dawley rats were housed in metabolic phenotyping chambers. Following acclimation to these chambers and to (subcutaneous (sc)) injections of saline, animals received daily injections (sc) of nornicotine, anabasine, anatabine, or nicotine for one week. Compared to saline-injected animals that gained body weight and body fat during the treatment phase, injections of nornicotine and anatabine prevented additional weight gain, alongside reductions in body fat. Rats receiving anabasine and nicotine gained body weight at a slower rate relative to rats receiving saline injections, and body fat remained unchanged. All compounds reduced the intake of chow pellets. Nornicotine and nicotine produced consistent increases in physical activity 6 h post-injection, whereas anabasine’s and anatabine’s effects on physical activity were more transient. These results show that short-term, daily administration of nornicotine, anabasine, and anatabine has positive effects on weight loss, through reductions in body fat and food intake and increases in physical activity. Together, these findings suggest that MTAs are worthy of further investigations as anti-obesity pharmacotherapies. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Appetite Regulation)
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14 pages, 5314 KiB  
Article
Acute Hypophagia and Changes in c-Fos Immunoreactivity in Adolescent Rats Treated with Low Doses of Oxytocin and Naltrexone
by Mitchell A. Head, Laura K. McColl, Anica Klockars, Allen S. Levine and Pawel K. Olszewski
J. Clin. Med. 2022, 11(1), 59; https://doi.org/10.3390/jcm11010059 - 23 Dec 2021
Cited by 2 | Viewed by 2211
Abstract
A recent case report has shown that an adjunctive oxytocin + naltrexone (OT + NTX) treatment promoted more robust hypophagia and body weight reduction than OT alone in an adolescent male with hypothalamic obesity after craniopharyngioma resection. Thus far, there has been no [...] Read more.
A recent case report has shown that an adjunctive oxytocin + naltrexone (OT + NTX) treatment promoted more robust hypophagia and body weight reduction than OT alone in an adolescent male with hypothalamic obesity after craniopharyngioma resection. Thus far, there has been no basic research in adolescent laboratory animals that would examine whether the benefit of OT + NTX on appetite extends onto adolescent individuals without surgically induced overeating. Thus, here we examined whether low doses of combined OT + NTX acutely affect post-deprivation intake of energy-dense, standard chow; intake of energy-dense and palatable high-fat high-sugar (HFHS) diet; or calorie-dilute, palaTable 10% sucrose solution without deprivation in adolescent male rats. We assessed whether OT + NTX decreases water intake after water deprivation or produces a conditioned taste aversion (CTA). Finally, by using c-Fos immunoreactivity, we determined changes in activity of feeding-related brain areas after OT + NTX. We found that individual subthreshold doses of OT and NTX decreased feeding induced by energy and by palatability. Significant c-Fos changes were noted in the arcuate and dorsomedial hypothalamic nuclei. The hypophagic doses of OT + NTX did not suppress water intake in thirsty rats and did not cause a CTA, which suggests that feeding reduction is not a secondary effect of gastrointestinal discomfort or changes in thirst processing. We conclude that OT + NTX is an effective drug combination to reduce appetite in adolescent male rats. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Appetite Regulation)
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26 pages, 11182 KiB  
Article
Hindbrain Administration of Oxytocin Reduces Food Intake, Weight Gain and Activates Catecholamine Neurons in the Hindbrain Nucleus of the Solitary Tract in Rats
by Vishwanath T. Anekonda, Benjamin W. Thompson, Jacqueline M. Ho, Zachary S. Roberts, Melise M. Edwards, Ha K. Nguyen, Andrew D. Dodson, Tami Wolden-Hanson, Daniel W. Chukri, Adam J. Herbertson, James L. Graham, Peter J. Havel, Tomasz A. Wietecha, Kevin D. O’Brien and James E. Blevins
J. Clin. Med. 2021, 10(21), 5078; https://doi.org/10.3390/jcm10215078 - 29 Oct 2021
Cited by 6 | Viewed by 1723
Abstract
Existing studies show that CNS oxytocin (OT) signaling is important in the control of energy balance, but it is unclear which neurons may contribute to these effects. Our goals were to examine (1) the dose-response effects of acute OT administration into the third [...] Read more.
Existing studies show that CNS oxytocin (OT) signaling is important in the control of energy balance, but it is unclear which neurons may contribute to these effects. Our goals were to examine (1) the dose-response effects of acute OT administration into the third (3V; forebrain) and fourth (4V; hindbrain) ventricles to assess sensitivity to OT in forebrain and hindbrain sites, (2) the extent to which chronic 4V administration of OT reduces weight gain associated with the progression of diet-induced obesity, and (3) whether nucleus tractus solitarius (NTS) catecholamine neurons are downstream targets of 4V OT. Initially, we examined the dose-response effects of 3V and 4V OT (0.04, 0.2, 1, or 5 μg). 3V and 4V OT (5 μg) suppressed 0.5-h food intake by 71.7 ± 6.0% and 60 ± 12.9%, respectively. 4V OT (0.04, 0.2, 1 μg) reduced food intake by 30.9 ± 12.9, 42.1 ± 9.4, and 56.4 ± 9.0%, respectively, whereas 3V administration of OT (1 μg) was only effective at reducing 0.5-h food intake by 38.3 ± 10.9%. We subsequently found that chronic 4V OT infusion, as with chronic 3V infusion, reduced body weight gain (specific to fat mass) and tended to reduce plasma leptin in high-fat diet (HFD)-fed rats, in part, through a reduction in energy intake. Lastly, we determined that 4V OT increased the number of hindbrain caudal NTS Fos (+) neurons (156 ± 25) relative to vehicle (12 ± 3). The 4V OT also induced Fos in tyrosine hydroxylase (TH; marker of catecholamine neurons) (+) neurons (25 ± 7%) relative to vehicle (0.8 ± 0.3%). Collectively, these findings support the hypothesis that OT within the hindbrain is effective at reducing food intake, weight gain, and adiposity and that NTS catecholamine neurons in addition to non-catecholaminergic neurons are downstream targets of CNS OT. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Appetite Regulation)
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Review

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23 pages, 434 KiB  
Review
Mediators of Amylin Action in Metabolic Control
by Christina N. Boyle, Yi Zheng and Thomas A. Lutz
J. Clin. Med. 2022, 11(8), 2207; https://doi.org/10.3390/jcm11082207 - 15 Apr 2022
Cited by 11 | Viewed by 4058
Abstract
Amylin (also called islet amyloid polypeptide (IAPP)) is a pancreatic beta-cell hormone that is co-secreted with insulin in response to nutrient stimuli. The last 35 years of intensive research have shown that amylin exerts important physiological effects on metabolic control. Most importantly, amylin [...] Read more.
