Introduction

Regulation of food intake and body weight due to the ability of the brain, especially the hypothalamus to integrate endocrine, behavioural, and autonomic functions via afferent and efferent pathways from brainstem and peripheral organs done (Elmquist et al. 2005; Jalali et al. 2019). It has been shown that the hypothalamus is the brain’s main area in controlling food intake. The peripheral and central signals are integrated together in the hypothalamus, and they regulate the level of central neuropeptides for managing energy expenditure and food intake (Wynne et al. 2005; Denbow and Cline 2014). Various studies have been shown that, ventromedial hypothalamus (VMH) is an anorexigenic center and lateral hypothalamus area (LHA) is an orexigenic center (Sohn 2015).

The hypothalamus control of food intake via special nuclei such as: arcuate nucleus (ARC), paraventricular nucleus (PVN), dorsomedial hypothalamus (DMH), VMH, and LHA (Fig. 1) (Wynne et al. 2005). ARC is a hypothalamic nucleus involved in controlling food intake. It is located in the vicinity of the third ventricle of the brain. This nucleus receives appetite-related signals from the peripheral circulation system (through the incomplete blood–brain-barrier) and other areas of the brain, such as nucleus of tract solitary (NTS). The ARC integrates these signals, and transmitted them as neural projections such as NPY, AgRP, melanocortin, and etc. to the second order neurons. The second order neurons are PVN, VMH, DMH, and LHA (Fig. 2). These projections and other information from the brain stem and cortex integrated in second order neurons (especially in the PVN), and via changes in other neuroendocrine systems, effect on energy homeostasis (Fekete et al. 2000; Jensen 2001; Wynne et al. 2005; Hamidi and Yousefvand 2017).

Fig. 1
figure 1

Different hypothalamic nuclei involved in controlling food intake. ARC arcuate nucleus, AM amygdala, CC corpus callosum, CCX cerebral cortex, DMN dorsomedial nucleus, FX fornix, HI hippocampus, LHA lateral hypothalamic area, ME medi-an eminence, OC optic chiasm, PFA perifornical area, PVN paraventricular nucleus, SE septum, 3 V third ventricle, TH thalamus, VMN ventromedial nucleus (Yu and Kim 2012)

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Fig. 2
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NPY projections in arcuate nucleus to second order neurons. 3rd third ventricle of the brain, ARC arcuate nucleus, PVN paraventricular nucleus, DMH dorsomedial hypothalamus, LH lateral hypothalamus, VMH ventromedial hypothalamus, NPY/AgRP neuropeptide Y/agouti-related protein, POMC pro-opiomelanocortin, Y1 NPY1 receptor, Y2 NPY2 receptor, Y5 NPY5 receptor (Joost 2012)

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PVN, the main place of the hypothalamus to send the multiple outputs to control of food intake, and it is located in the dorso rostral hypothalamus, and adjust to the third brain ventricular (Cone 2005; Ferguson et al. 2008; Sohn 2015). PVN is an anorexigenic center. Indeed, researchers have shown that the damage to this nucleus causes overeating and obesity in rodents (Duplan et al. 2009). This nucleus receives the series of axons from the subcortical regions of the areas involved in motor behaviour including hypothalamus, hippocampus, amygdala, locus coeruleus, periaqueductal gravy matter and the raphe nucleus (Van der werf et al. 2002). As well, receive various inputs (such as insulin, leptin, and etc.) from other parts of the hypothalamus, and through this effect on food intake (Sutton et al. 2016). Therefore, PVN is a key area in the control of appetite. Projections from NPY-containing neurons in the ARC, are sent to the PVN, and through these regulate energy intake via other pathways such as Thyrotropin- releasing hormone (TRH) secretion (Nillni 2010). In addition, PVN is involved in the regulation of osmotic balance and water intake regulation. Numerous neurotransmitters effects water intake through this nucleus (De Arruda et al. 2003; De Souza Villa et al. 2008; Karasawa et al. 2014).

Considering the importance of PVN as a place for integrate multiple inputs to the hypothalamus and exporting appropriate hypothalamic outputs for central regulation of feeding behaviours, this study examined the role of PVN in the central regulation of nutritional behaviours.

