Arcuate Nucleus of the Hypothalamus: Anatomy, Physiology, and Diseases

Abstract

The hypothalamus is part of the diencephalon and has several nuclei, one of which is the arcuate nucleus. The arcuate nucleus of hypothalamus (ARH) consists of neuroendocrine neurons and centrally-projecting neurons. The ARH is the center where the homeostasis of nutrition/metabolism and reproduction are maintained. As such, dysfunction of the ARH can lead to disorders of nutrition/metabolism and reproduction. Here, we review various types of neurons in the ARH and several genetic disorders caused by mutations in the ARH.

INTRODUCTION

The hypothalamus is a component of the diencephalon located inferior to the thalamus and superior to the midbrain. It serves as the highest regulator of the autonomic nervous system and plays a crucial role in maintaining glucose homeostasis and regulating the secretion of insulin, glucagon and various hormones. Although Claudius Galen in the second century and Andreas Vesalius in the 16th century described the brain region corresponding to the part of the hypothalamus, it was Wilhelm His who coined the term “hypothalamus” in 1893. The hypothalamus has several nuclei, which are aggregations of neurons: paraventricular nucleus (PVH), ventromedial nucleus (VMH), dorsomedial nucleus (DMH), preoptic nucleus, supraoptic nucleus, suprachiasmatic nucleus, lateral hypothalamic area (LHA) and arcuate nucleus. These hypothalamic nuclei are connected to each other and various surrounding brain regions, regulating the secretion of various peptides and neurotransmitters. The arcuate nucleus is also referred to as the infundibular nucleus or the arcuate nucleus of the hypothalamus (ARH) to distinguish it from another arcuate nucleus in the medulla oblongata (MO). The ARH was first described as nucleus infundibularis in 1948 by Hugo Spatz and colleagues, and is located in the mediobasal hypothalamus, adjacent to the third ventricle and the median eminence (ME) [1-4].

The ARH consists of various neurons that have diverse physiological roles ranging from cardiovascular regulation, feeding, energy expenditure, and fertility to metabolism. These neurons can be classified into two groups: neuroendocrine neurons and centrally-projecting neurons, which are not mutually exclusive. The neuroendocrine neurons release various neurotransmitters and/or neuropeptides, such as neuropeptide Y (NPY), agouti-related peptide (AgRP), cocaine- and amphetamine-regulated transcript (CART), dopamine, gonadotropin-releasing hormone (GnRH), growth hormone–releasing hormone (GHRH), kisspeptin (Kiss1), neurokinin B (NKB), dynorphin A, proopiomelanocortin (POMC) and substance P (SP). The centrally-projecting neurons transmit information to other hypothalamic nuclei or other brain regions outside the hypothalamus [2, 5-7].

This review describes the physiological and molecular functions and genetic disorders of various neurons in the ARH.

NEUROENDOCRINE NEURONS

NPY-expressing neurons

NPY, a 36-amino-acid orexigenic neuropeptide [8], was first identified from extracts of porcine brains without the cerebellum and pituitary gland by Tatemoto et al. [9]. In 1984, Clark and colleagues reported that intraventricular administration of NPY to ovariectomized rats pretreated with estradiol benzoate plus progesterone stimulated feeding behavior [10] (Table 1). Intraventricular infusion of NPY suppresses pulsatile GH release in rats [11-13]. However, genetic ablation of NPY in mice does not alter food intake and body weight, suggesting a functional redundancy of NPY [14, 15].

Table 1.

