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20 pages, 4189 KiB

Open AccessArticle

Palmitoylation of Prolactin-Releasing Peptide Increased Affinity for and Activation of the GPR10, NPFF-R2 and NPFF-R1 Receptors: In Vitro Study

by Alena Karnošová, Veronika Strnadová, Lucie Holá, Blanka Železná, Jaroslav Kuneš and Lenka Maletínská

Int. J. Mol. Sci. 2021, 22(16), 8904; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168904 - 18 Aug 2021

Cited by 10 | Viewed by 2263

Abstract

The anorexigenic neuropeptide prolactin-releasing peptide (PrRP) is involved in the regulation of food intake and energy expenditure. Lipidization of PrRP stabilizes the peptide, facilitates central effect after peripheral administration and increases its affinity for its receptor, GPR10, and for the neuropeptide FF (NPFF) [...] Read more.

The anorexigenic neuropeptide prolactin-releasing peptide (PrRP) is involved in the regulation of food intake and energy expenditure. Lipidization of PrRP stabilizes the peptide, facilitates central effect after peripheral administration and increases its affinity for its receptor, GPR10, and for the neuropeptide FF (NPFF) receptor NPFF-R2. The two most potent palmitoylated analogs with anorectic effects in mice, palm¹¹-PrRP31 and palm-PrRP31, were studied in vitro to determine their agonist/antagonist properties and mechanism of action on GPR10, NPFF-R2 and other potential off-target receptors related to energy homeostasis. Palmitoylation of both PrRP31 analogs increased the binding properties of PrRP31 to anorexigenic receptors GPR10 and NPFF-R2 and resulted in a high affinity for another NPFF receptor, NPFF-R1. Moreover, in CHO-K1 cells expressing GPR10, NPFF-R2 or NPFF-R1, palm¹¹-PrRP and palm-PrRP significantly increased the phosphorylation of extracellular signal-regulated kinase (ERK), protein kinase B (Akt) and cAMP-responsive element-binding protein (CREB). Palm¹¹-PrRP31, unlike palm-PrRP31, did not activate either c-Jun N-terminal kinase (JNK), p38, c-Jun, c-Fos or CREB pathways in cells expressing NPFF-1R. Palm-PrRP31 also has higher binding affinities for off-target receptors, namely, the ghrelin, opioid (KOR, MOR, DOR and OPR-L1) and neuropeptide Y (Y₁, Y₂ and Y₅) receptors. Palm¹¹-PrRP31 exhibited fewer off-target activities; therefore, it has a higher potential to be used as an anti-obesity drug with anorectic effects. Full article

(This article belongs to the Special Issue Neuropeptides in Food Intake Regulation)

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16 pages, 2520 KiB

Open AccessArticle

Conditional Inactivation of Limbic Neuropeptide Y-1 Receptors Increases Vulnerability to Diet-Induced Obesity in Male Mice

by Silvia Paterlini, Riccardo Panelli, Laura Gioiosa, Stefano Parmigiani, Paolo Franceschini, Ilaria Bertocchi, Alessandra Oberto, Alessandro Bartolomucci, Carola Eva and Paola Palanza

Int. J. Mol. Sci. 2021, 22(16), 8745; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168745 - 14 Aug 2021

Cited by 5 | Viewed by 3097

Abstract

NPY and its Y1 cognate receptor (Y1R) have been shown to be involved in the regulation of stress, anxiety, depression and energy homeostasis. We previously demonstrated that conditional knockout of Npy1r gene in the excitatory neurons of the forebrain of adolescent male mice [...] Read more.

NPY and its Y1 cognate receptor (Y1R) have been shown to be involved in the regulation of stress, anxiety, depression and energy homeostasis. We previously demonstrated that conditional knockout of Npy1r gene in the excitatory neurons of the forebrain of adolescent male mice (Npy1r^rfb mice) decreased body weight growth and adipose tissue and increased anxiety. In the present study, we used the same conditional system to examine whether the targeted disruption of the Npy1r gene in limbic areas might affect susceptibility to obesity and associated disorders during adulthood in response to a 3-week high-fat diet (HFD) regimen. We demonstrated that following HFD exposure, Npy1r^rfb male mice showed increased body weight, visceral adipose tissue, and blood glucose levels, hyperphagia and a dysregulation of calory intake as compared to control Npy1r^2lox mice. These results suggest that low expression of Npy1r in limbic areas impairs habituation to high caloric food and causes high susceptibility to diet-induced obesity and glucose intolerance in male mice, uncovering a specific contribution of the limbic Npy1r gene in the dysregulation of the eating/satiety balance. Full article