Therefore, this paper will discusses about the non-specific receptors involved in PVN function in food intake, the signalling process related to central control of food intake, and finally the role of this nucleus in central control of feeding behaviours.

Study Methodology

In this overview, various valid papers from electronic sources used, which in them the role of paraventricular nucleus in regulation of feeding behaviours investigated. Authentic articles indexed in the Web of Science, Scopus, PubMed, SID, Google scholar, and ISI databases by using of Key words: Central regulation of food intake, Hypothalamus, Paraventricular nucleus, Brain ventriculars, Brain neurotransmitters, and Feeding behaviours studied (Fig. 3). The review articles entered in this study are presented in Table 1.

Fig. 3
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The flowchart of stages to import recourses into review article

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Table 1 The Review articles entered in this study
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The Role OF Some Non-specific Receptors on PVN in Central Regulation of Food Intake

Central regulation of food intake is carried out in different nuclei of the hypothalamus by multiple inputs from various regions of the brain. Among the different nuclei of the hypothalamus, PVN plays a critical role in receiving and integrating these inputs. These inputs apply their effects on PVN through their specific and non-specific receptors located on the PVN (Lenard and Berthoud 2008; Sorrentino and Ragozzino 2017). Therefore, the receptors located on PVN play the important roles in the function of this nucleus in central regulation of food intake. Then, briefly discuss the roles of some of non-specific receptors.

  1. 1.1.

    Neuropeptide Y (NPY) receptors: NPY receptors are important receptors in the central regulation of food intake. These receptors are distributed throughout the central nervous system (CNS). Among the NPY receptors involved in central food intake regulation (NPY1, NPY2, and NPY5), NPY1 and NPY5 receptors are located in the PVN. NPY receptors are G-protein coupled receptors. By attaching the ligand to these receptors, the output of PVN is a central increase in food intake. In fact, these receptors are orexigenic receptors (Henry et al. 2005; Yousefvand et al. 2018a, b, 2019).

  2. 1.2.

    Melanocortin (MC) receptors: Hypothalamic melanocortin system consists of pro-opiomelanocortin (POMC), and central melanocortin receptors include: MCR3 and MCR4. These two receptors are important mediator of the effects of melanocortin ligands such as: alpha-melanocyte-stimulating hormone (α-MSH) and agouti related protein (AGRP) on nutritional behaviour and energy balance. In birds, only MC4R plays an important role in controlling energy balance (Strader et al. 2003; Lee et al. 2008). These receptors are located on PVN, and by their activation, reduce food intake and increase energy consumption. So these receptors are anorexigenic receptors, which located in the PVN (Kim et al. 2014).

  3. 1.3.

    α2-adrenoceptors: α2-adrenoreceptors are involved in the central control of food intake, and from the G-protein coupled receptors family. These receptors are located on the PVN. α2-adrenoreceptors mediated the hyperphagic effects of noradrenaline, and other α2-adrenoreceptors mimics. Activation of these receptors leads to exit of orexigenic messages from PVN (Taksande et al. 2011). Therefore, these receptors are orexigenic receptors.

Signalling Mechanisms in the Paraventricular Nucleus

The signalling pathway of the neurotransmitters related to regulation of food intake in the PVN maybe is AMP-activated protein kinase (AMPK) signal. This signal is a heterodimer which including catalytic and regulatory subunits. Some factors such as leptin, insulin and MC3/MC4 agonist inhibits 2AMPK activity in the ARC nucleus and PVN, while another factors such as AgRP, stimulate 2AMPK. Indicated that, increasing in AMPK level in the PVN leads to accretion food intake. Activity of 2AMPK perhaps controlled with MC4R (Andersson et al. 2004). PVN with integration of multiple signals, initiates changes in other neuroendocrine systems.

Thyrotropin releasing hormone neurons (TRHN) in the PVN are innervated with NPY/AgRP and melanocortin projections from the ARC. NPY via inhibiting of phosphorylation of cAMP response element binding Protein (CREB), has an inhibitory effect on gene expression of pro-thyrotropin-releasing hormone (pro-TRH) in PVN (Fig. 4), while MSH projections apply motivatory effcet on gene expression of pro-TRH (Fekete et al. 2000). In fact MSH via increased phosphorylation of CREB, has a stimulatory effect on gene expression of pro-TRH. Therefore, there is an interaction between NPY and MSH neurons in regulating gene expression of pro-TRH in PVN. Projections of NPY to the PVN operate on corticotrophin releasing hormone-expressing neurons which effect on energy homeostasis (Sarkar and Lechan 2003).