Amylin (also called islet amyloid polypeptide (IAPP)) is a pancreatic beta-cell hormone that is co-secreted with insulin in response to nutrient stimuli. The last 35 years of intensive research have shown that amylin exerts important physiological effects on metabolic control. Most importantly, amylin is a physiological control of meal-ending satiation, and it limits the rate of gastric emptying and reduces the secretion of pancreatic glucagon, in particular in postprandial states. The physiological effects of amylin and its analogs are mediated by direct brain activation, with the caudal hindbrain playing the most prominent role. The clarification of the structure of amylin receptors, consisting of the calcitonin core receptor plus receptor-activity modifying proteins, aided in the development of amylin analogs with a broad pharmacological profile. The general interest in amylin physiology and pharmacology was boosted by the finding that amylin is a sensitizer to the catabolic actions of leptin. Today, amylin derived analogs are considered to be among the most promising approaches for the pharmacotherapy against obesity. At least in conjunction with insulin, amylin analogs are also considered important treatment options in diabetic patients, so that new drugs may soon be added to the only currently approved compound pramlintide (Symlin®). This review provides a brief summary of the physiology of amylin’s mode of actions and its role in the control of the metabolism, in particular energy intake and glucose metabolism. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Appetite Regulation)
18 pages, 976 KiB  
Review
Fibroblast Growth Factor 21 Facilitates the Homeostatic Control of Feeding Behavior
by Chih-Ting Wu, Aki T. Chaffin and Karen K. Ryan
J. Clin. Med. 2022, 11(3), 580; https://doi.org/10.3390/jcm11030580 - 24 Jan 2022
Cited by 11 | Viewed by 3413
Abstract
Fibroblast growth factor 21 (FGF21) is a stress hormone that is released from the liver in response to nutritional and metabolic challenges. In addition to its well-described effects on systemic metabolism, a growing body of literature now supports the notion that FGF21 also [...] Read more.
Fibroblast growth factor 21 (FGF21) is a stress hormone that is released from the liver in response to nutritional and metabolic challenges. In addition to its well-described effects on systemic metabolism, a growing body of literature now supports the notion that FGF21 also acts via the central nervous system to control feeding behavior. Here we review the current understanding of FGF21 as a hormone regulating feeding behavior in rodents, non-human primates, and humans. First, we examine the nutritional contexts that induce FGF21 secretion. Initial reports describing FGF21 as a ‘starvation hormone’ have now been further refined. FGF21 is now better understood as an endocrine mediator of the intracellular stress response to various nutritional manipulations, including excess sugars and alcohol, caloric deficits, a ketogenic diet, and amino acid restriction. We discuss FGF21’s effects on energy intake and macronutrient choice, together with our current understanding of the underlying neural mechanisms. We argue that the behavioral effects of FGF21 function primarily to maintain systemic macronutrient homeostasis, and in particular to maintain an adequate supply of protein and amino acids for use by the cells. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Appetite Regulation)
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13 pages, 1886 KiB  
Review
Brain Signaling of Indispensable Amino Acid Deficiency
by Dorothy W. Gietzen
J. Clin. Med. 2022, 11(1), 191; https://doi.org/10.3390/jcm11010191 - 30 Dec 2021
Cited by 3 | Viewed by 1990
Abstract
Our health requires continual protein synthesis for maintaining and repairing tissues. For protein synthesis to function, all the essential (indispensable) amino acids (IAAs) must be available in the diet, along with those AAs that the cells can synthesize (the dispensable amino acids). Here [...] Read more.
Our health requires continual protein synthesis for maintaining and repairing tissues. For protein synthesis to function, all the essential (indispensable) amino acids (IAAs) must be available in the diet, along with those AAs that the cells can synthesize (the dispensable amino acids). Here we review studies that have shown the location of the detector for IAA deficiency in the brain, specifically for recognition of IAA deficient diets (IAAD diets) in the anterior piriform cortex (APC), with subsequent responses in downstream brain areas. The APC is highly excitable, which makes is uniquely suited to serve as an alarm for reductions in IAAs. With a balanced diet, these neurons are kept from over-excitation by GABAergic inhibitory neurons. Because several transporters and receptors on the GABAergic neurons have rapid turnover times, they rely on intact protein synthesis to function. When an IAA is missing, its unique tRNA cannot be charged. This activates the enzyme General Control Nonderepressible 2 (GCN2) that is important in the initiation phase of protein synthesis. Without the inhibitory control supplied by GABAergic neurons, excitation in the circuitry is free to signal an urgent alarm. Studies in rodents have shown rapid recognition of IAA deficiency by quick rejection of the IAAD diet. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Appetite Regulation)
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