(This article belongs to the Special Issue Neuropeptides in Food Intake Regulation)

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18 pages, 4402 KiB

Open AccessArticle

Alanine Scanning Mutagenesis of the DRYxxI Motif and Intracellular Loop 2 of Human Melanocortin-4 Receptor

by Li-Kun Yang and Ya-Xiong Tao

Int. J. Mol. Sci. 2020, 21(20), 7611; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207611 - 15 Oct 2020

Cited by 9 | Viewed by 2603

Abstract

The melanocortin-4 receptor (MC4R) is a member of the G-protein-coupled receptor (GPCR) superfamily, which has been extensively studied in obesity pathogenesis due to its critical role in regulating energy homeostasis. Both the Gs-cAMP and ERK1/2 cascades are known as important intracellular signaling pathways [...] Read more.

The melanocortin-4 receptor (MC4R) is a member of the G-protein-coupled receptor (GPCR) superfamily, which has been extensively studied in obesity pathogenesis due to its critical role in regulating energy homeostasis. Both the Gs-cAMP and ERK1/2 cascades are known as important intracellular signaling pathways initiated by the MC4R. The DRYxxI motif at the end of transmembrane domain 3 and the intracellular loop 2 (ICL2) are thought to be crucial for receptor function in several GPCRs. To study the functions of this domain in MC4R, we performed alanine-scanning mutagenesis on seventeen residues. We showed that one residue was critical for receptor cell surface expression. Eight residues were important for ligand binding. Mutations of three residues impaired Gs-cAMP signaling without changing the binding properties. Investigation on constitutive activities of all the mutants in the cAMP pathway revealed that six residues were involved in constraining the receptor in inactive states and five residues were important for receptor activation in the absence of an agonist. In addition, mutations of four residues impaired the ligand-stimulated ERK1/2 signaling pathway without affecting the binding properties. We also showed that some mutants were biased to the Gs-cAMP or ERK1/2 signaling pathway. In summary, we demonstrated that the DRYxxI motif and ICL2 were important for MC4R function. Full article

(This article belongs to the Special Issue Neuropeptides in Food Intake Regulation)

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20 pages, 4347 KiB

Open AccessArticle

Cellular Signaling and Anti-Apoptotic Effects of Prolactin-Releasing Peptide and Its Analog on SH-SY5Y Cells

by Anna Zmeškalová, Andrea Popelová, Aneta Exnerová, Blanka Železná, Jaroslav Kuneš and Lenka Maletínská

Int. J. Mol. Sci. 2020, 21(17), 6343; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176343 - 01 Sep 2020

Cited by 5 | Viewed by 2885

Abstract

Prolactin-releasing peptide (PrRP), a natural ligand for the GPR10 receptor, is a neuropeptide with anorexigenic and antidiabetic properties. Due to its role in the regulation of food intake, PrRP is a potential drug for obesity treatment and associated type 2 diabetes mellitus (T2DM). [...] Read more.

Prolactin-releasing peptide (PrRP), a natural ligand for the GPR10 receptor, is a neuropeptide with anorexigenic and antidiabetic properties. Due to its role in the regulation of food intake, PrRP is a potential drug for obesity treatment and associated type 2 diabetes mellitus (T2DM). Recently, the neuroprotective effects of lipidized PrRP analogs have been proven. In this study, we focused on the molecular mechanisms of action of natural PrRP31 and its lipidized analog palm¹¹-PrRP31 in the human neuroblastoma cell line SH-SY5Y to describe their cellular signaling and possible anti-apoptotic properties. PrRP31 significantly upregulated the phosphoinositide-3 kinase-protein kinase B/Akt (PI3K-PKB/Akt) and extracellular signal-regulated kinase/cAMP response element-binding protein (ERK-CREB) signaling pathways that promote metabolic cell survival and growth. In addition, we proved via protein kinase inhibitors that activation of signaling pathways is mediated specifically by PrRP31 and its palmitoylated analog. Furthermore, the potential neuroprotective properties were studied through activation of anti-apoptotic pathways of PrRP31 and palm¹¹-PrRP31 using the SH-SY5Y cell line and rat primary neuronal culture stressed with toxic methylglyoxal (MG). The results indicate increased viability of the cells treated with PrRP and palm¹¹-PrRP31 and a reduced degree of apoptosis induced by MG, suggesting their potential use in the treatment of neurological disorders. Full article