Fig. 4
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The key appetite signal which integration in the special nuclei of the hypothalamus. ARC arcuate nucleus, PVN paraventricular nucleus, LHA lateral hypothalamus area, POMC pro-opiomelanocortin, CART Cocaine and amphetamine-regulated transcript, Y2R NPY2 receptor, GHSR growth hormone secretagogues receptor, LepR Leptin receptor, InsR Insulin receptor, ORX orexin receptor, TRH Thyrotropin-releasing hormone, CRH Corticotropin-releasing hormone, MCH Melanin-concentrating hormone (Schellekens et al. 2012)

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The Role of Paraventricular Nucleus in Regulation of Feeding Behaviour

Many factors in the CNS are affected in regulating food intake in mammals and birds. In these species central regulation of food intake is complicated and impressed by many neurotransmitters (Richards et al. 2007; Hussain and Bloom 2013; Zendehdel et al. 2013a, c); although there are differences between these two species in regulation of feeding behaviour (Zendehdel and Hassanpour 2014). Mostly, feeding control neurons are located in the hypothalamus. It’s obvious that, the hypothalamus plays the major role in central regulation of food intake (Jensen 2001). Among the hypothalamus nuclei, PVN is very sensitive to injection of various neurohormones or neurotransmitters involved in feeding behaviour (Lawrence et al. 2002; Wynne et al. 2005). To identify neural pathways and the role of neurotransmitters on central control of food intake, various studies have been conducted on the laboratory animals (Table 2). These studies performed on regulation of food intake by direct injection into the nucleus, intracerebroventricular (ICV) injection, and injection to the third ventricular of the brain (Hamidi and Yousefvand 2017; Zendehdel et al. 2013b, 2015). Water intake and energy balance are important topics in physiology. Water is a critical component for living organisms and plays an important role in metabolic processes and temperature regulation (Biranvand et al. 2014; Yousefvand et al. 2017). In central control of water intake and osmotic pressure, different brain areas such as PVN are involved. Several studies in this field confirm the role of PVN in regulating water intake (Silverstein and Plisetskaya 2000; Hajdu et al. 2000; Hashimoto et al. 2007; Mietlicki et al. 2009; Karasawa et al. 2014b). The current review study was designed to summarize various studies performed on the PVN. The following is an explanation of the effect of some important neurotransmitters, which very effective in the processes involved in regulation of food intake, and numerous studies have been done them (Table 2) on central regulation of feeding behaviour and their mechanism of action in the PVN. However, in some cases the contradictory effects of these neurotransmitters in central control of food intake have been reported.

Table 2 Various studies conducted on feeding behaviour in PVN
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Leptin is the most important mediators involved in controlling energy homeostasis. This mediator acts on central control of energy expenditure through arcuate nucleus-paraventricular nucleus axis (Ahima et al. 2000). Leptin directly controls the circuits involved in controlling energy balance which from the arcuate nucleus to the paraventricular nucleus. This Probabilistic control is done via MC4R receptor and in three ways: (1) direct postsynaptic modulation by leptin. (2) Regulation of MC4R mRNA expression and α-MSH responsiveness by leptin. (3) Regulation by the constitutive activity of the MC4R signalling (Ghamari-Langroudi and Cone 2011).

Insulin as a hormone secreted from pancreas and controls blood sugar, and it is an important adiposetic signal to the brain. Insulin synthesized in the brain nuclei and has direct effects on central control of food intake and energy consumption (Plum et al. 2005). Several researches have been conducted on the effect of central insulin on regulation of food intake (Benoit et al. 2002; Honda et al. 2007; Shiraishi et al. 2008, Shiraishi et al. 2011; Yousefvand et al. 2018a, 2019). Central insulin reduces food intake and its hypophagic effect as follows: Insulin receptors are located on the POMC and NPY neurons in ARC nucleus, and as well POMC (MC3/4R) and NPY1 receptors are located on the PVN. Administration of insulin to the ventricles of the brain resulted in POMC neurons stimulated and NPY neurons inhibited, so increased in POMC and decreased in NPY gene expression. After that, POMC level raised and NPY level decreased. Increased in POMC level resulted in stimulated the POMC receptors and decreased in NPY level in synaptic space cussed reduced activity of NPY1 receptor (Benoit et al. 2002; Yousefvand et al. 2018a). Therefore PVN exported hypophagic output, and cusses reduction in food intake.

