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Table of Contents
Year : 2019  |  Volume : 62  |  Issue : 2  |  Page : 47-52

Neuropeptide FF modulates neuroendocrine and energy homeostasis through hypothalamic signaling

1 Department of Physiology and Pharmacology, Graduate Institute of Biomedical Sciences, School of Medicine; Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan
2 Department of Physiology and Pharmacology, Graduate Institute of Biomedical Sciences, School of Medicine; Healthy Aging Research Center, Chang Gung University; Neuroscience Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan

Date of Submission07-Dec-2018
Date of Acceptance26-Feb-2019
Date of Web Publication25-Apr-2019

Correspondence Address:
Dr. Jin-Chung Chen
259 Wenhua 1st Road, Guishan Dist., Taoyuan 33302
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/CJP.CJP_23_19

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Neuropeptide FF (NPFF) is known as a morphine-modulating peptide and was first isolated in 1985. It has been characterized as an RF-amide peptide. The traditional role of NPFF is mediation of the pain response, and it displays both anti-opioid and pro-opioid actions through central nervous system. In the recent decade, additional evidence has revealed some untraditional features of NPFF, such as regulation of the neuroendocrine system, energy homeostasis, anti-inflammation, pain transmission, and peripheral modulation of adipose tissue macrophages. Neuropeptide FF receptor 2 (NPFFR2) is a physiological receptor of NPFF, and the actions of NPFF may occur through downstream NPFFR2 signaling. NPFF and NPFFR2 increase the neuronal activity in various areas of the hypothalamus to modulate the hypothalamic–pituitary–adrenal axis, the autonomic nervous system, food intake, and energy balance. These underlying cellular mechanisms have been explored in the past few years. Here, we review the impact of NPFF and related RF-amide peptides on hypothalamic function. The interaction of NPFF with NPFFR2 in the hypothalamus is emphasized, and NPFF-NPFFR2 system may represent an important therapeutic target in hypothalamic-related disorders in the future.

Keywords: Anxiety, depression, energy homeostasis, food intake, hypothalamic–pituitary–adrenal axis, hypothalamus, neuroendocrine, neuropeptide FF, neuropeptide FF receptor 2, obesity, paraventricular nucleus, thermogenesis

How to cite this article:
Lin YT, Chen JC. Neuropeptide FF modulates neuroendocrine and energy homeostasis through hypothalamic signaling. Chin J Physiol 2019;62:47-52

How to cite this URL:
Lin YT, Chen JC. Neuropeptide FF modulates neuroendocrine and energy homeostasis through hypothalamic signaling. Chin J Physiol [serial online] 2019 [cited 2023 Nov 30];62:47-52. Available from: https://www.cjphysiology.org/text.asp?2019/62/2/47/257181

  Introduction Top

The Phe-Met-Arg-Phe-NH2 (FMRF-amide) peptide is characterized as a cardioexcitatory peptide and has been originally isolated from the ganglia of Macrocallista nimbosa in 1977.[1] Two of the FMRF-amide-like peptides have been identified by cross-reaction with FMRF-amide antiserum from the bovine central nervous system (CNS). Their sequences are Ala-Gly-Glu-Gly-Leu-Ser-Ser-Pro-Phe-Trp-Ser-Leu-Ala-Ala-Pro-Gln-Arg-Phe-NH2 (neuropeptide AF [NPAF]) and Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2 (neuropeptide FF [NPFF]).[2] NPFF and NPAF are known as mammalian RF-amide peptides. RMFR-amide peptides are identified as pain modulation peptides and show anti-opioid profiles.[3] Intraventricular (ICV) injection of NPFF (5 μg) and NPAF (20 μg) increases the pain response in rats. NPFF further reverses the analgesic effect of morphine.[2] NPFF and NPAF are encoded by a common precursor and are expressed as a splicing mRNA, which is also characterized as the gene for proNPFFA-related peptides.[4],[5] ProNPFFB-related peptides are encoded by a distinct gene, which generates RF-amide-related peptide-1 (RFRP-1, also known as NPSF) and RFRP-3 (also known as NPVF).[6]