(This article belongs to the Special Issue Neuropeptides in Food Intake Regulation)

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Review

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18 pages, 369 KiB

Open AccessReview

Oxytocin and Food Intake Control: Neural, Behavioral, and Signaling Mechanisms

by Clarissa M. Liu, Mai O. Spaulding, Jessica J. Rea, Emily E. Noble and Scott E. Kanoski

Int. J. Mol. Sci. 2021, 22(19), 10859; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910859 - 08 Oct 2021

Cited by 15 | Viewed by 4843

Abstract

The neuropeptide oxytocin is produced in the paraventricular hypothalamic nucleus and the supraoptic nucleus of the hypothalamus. In addition to its extensively studied influence on social behavior and reproductive function, central oxytocin signaling potently reduces food intake in both humans and animal models [...] Read more.

The neuropeptide oxytocin is produced in the paraventricular hypothalamic nucleus and the supraoptic nucleus of the hypothalamus. In addition to its extensively studied influence on social behavior and reproductive function, central oxytocin signaling potently reduces food intake in both humans and animal models and has potential therapeutic use for obesity treatment. In this review, we highlight rodent model research that illuminates various neural, behavioral, and signaling mechanisms through which oxytocin’s anorexigenic effects occur. The research supports a framework through which oxytocin reduces food intake via amplification of within-meal physiological satiation signals rather than by altering between-meal interoceptive hunger and satiety states. We also emphasize the distributed neural sites of action for oxytocin’s effects on food intake and review evidence supporting the notion that central oxytocin is communicated throughout the brain, at least in part, through humoral-like volume transmission. Finally, we highlight mechanisms through which oxytocin interacts with various energy balance-associated neuropeptide and endocrine systems (e.g., agouti-related peptide, melanin-concentrating hormone, leptin), as well as the behavioral mechanisms through which oxytocin inhibits food intake, including effects on nutrient-specific ingestion, meal size control, food reward-motivated responses, and competing motivations. Full article

(This article belongs to the Special Issue Neuropeptides in Food Intake Regulation)

13 pages, 970 KiB

Open AccessReview

The Role of Neuropeptide B and Its Receptors in Controlling Appetite, Metabolism, and Energy Homeostasis

by Tatiana Wojciechowicz, Maria Billert, Mariami Jasaszwili, Mathias Z. Strowski, Krzysztof W. Nowak and Marek Skrzypski

Int. J. Mol. Sci. 2021, 22(12), 6632; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126632 - 21 Jun 2021

Cited by 4 | Viewed by 2613

Abstract

Neuropeptide B (NPB) is a peptide hormone that was initially described in 2002. In humans, the biological effects of NPB depend on the activation of two G protein-coupled receptors, NPBWR1 (GPR7) and NPBWR2 (GPR8), and, in rodents, NPBWR1. NPB and its receptors are [...] Read more.

Neuropeptide B (NPB) is a peptide hormone that was initially described in 2002. In humans, the biological effects of NPB depend on the activation of two G protein-coupled receptors, NPBWR1 (GPR7) and NPBWR2 (GPR8), and, in rodents, NPBWR1. NPB and its receptors are expressed in the central nervous system (CNS) and in peripheral tissues. NPB is also present in the circulation. In the CNS, NPB modulates appetite, reproduction, pain, anxiety, and emotions. In the peripheral tissues, NPB controls secretion of adrenal hormones, pancreatic beta cells, and various functions of adipose tissue. Experimental downregulation of either NPB or NPBWR1 leads to adiposity. Here, we review the literature with regard to NPB-dependent control of metabolism and energy homeostasis. Full article