Ghrelin neurotransmitter is involved in the central control of food intake. Ghrelin inhibits food intake in birds, but in mammals is a strong stimulant for food intake. This contradiction shows the difference in central regulation of food intake between mammals and birds (Zendehdel and Hassanpour 2014; Denbow and Cline 2014; Thomas et al. 2015). The hypothetical mechanism of inhibition of food intake in birds by ghrelin neurotransmitter: ghrelin (by ICV injection) stimulates the 5Hydroxytryptamin2A (5HT2A) receptor in Corticotropin-releasing factor (CRF) neurons located on PVN. CRF neurons are anorexigenic neurons in PVN, and receive messages from ARC nucleus through receptors that are located on it. Ghrelin stimulated these neurons, and increase CRF expression. By increasing CRF expression, the PVN exerts an inhibitory message for food intake. Therefore reduced food intake (Saito et al. 2005; Honda et al. 2007; Zendehdel et al. 2013c; Dos-Santos et al. 2018). The assumptive mechanism for increase food intake via ghrelin in mammals: the growth hormone secretagogues receptor (GHSR) (ghrelin receptor) located on AGRP/NPY neurons on ARC nucleus. ICV injection of ghrelin resulted in stimulated AGRP/NPY neurons via GHSR, and increased NPY level and excited NPY1 receptor on PVN (Thomas et al. 2015). Therefore via stimulation of NPY1 receptor on PVN, increased food intake. Ghrelin in mammals exert hyperphagic effect on food intake via NPY/AGRP neurons in ARC nucleus and NPY1 receptor in PVN (Kamegai et al. 2000; Wren et al. 2001; Nakazato et al. 2001).

Somatostatin is known to be a hypothalamic inhibitor of the secretion of growth hormone from pituitary gland. Somatostatin acts in the brain as an inhibitory neurotransmitter. This neurotransmitter distributed in multiple areas of the brain, particularly in ARC, PVN, and VMH in hypothalamus. Since these brain regions involved in central control of food intake, the role of somatostatin in central regulation of food intake is not surprising (Viollet et al. 2008; Schneeberger et al. 2014; Stengel et al. 2015). Somatostatin has an increased food intake via a different neural pathway in the PVN. From different somatostatin receptors (SST1-SST5), SST2/SST3 receptors are located on the PVN (Stengel et al. 2015). Indicated that, SST2 receptor is the primary role in the orexigenic effect of somatostatin. SST2 receptor activated Orexin1 receptor (OX1R) in LHA, and this receptor stimulated NPY1 receptor on PVN. Therefore PVN increased central food intake (Stengel et al. 2010a, b; Karasawa et al. 2014; Yousefvand et al. 2018b).

Conclusion

The PVN is an important nucleus for central regulation of food intake in the hypothalamus. This nucleus receives many inputs from different areas of the brain such as: hypothalamus, hippocampus, amygdala, locus coeruleus, periaqueductal gravy matter and the raphe nucleus and peripheral circulation include: insulin, leptin, and etc. then, integrated these inputs and transmitted final outputs for other reigns for effect on food intake. On this nucleus, there are several receptors through which they receive different signals and send the required response. Many neurotransmitters, either inside or outside of this nucleus (due to neuromodulators), have their effects on food intake. Because the number of neurotransmitters was high, in this review article just to mention of the most important neurotransmitters, including leptin, insulin, ghrelin, and somatostatin. Leptin and insulin is an anorexigenic, somatostatin is orexigenic neurotransmitters, and ghrelin has biphasic effect: in birds, anorexigenic and in mammals, orexigenic neurotransmitter. These neurotransmitters apply their effects on central regulation of food intake via PVN.