NPFF is referred to as an F8F-amide or morphine-modulating peptide. It plays a role in multiple neural and pathological functions, such as pain sensation, morphine tolerance, feeding behavior, and acts in the cardiovascular system.[3],[7],[8] However, different functions of NPFF have been reported including involvement in the inflammatory pathway and the neuroendocrine system, and it modulates stress-induced analgesia, pain transmission, and the peripheral activation of M2 macrophages.[9],[10],[11],[12],[13]

NPFF is abundant in the hypothalamic area. There is growing evidence supporting the modulatory role of the NPFF and NPFF receptor systems in the hypothalamus to maintain physiological homeostasis.[8] The atypical function of NPFF may be beneficial in developing a therapeutic strategy for stress-related disorders and obesity. This review focuses on the characterization of NPFF and its receptor type 2 (NPFFR2) for their involvement in the neuroendocrine regulation, energy homeostasis and the cardiovascular system.

Neuropeptide FF receptors and downstream signaling

Neuropeptide FF receptors

Two receptors of NPFF have been cloned, the NPFF receptor type 1 (NPFFR1, also known as GPR147 and OT7T022) and the NPFF receptor type 2 (NPFFR2, also known as GPR74 and HLWAR77).[6],[14],[15] Both are seven transmembrane G-protein-coupled receptors that are coupled to Gi/o proteins.[3] The stimulation of NPFF receptors inhibits the activity of adenylyl cyclase on membranes and reduces cyclic AMP production. ProNPFFA-related peptides can bind to either receptor but show higher affinity toward NPFFR2 than NPFFR1.[16] ProNPFFB-related peptides display higher affinity toward NPFFR1 and show poor agonist activity to NPFFR2.[16],[17] In this context, NPFFR2 is considered to be the physiological receptor for NPFF, and NPFFR1 is the physiological receptor for NPVF.[3]

Downstream signaling of neuropeptide FF-neuropeptide FF receptor 2

NPFF mediates the action of opiates which includes analgesia, tolerance, dependence, locomotor activity, food intake, and opioid-dependent reward.[18] However, NPFF and other FMRP-amide-related peptides show no binding affinity to mu, delta, and kappa opiate receptors.[19] The signaling regulation of NPFF on mu opioid receptor (MOR) is largely reported. An analogue of NPFF reverses the MOR-inhibited calcium conductance in cultured rat spinal ganglion neurons.[20] NPFFR2 forms a heteromeric receptor complex with MOR. The activation of NPFFR2 induces heterologous desensitization of MOR through the G protein receptor kinase, i.e. GRK2, and this receptor complex is transphosphorylated in SH-SY5Y cells.[21] Different phosphorylation sites of NPFFR2 have been identified in SH-SY5Y cell lines, including412 TNST415 s,372 TS373, and Ser395.[22] NPFFR2 activates MAP kinase 1/2 and NF kappa B signaling pathways in SH-SY5Y cell lines.[22],[23]

The mammalian RF-amide peptide superfamily

Five groups of the RF-amide peptide family that share an Arg-Phe-NH2 sequence include NPFF, prolactin-releasing peptide (PrRP), RFRP, kisspeptin, and pyroglutamylated RFamide peptide.[24] The corresponding peptides in the different subgroups are NPFF and NPAF for the NPFF group, PrRP-20 and PrRP-31 for the PrRP group, RFRP-1 (NPSF) and RFRP-3 (NPVF) for the RFRP group, kisspeptin and metastin for the kisspeptins group, and 43RFa and 26RFa for the QRPF group.[24],[25] NPFF, NPAF, and NPVF share the N-terminal sequence homology (PQRF) and contain a different number of amino acids. The sequences of mammalian RF-amide and the corresponding receptors in humans, rats, and mice are documented by Ayachi and Simonin.[26] These RF-amide peptides are involved in the modulation of nociception[26] and hypothalamic function, including energy homeostasis, reproduction, food intake, and the stress response.[8],[24]