Types of neurons in the ARH

	Types of neurons	References numbers
Neuroendocrine neurons in ARH	NPY-expressing neurons	[8-10]
	AgRP-expressing neurons	[16-18]
	CART-expressing neurons	[37-39]
	Dopamine-expressing neurons	[47-50]
	GnRH-expressing neurons	[55-59]
	GHRH-expressing neurons	[68-75]
	Kiss1-expressing neurons	[79, 80, 82-86]
	NKB-expressing neurons	[93-98]
	Dynorphin A-expressing neurons	[99-102]
	POMC-expressing neurons	[105-109]
	SP-expressing neurons	[117-125]
Centrally-projecting neurons in ARH	ARH neurons projecting to the PVH	[16, 51, 126-129]
	ARH neurons projecting to the LHA	[132, 133]
	ARH neurons projecting to the DMH	[127, 134]
	ARH neurons projecting to the aBNST	[133, 135]
	ARH neurons projecting to the PVT	[136]
	ARH neurons projecting to the CEA	[24, 137-139]
	ARH neurons projecting to the PAG	[142]
	ARH neurons projecting to the PBN	[145, 146]
	ARH neurons projecting to the VTA	[147]
	ARH neurons projecting to the nucleus raphe obscurus	[148]
	ARH neurons projecting to the NTS	[148]
	ARH neurons projecting to the NAc	[149-151]
	Projections from the PVHTRH/PACAP+ to the ARHAgRP+ neurons	[152]
	Projections from the vDMH to the ARHAgRP+ neurons	[153]
	Projections from the NTS to the ARHPOMC+ neurons	[154]

AgRP-expressing neurons

In 1997, the Barsh group showed that AgRP is a selective antagonist of the melanocortin receptors MC3R and MC4R and that transgenic mice expressing human AgRP develop obesity [16]. AgRP is an orexigenic peptide consisting of 132 amino acids – its mature form has 112 amino acids [17]. The Schwartz group demonstrated in 1998 that NPY and AgRP are co-expressed in fasting-activated ARH neurons [18]. ARH neurons expressing NPY/AgRP (ARH^NPY/AgRP+) are GABAergic [19, 20]. They are activated by ghrelin [21, 22], and inactivated by leptin [19, 23], insulin, and glucose in the blood [24, 25], thus regulating energy balance and food intake [24-27]. Knockout of AgRP in mice show normal food intake and body weight, implying its functional redundancy [15], and have an extended life span with their point estimate of median survival exceeding that of their littermates by 9.8% [28].

Optogenetic activation of AgRP neurons in mice triggers voracious feeding within minutes [29]. In addition, chemical activation of these neurons in mice evoked food consumption, decreased energy expenditure, and enhanced fat stores [30]. Either ablation or suppression of ARH^AgRP+ neurons causes aphagia [17, 30-32]. In vivo Ca²⁺ imaging using GCaMP6s has shown that sensory detection of food inhibits mice AgRP neurons very rapidly [33]. The Knight group showed that food intake stimulates mechanoreceptors in the intestinal vagal sensory neurons, which in turn inhibits ARH^AgRP+ neurons [34]. The Horvath, Nitsch, and Vogt groups proposed that fasting evoked activation of ARH^AgRP+ neurons elevates lysophosphatidic acid (LPA) species in the blood and cerebrospinal fluid, which subsequently elevates cortical excitability leading to hyperphagia [35]. The Anderman group showed that preemptive photostimulation of AgRP neurons in a home cage, but not in a threat-containing task arena, induces conditioned food seeking under threat [36].

CART-expressing neurons

The Douglass group identified in the rat brain an mRNA that was induced four- to fivefold by the administration of cocaine or amphetamine and named it CART in 1995. Human proCART has 89 amino acids. ARH neurons express CART [37], which functions as an anorexigenic peptide [38, 39]. Mice lacking CART exhibit an obesity phenotype [40, 41]. CART is also implicated in immunity, fluid balance, reproduction, learning and memory, sleep, stress, addiction and depression [42, 43]. G-protein coupled receptor (GPR) 160 was reported as a CART receptor [44, 45]. Single-cell RNA sequencing revealed that of three POMC clusters, ARH^CART+ neurons overlap most abundantly with POMC/Anxa2 cluster neurons, yet showed little to no overlap with POMC/Ttr cluster and POMC/Glipr1 cluster neurons [46].

Dopamine-expressing neurons

In the 1960s and 1970s, dopamine released from tuberoinfundibular dopaminergic (TIDA) neurons in the ARH was reported to regulate prolactin secretion [47-50]. The Murakami group found that Neuromedin U inhibits prolactin secretion via activation of TIDA neurons [51]. Zufall, Leinders-Zufall and colleagues demonstrated that deletion of transient receptor potential (TRP) channel Trpc5 enhances dopamine release from TIDA neurons, which in turn causes hypoprolactinemia [52]. Approximately half of TIDA neurons are GABAergic and do not participate in the regulation of prolactin secretion [53].