(This article belongs to the Special Issue Neuropeptides in Food Intake Regulation)

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30 pages, 4008 KiB

Open AccessReview

Neuropeptidergic Control of Feeding: Focus on the Galanin Family of Peptides

by P. Marcos and R. Coveñas

Int. J. Mol. Sci. 2021, 22(5), 2544; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052544 - 03 Mar 2021

Cited by 18 | Viewed by 3564

Abstract

Obesity/overweight are important health problems due to metabolic complications. Dysregulation of peptides exerting orexigenic/anorexigenic effects must be investigated in-depth to understand the mechanisms involved in feeding behaviour. One of the most important and studied orexigenic peptides is galanin (GAL). The aim of this [...] Read more.

Obesity/overweight are important health problems due to metabolic complications. Dysregulation of peptides exerting orexigenic/anorexigenic effects must be investigated in-depth to understand the mechanisms involved in feeding behaviour. One of the most important and studied orexigenic peptides is galanin (GAL). The aim of this review is to update the mechanisms of action and physiological roles played by the GAL family of peptides (GAL, GAL-like peptide, GAL message-associated peptide, alarin) in the control of food intake and to review the involvement of these peptides in metabolic diseases and food intake disorders in experimental animal models and humans. The interaction between GAL and NPY in feeding and energy metabolism, the relationships between GAL and other substances involved in food intake mechanisms, the potential pharmacological strategies to treat food intake disorders and obesity and the possible clinical applications will be mentioned and discussed. Some research lines are suggested to be developed in the future, such as studies focused on GAL receptor/neuropeptide Y Y₁ receptor interactions in hypothalamic and extra-hypothalamic nuclei and sexual differences regarding the expression of GAL in feeding behaviour. It is also important to study the possible GAL resistance in obese individuals to better understand the molecular mechanisms by which GAL regulates insulin/glucose metabolism. GAL does not exert a pivotal role in weight regulation and food intake, but this role is crucial in fat intake and also exerts an important action by regulating the activity of other key compounds under conditions of stress/altered diet. Full article

(This article belongs to the Special Issue Neuropeptides in Food Intake Regulation)

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29 pages, 5571 KiB

Open AccessReview

Structural Complexity and Plasticity of Signaling Regulation at the Melanocortin-4 Receptor

by Gunnar Kleinau, Nicolas A. Heyder, Ya-Xiong Tao and Patrick Scheerer

Int. J. Mol. Sci. 2020, 21(16), 5728; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21165728 - 10 Aug 2020

Cited by 12 | Viewed by 4501

Abstract

The melanocortin-4 receptor (MC4R) is a class A G protein-coupled receptor (GPCR), essential for regulation of appetite and metabolism. Pathogenic inactivating MC4R mutations are the most frequent cause of monogenic obesity, a growing medical and socioeconomic problem worldwide. The MC4R mediates either ligand-independent [...] Read more.

The melanocortin-4 receptor (MC4R) is a class A G protein-coupled receptor (GPCR), essential for regulation of appetite and metabolism. Pathogenic inactivating MC4R mutations are the most frequent cause of monogenic obesity, a growing medical and socioeconomic problem worldwide. The MC4R mediates either ligand-independent or ligand-dependent signaling. Agonists such as α-melanocyte-stimulating hormone (α-MSH) induce anorexigenic effects, in contrast to the endogenous inverse agonist agouti-related peptide (AgRP), which causes orexigenic effects by suppressing high basal signaling activity. Agonist action triggers the binding of different subtypes of G proteins and arrestins, leading to concomitant induction of diverse intracellular signaling cascades. An increasing number of experimental studies have unraveled molecular properties and mechanisms of MC4R signal transduction related to physiological and pathophysiological aspects. In addition, the MC4R crystal structure was recently determined at 2.75 Å resolution in an inactive state bound with a peptide antagonist. Underpinned by structural homology models of MC4R complexes simulating a presumably active-state conformation compared to the structure of the inactive state, we here briefly summarize the current understanding and key players involved in the MC4R switching process between different activity states. Finally, these perspectives highlight the complexity and plasticity in MC4R signaling regulation and identify gaps in our current knowledge. Full article

(This article belongs to the Special Issue Neuropeptides in Food Intake Regulation)

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