GPR10 gene deletion in mice increases basal neuronal activity, disturbs insulin sensitivity and alters lipid homeostasis

Pražienková, Veronika; Funda, Jiří; Pirník, Zdeno; Karnošová, Alena; Hrubá, Lucie; Kořínková, Lucia; Neprašová, Barbora; Janovská, Petra; Benzce, Michal; Kadlecová, Michaela; Blahoš, Jaroslav; Kopecký, Jan; Železná, Blanka; Kuneš, Jaroslav; Bardová, Kristina; Maletı́nská, Lenka

doi:10.1016/j.gene.2021.145427

Cited by 16 publications

(15 citation statements)

References 45 publications

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“…Meanwhile, as the receptor in the PrRP-GPR10 system, GPR10 mRNA is expressed in the rat adrenal medulla, epididymis, and testis [ 35 ]. Given that the pons and hypothalamus are both key parts of controlling food intake and energy metabolism [ 36 ], the above data shows that PrRP-GPR10 should play a key role in neuroendocrine metabolism and may even be a potential target for anti-obesity therapy [ 29 , 37 , 38 ].…”

Section: Discussionmentioning

confidence: 99%

“…These data suggest that GPR10 is involved in energy metabolism and food intake [ 8 , 40 ]. Very recently, the Lenka Maletínská team find that GPR10 gene deletion in C57BL/6J mice causes significant metabolic disturbances, as GPR10 KO mice demonstrate enhanced basal neuronal activity, disturbed lipid homeostasis, and altered insulin sensitivity [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

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Prolactin-Releasing Peptide Differentially Regulates Gene Transcriptomic Profiles in Mouse Bone Marrow-Derived Macrophages

Sun

Zuo

Kuang

2021

IJMS

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Prolactin-releasing Peptide (PrRP) is a neuropeptide whose receptor is GPR10. Recently, the regulatory role of PrRP in the neuroendocrine field has attracted increasing attention. However, the influence of PrRP on macrophages, the critical housekeeper in the neuroendocrine field, has not yet been fully elucidated. Here, we investigated the effect of PrRP on the transcriptome of mouse bone marrow-derived macrophages (BMDMs) with RNA sequencing, bioinformatics, and molecular simulation. BMDMs were exposed to PrRP (18 h) and were subjected to RNA sequencing. Differentially expressed genes (DEGs) were acquired, followed by GO, KEGG, and PPI analysis. Eight qPCR-validated DEGs were chosen as hub genes. Next, the three-dimensional structures of the proteins encoded by these hub genes were modeled by Rosetta and Modeller, followed by molecular dynamics simulation by the Gromacs program. Finally, the binding modes between PrRP and hub proteins were investigated with the Rosetta program. PrRP showed no noticeable effect on the morphology of macrophages. A total of 410 DEGs were acquired, and PrRP regulated multiple BMDM-mediated functional pathways. Besides, the possible docking modes between PrRP and hub proteins were investigated. Moreover, GPR10 was expressed on the cell membrane of BMDMs, which increased after PrRP exposure. Collectively, PrRP significantly changed the transcriptome profile of BMDMs, implying that PrRP may be involved in various physiological activities mastered by macrophages.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Prolactin-Releasing Peptide Differentially Regulates Gene Transcriptomic Profiles in Mouse Bone Marrow-Derived Macrophages

Sun

Zuo

Kuang

2021

IJMS

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“…An exogenously influenced CCK system was also shown to be involved in the central anorexigenic effect of peripherally applied palm-PrRP (Pirnik et al, 2021). We can thus hypothesize that peripheral signals (leptin, CCK) and the central neuropeptide PrRP cooperate in the stimulation of food intake-regulating pathways, leading to a decrease in food intake.…”

Section: Introductionmentioning

confidence: 94%

“…Our work further supports several indirect studies confirming that the food intake-lowering effect of these analogs is mainly central. There was a significant and dosedependent decrease in food intake in lean overnight-fasted or freely fed mice after subcutaneous (SC) injection of palm-PrRP31, myr-PrRP20 (Maletínská et al, 2015) or palm 11 -PrRP31 (Pražienková et al, 2017;Pirnik et al, 2021), while analogs lipidized with shorter carbon chains or natural PrRP20 or PrRP31 had no effect on food intake (Maletínská et al, 2015). Moreover, neuronal activity (manifested by increased expression of the immediate early gene c-Fos in brain areas related to food intake regulation) was significantly increased in specific brain nuclei or in areas such as the Arc, PVN, DMN and NTS 90 min after SC application of myr-PrRP20, palm-PrRP31 and palm 11 -PrRP31 but not after natural PrRP31 or octanoyl-PrRP31 administration (Maletínská et al, 2015;Pražienková et al, 2017;Pirník et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Lipidized Prolactin-Releasing Peptide as a New Potential Tool to Treat Obesity and Type 2 Diabetes Mellitus: Preclinical Studies in Rodent Models

et al. 2021

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Obesity and type 2 diabetes mellitus (T2DM) are preconditions for the development of metabolic syndrome, which is reaching pandemic levels worldwide, but there are still only a few anti-obesity drugs available. One of the promising tools for the treatment of obesity and related metabolic complications is anorexigenic peptides, such as prolactin-releasing peptide (PrRP). PrRP is a centrally acting neuropeptide involved in food intake and body weight (BW) regulation. In its natural form, it has limitations for peripheral administration; thus, we designed analogs of PrRP lipidized at the N-terminal region that showed high binding affinities, increased stability and central anorexigenic effects after peripheral administration. In this review, we summarize the preclinical results of our chronic studies on the pharmacological role of the two most potent palmitoylated PrRP31 analogs in various mouse and rat models of obesity, glucose intolerance, and insulin resistance. We used mice and rats with diet-induced obesity fed a high-fat diet, which is considered to simulate the most common form of human obesity, or rodent models with leptin deficiency or disrupted leptin signaling in which long-term food intake regulation by leptin is distorted. The rodent models described in this review are models of metabolic syndrome with different severities, such as obesity or morbid obesity, prediabetes or diabetes and hypertension. We found that the effects of palmitoylated PrRP31 on food intake and BW but not on glucose intolerance require intact leptin signaling. Thus, palmitoylated PrRP31 analogs have potential as therapeutics for obesity and related metabolic complications.

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“…However, soon after this finding, Lawrence et al showed a reduction in food intake and body weight and an increase in energy expenditure after intracerebroventricular (ICV) PrRP injection in rats and questioned the role of PrRP in prolactin secretion [3,4]. The effects of PrRP, mostly mediated through the GPR10 receptor, which is widely expressed throughout the brain mainly in areas related to the regulation of food intake and energy homeostasis, confirm GPR10 knockout (KO) mouse studies showing an increase in body weight in KO mice [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

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

Karnošová

Strnadová

Holá

et al. 2021

IJMS

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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.

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GPR10 gene deletion in mice increases basal neuronal activity, disturbs insulin sensitivity and alters lipid homeostasis

Cited by 16 publications

References 45 publications

Prolactin-Releasing Peptide Differentially Regulates Gene Transcriptomic Profiles in Mouse Bone Marrow-Derived Macrophages

Prolactin-Releasing Peptide Differentially Regulates Gene Transcriptomic Profiles in Mouse Bone Marrow-Derived Macrophages

Lipidized Prolactin-Releasing Peptide as a New Potential Tool to Treat Obesity and Type 2 Diabetes Mellitus: Preclinical Studies in Rodent Models

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

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