Optogenetic activation of mouse ARH neurons expressing tyrosine hydroxylase (TH) suppresses POMC neurons and induces hyperphagia. TH is an enzyme that converts L-tyrosine to L-DOPA, a precursor of dopamine. Conversely, ablation of ARH^TH+ neurons decreases body weight [54].

GnRH-expressing neurons

GnRH, a decaneuropeptide, stimulates the biosynthesis and release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary gland. The primary structure of mammalian GnRH was characterized in the early 1970s [55, 56]. In mammals, GnRH-expressing neurons originate in the developing olfactory pit, and migrate towards the hypothalamus, encompassing the primarily preoptic area and ARH, during early embryogenesis [57-59]. Estradiol feedback and Kiss1 modulate the excitability of ARH^GnRH+ neurons [60]. ARH neurons that co-express Kiss1, NKB and dynorphin A (dubbed KNDy neurons) act in coordination to facilitate pulsatile secretion of GnRH, which is critical to reproductive endocrine function [61-64]. Mice carrying homozygous null GnRH mutation show hypogonadotropic hypogonadism [65-67].

GHRH-expressing neurons

GHRH, a 44-amino acid peptide hormone, binds to the its cognate receptor in the anterior pituitary gland, thereby stimulating the secretion of growth hormone (GH) [68-70]. The primary structure of human GHRH was elucidated in 1982 [71, 72]. In mammals, GHRH is synthesized in ARH neurons [73-75]. The knockout of GHRH in mice results in reduced body weight, increased insulin sensitivity and a prolonged lifespan compared to their littermates [76-78].

Kiss1-expressing neurons

Initially identified as a protein that suppresses the metastasis of human malignant melanoma [79], Kiss1 is synthesized in hypothalamic nuclei including the ARH [80]. Kiss1⁺ neurons exhibit electrophysiological properties characteristic of pacemaker neurons [81], and synthesize NKB and dynorphin as well [82]. Upon binding to its cognate receptor, GPR54 (also known as Kiss1 receptor [Kiss1R]), Kiss1 stimulates GnRH neurons triggering pulsatile GnRH release into the portal circulation. This induces the secretion of LH and FSH from the anterior pituitary gland [83-86]. Prolactin binds to prolactin receptors in ARH^Kiss+ neurons and thus decreases Kiss1 expression in female rats, leading to suppression of LH secretion and subsequent infertility [87].

Mice with a Kiss1 hypomorph mutation exhibit sexually dimorphic reproductive phenotypes: male mutants are fertile, whereas female mutants show impaired fertility and ovulation [88, 89]. The genetic ablation of Kiss1⁺ neurons results in fertile mice with smaller ovaries compared to their littermates, with no impact on the timing of female puberty onset [90]. ARH-specific deletion of Kiss1 leads to arrested folliculogenesis, hypogonadism and infertility in female mice, and hypogonadism, and variable, defective spermatogenesis, and subfertility in male mice [91]. Furthermore, ARH^Kiss1+ neurons are a necessary component of the hypothalamic circadian oscillator circuit [92].

NKB-expressing neurons

NKB, identified as a decaneuropeptide in 1983 [93-95], is generated through the proteolytic cleavage of a preproprotein encoded by TAC3. Its primary receptor is neurokinin 3 receptor (NK3R), also known as tachykinin receptor 3 (TACR3), which is a GPCR. TACR3 is not only found in the central nervous system (CNS), but also in the uterus, mesenteric vein, gut neurons, and placenta [96, 97]. Upon binding to NK3R, NKB stimulates GnRH neurons to release GnRH into the portal circulation [98].

Dynorphin A-expressing neurons

Dynorphin A is a potent opioid peptide consisting of 13 amino acids and its amino acid sequence was determined by the Avram Goldstein laboratory in 1981 [99, 100]. It activates the κ-opioid receptor (KOR), which is expressed throughout the brain and spinal cord [101], resulting in the modulation of pain, addiction and mood [102]. In mice lacking dynorphin, corticotropin releasing factor is unable to activate KOR in the basolateral amygdala, dorsal hippocampus and bed nucleus of the stria terminalis (BNST), all of which are brain regions associated with fear and anxiety [103, 104].