Although GRP10 is the endogenous receptor for PrRP, PrRP shows high-binding affinity toward NPFFR2.[8],[27] NPFF and RFRP bind to both NPFFR1 and NPFFR2, but RFRP binds to NPFFR1 with higher binding affinity than NPFFR2, while NPFF binds to NPFFR2 with higher binding affinity than NPFFR1.[25] Most endogenous mammalian RF-amide peptides modulate nociception and morphine analgesia. These peptides all bind with human NPFF receptors (Ki between 0.2 and 84 nM for NPFFR1; Ki between 0.1 and 131 nM for NPFFR2).[28] For this reason, it is difficult to distinguish the effects between ligands and receptors, particularly because of lack of selective agonists or antagonists.

The distribution of neuropeptide FF-neuropeptide FF receptor 2 in the nervous system

NPFF and its receptors are ubiquitously expressed in the CNS with prevalence in the spinal cord, posterior pituitary, and hypothalamus, of which NPFFR2 is more dominant in the CNS than NPFFR1.[29],[30],[31],[32] There are high levels of NPFF and NPFFR2 expression in the superficial laminae of the dorsal spinal cord in most mammals.[30],[33] Among the receptors of the RF-amide peptides, only NPFFR2 is expressed in the spinal cord.[25] This indicates that most of the RF-amide peptides mediate the pain response, but actin in spinal cord is only through the interaction of NPFFR2 and not other endogenous receptors.[26],[28],[34] NPFF and NPFFR2 are also expressed in the dorsal root ganglia (DRG).[35],[36] NPFFR2 is synthesized in the DRG and translocates to the nerve terminals of primary sensory neurons in the spinal dorsal horn.[36]

NPFF and NPFFR2 immunoreactivities have been detected in different areas of the hypothalamus, including the paraventricular nucleus (PVN), the perifornical nucleus (PFA), the posterior hypothalamic area, ventromedial hypothalamic nucleus and dorsomedial hypothalamic nucleus (VMH and DMH), the arcuate nucleus (ARC), and the lateral hypothalamic area (LHA) of human and rodents.[29],[37] These brain areas are involved in the central control of energy homeostasis, neuroendocrine regulation, and the stress response.

The modulation of neuropeptide FF on the hypothalamic–pituitary–adrenal axis

The action of the neuropeptide FF-neuropeptide FF receptor system in the hypothalamus

The hypothalamic–pituitary–adrenal (HPA) axis is viewed as key neural circuitry in maintaining homeostasis and adaptive reactions in response to stress status. Within the hypothalamic nuclei, PVN, which contains magnocellular and parvocellular subdivisions, is the primary regulator of the HPA axis and mediates physiological responses when individuals face environmental or homeostatic challenges.[38],[39] The magnocellular PVN contains neurosecretory cells which synthesize and secrete vasopressin or oxytocin into posterior pituitary.[40] Parvocellular PVN consists of both neurosecretory and non-neurosecretory cells. The neurosecretory cells synthesize and secrete corticotropin-releasing factor (CRF) into the anterior pituitary to regulate the secretion of adrenocorticotrophic hormone (ACTH). ACTH is further released into the circulation and triggers the secretion of cortisol (corticosteroid [CORT] in rodents) from the adrenal cortex. The parvocellular non-neurosecretory neurons are known as autonomic neurons, whose axons project into the brain stem and spinal cord.[39],[41] The HPA axis can be modulated by the hippocampus (inhibition) and the amygdala (excitation) through the action of γ-aminobutyric acid (GABA) originating in the bed nucleus of the stria terminals to parvocellular PVN.[39],[42] The HPA axis not only controls the stress response but also regulates metabolism, food intake, and function of the immune, cardiovascular, and reproductive systems.[39],[43]

NPFF is an important neuromodulator that controls the neuroendocrine and autonomic stress systems. Central injection (ICV) of NPFF causes the activation of PVN neurons, which are mainly located in the parvocellular compartments, including VMH, DMH, and the dorsal subdivisions.[44] The CRF is predominantly expressed in the DMH neurons and regulates the downstream HPA axis. Both NPFF and NPVF activate the PVN parvocellular neurons through disinhibiting the GABA-ergic (GABAergic) terminals in PVN. The NPFF-induced reduction of inhibitory postsynaptic currents is further inhibited by the nonselective NPFF receptor antagonist RF9.[45] PrRP also disinhibits GABA signaling and activates the CRF-containing neurons in the parvocellular PVN. Due to the high-binding affinity of PrRP toward NPFFR2, the effect may be mediated through NPFFR2.[27],[46],[47] On the other hand, central administration of NPFF inhibits the release of vasopressin, a peptide hormone secreted from the magnocellular subdivision of PVN.[48] This effect is most likely mediated by NPFF-augmented GABAergic neurotransmission in the magnocellular neurons.[49]

Central administration of the NPFFR2-specific agonist (dNPA or AC-263093) increases the neural activity of hypothalamic PVN and the amount of circulating CORT. These actions can be counteracted by either NPFF or CRF antagonists.[11] The NPFFR1 agonist, i.e. RFRP-3 stimulates the release of CORT through the activation of PVN CRF-expressing neurons.[50] Other RF-amide peptides activate the HPA axis and increase the circulation of CORT, including PrRP, NPSF, NPAF, and kisspeptin-13.[51],[52],[53],[54] Distinguishing the action of these receptors is difficult because all of these peptides show binding affinity to NPFFR1 and NPFFR2.[28]

Effect of neuropeptide FF on hypothalamic-dependent behaviors

The HPA axis serves as a stress response pathway in dealing with environmental challenges. Hyperactivity of the HPA axis triggers behavioral changes, including depressive- and anxiety-like behaviors. The chronic stress increases the risk of mood disorders through disruption of neuroplasticity at the structural and functional level.[55] The biochemical changes include the impairment of hippocampal-negative feedback, high circulating CORT, downregulation of glucocorticoid receptor, and reduced neurogenesis.[56],[57],[58] NPFF regulates the stress response, i.e. activation of the HPA axis and consequent behavioral changes.[10] Central administration of the NPFF antagonist, dansyl-PQR-amide, or RF9 restores ethanol or amphetamine withdrawal-induced anxiety behavior.[59],[60] NPFF-related RF-amide neuropeptides induce anxiety behavior through the stimulation of the HPA axis.[50],[51],[52],[53] Chronic stimulation of NPFFR2 signaling by systemic injection of the NPFFR2 agonist or in NPFFR2 overexpressed transgenic mice induces depressive- and anxiety-like behaviors.[10] These mice display depressive-like behavior, hyperactivity of the HPA axis, impairment of hippocampal negative feedback and neurogenesis, of which similar to chronic mild stress-induced phenotypes. The depressive-like behavior is ameliorated by bilateral intra-PVN injection of NPFFR2-shRNA.[10] Impact of RF-amide peptides in the hypothalamus on HPA axis activity and animal behavior is summarized in [Table 1]. The findings pinpoint the importance of NPFFR2 on the HPA axis and the stress response through upstream PVN.
Table 1: Summary of the impacts of RF-amide peptides on the hypothalamic–pituitary–adrenal axis

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Of importance, NPFF regulates the cardiovascular system through its cellular effects on PVN neurons.[46],[48] The NPFF immunopositive cells of the hypothalamus are increased in hypertensive patients compared to healthy controls.[61] These events may be mediated through the autonomic nervous system and the neuroendocrine system.

Food consumption and energy homeostasis

The hypothalamus serves as an important brain area in regulating food intake and energy homeostasis, including ARC, PVN, VMH, DMH, LHA, and PFA, of which, all contain NPFF and NPFFR2 proteins.

Various hormones, transmitters, and peptides function in the modulation of appetite. These include noradrenaline, serotonin, dopamine, neuropeptide Y (NPY), pro-opiomelanocortin and its posttranslational product, α-melanocyte-stimulating hormone, agouti-related protein, cocaine- and amphetamine-regulated transcript, insulin, leptin, ghrelin, and cholecystokinin (CCK).[62],[63],[64] The hypothalamus receives the peripheral adiposity and satiety signals such as insulin, leptin, ghrelin, and CCK to stimulate the catabolic or anabolic pathways and further responds to signals from the nucleus of the solitary tract (NTS) to maintain energy balance.[65]

Neuropeptide FF and food consumption

NPFF regulates food consumption through modulation of hypothalamic function. The ICV injection of NPFF reduces food intake with no influence on water consumption in chicks. The NPFF-treated chicks show higher hypothalamic activity in PVN, DMH, and VMH as identified by c-ios expression.[66] Similar result was reported that ICV injection of NPFF reduces food intake but also causes a large increase of water consumption in rats.[67] These findings suggest that NPFF exhibits a direct action on hypothalamic neurons to modulate feeding behavior. NPFF has numerous interactions with the central opioid system, including the modulation of food intake. NPFF modulates feeding behavior through pro- and anti-opioid actions in the parabrachial nucleus (PBN), which receives NPFF projections from the NTS.[68] PBN infusion of NPFF increases food intake in rats and this effect is further inhibited by co-injection with the MOR antagonist, i.e., naloxone. Pretreatment of NPFF in PBN diminishes DAMGO (a μ-opioid agonist)-induced food intake.[68]

Neuropeptide FF receptor 2 signaling and energy homeostasis

The NPFF-NPFFR2 system participates in the modulation of energy metabolism. NPFF exhibits metabolic benefit in mice through NPFFR2 signaling. Mice chronically treated with NPFF exhibit lower blood glucose, increased glucose metabolism, and higher sensitivity to insulin.[12] The treatment of NPFF in mice on a high-fat diet (HFD) provokes the M2 activation of adipose tissue macrophages, which supports the health of adipocytes.[12] NPFFR2 signaling also mediates diet-induced thermogenesis. HFD-fed NPFFR2 knockout mice exhibit an impaired thermogenic response of brown adipose tissue, which results in obesity when compared to control mice.[69] ARC NPFFR2 signaling is required for the expression of NPY, which has an important role in directing energy homeostasis from the central to the peripheral systems.

RF-amide peptides on feeding and energy metabolism

RF-amide peptides, in addition to NPFF, have a role in feeding behavior and energy homeostasis.[7] ICV injection of PrRP inhibits food intake in fasting rats and rats with free access to food, which is mediated through central satiating actions of CCK.[70],[71] Leptin receptors in PrRP-containing DMN neurons are required for the thermogenic response of PrRP to leptin. PrRP knockout mice exhibit the obese phenotype with a reduced response to leptin and CCK.[72] Kisspeptin also reduces energy metabolism and impairs glucose tolerance.[73] Since PrRP and kisspeptin can bind to NPFFR2,[27],[28] it is likely that their influence on energy homeostasis is through NPFFR2 signaling. These overall findings support the role of NPFF and NPFFR2 signaling on energy metabolism that is controlled in the hypothalamus, and the action is manifested peripherally.

  Conclusion Top

NPFF mediates the pain response by interaction with the NPFFR2. NPFF and its related RF-amide peptides in their interactions with NPFFR2 can also increase the neuronal activity of various areas of the hypothalamus to modulate the HPA axis, the autonomic nervous system, food intake, and energy homeostasis. The underlying cellular mechanisms of these actions can now be explored because of the recent development of genomic and pharmacological tools. NPFFR2 signaling in part of the stress-modulation pathway induces depressive- and anxiety-like behaviors. NPFFR2 also regulates the energy homeostasis cascade to increase brown adipose tissue-mediated thermogenesis. This leads to benefiting body health and reduces the obese phenotypes. NPFFR2 signaling might be a potential therapeutic target of stress- and obese-related disorders. Specific NPFF receptor agonists and antagonists have not been identified. Once this has occurred, it will lead to a better understanding of the function and signaling of the RF-amide peptides on specific receptors.


We thank Prof. Arnold Stern for providing English editing.

Financial support and sponsorship

This work was supported by the Chang Gung Memorial Hospital (CMRPD1H0431) and Healthy Aging Research Center, Chang Gung University (EMRPD1H0551).

Conflicts of interest

There are no conflicts of interest.

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