POMC-expressing neurons

Proteolytic cleavage of POMC results in the formation of various biologically active peptides including adrenocorticotropic hormone (ACTH), N-POMC, β–endorphin, α-, β– and γ-melanocyte-stimulating hormones (MSH). While POMC is primarily synthesized in the anterior pituitary, some ARH neurons also express POMC. Once secreted, POMC undergoes cleavage into α-MSH that binds to MC3/4R in the PVH neurons, thereby activating satiety signals [105-107]. POMC neurons regulate food intake and energy expenditure by responding to circulating blood glucose levels [108, 109]. Optogenetic activation of POMC neurons in mice has reduces food intake and body weight [29]. In vivo Ca²⁺ imaging using GCaMP6s revealed that food presentation to fasted mice activates POMC neurons very rapidly [33]. Glucagon-like peptide-1 (GLP-1) binds to the GLP-1 receptor in ARH^POMC+ neurons, thus suppressing food intake [110-112]. The Horvath group reported that activation of cannabinoid receptor 1 (CB₁R) in the presynaptic terminals of POMC neurons triggers β–endorphin release and drives feeding [113]. The Yu group discovered that β–endorphin in the ARH contributes to antinociception in rats with inflammation [114]. The Low group observed that conditional knockout of POMC in the mouse ARH elicited hyperphagia, insulin resistance, obesity and improved glucose tolerance [115, 116].

SP-expressing neurons

SP was named by Gaddum and Schild [117] in 1934 and its 11-amino acid long sequence was determined in 1971 [118]. This neurokinin peptide is encoded by preprotachykinin A (PPTA or Tac1). PPTA also generates neurokinin A through alternate slicing [119]. SP is widely expressed in the brain including the ARH [120] and is implicated in nociception, respiration, inflammation, thermoregulation, the cardiovascular function and emotional and anxiety-related behaviors [121-123]. Glutamate induces SP release from the ARH and ME, thereby stimulating the secretion of gonadotropins [124]. The expression of SP and its receptor in the ARH peaks before mice puberty, and SP^-/- mice exhibit delayed puberty and female subfertility [125].

CENTRALLY-PROJECTING NEURONS

The ARH receives signals from various sources, including hormonal and nutrient signals through the ME, afferent inputs from the vagus nerve and other brain nuclei, coordinates them and sends feedback responses via centrally-projecting neurons.

ARH neurons projecting to the PVH

ARH neurons expressing orexigenic (appetite-stimulating) peptides AgRP and NPY project to the PVH, where they bind to MC3/4R and NPY Y1 receptor (NPY1R), respectively. The binding of AgRP to MC3/4R, a receptor for α-MSH, suppresses the anorexigenic effect of α-MSH in the PVH [16]. In addition, the binding of NPY to NPY1R activates GABAergic neurons in the intermediate and parvicellular reticular nuclei of the MO possibly via the nucleus tractus solitarius (NTS) in the MO. This results in the stimulation of feeding behavior through the activation of the masticatory motor region and a decrease in energy expenditure via reduced sympathetic output to the brown adipose tissue (BAT) thermogenesis [51, 126-128].

Upon nutrient ingestion, ARH neurons expressing POMC (ARH^POMC+) that project to the PVH release α-MSH, activating MC4R on PVH neurons (Fig. 1). As a result, food intake is suppressed [129, 130]. ARH neurons expressing TH project to the PVH and the optogenetic activation of ARH^TH+ axons releases both dopamine and GABA, thus inhibiting PVH neurons [54]. Projections from ARH^AgRP/NPY+ to PVH can be remodeled both morphologically and functionally by fasting in mice [131].

Fig. 1.

Schematic illustration of projections to and from ARH neurons. aBNST, anterior bed nucleus of the stria terminalis; ARH, arcuate nucleus of hypothalamus; CEA, central nucleus of the amygdala; DMH, dorsomedial nucleus; LHA, lateral hypothalamic area; NAc, nucleus accumbens; NTS, nucleus tractus solitarius; PAG, periaqueductal gray; PBN, parabrachial nucleus; POMC, proopiomelanocortin; PVH, paraventricular nucleus; PVT, paraventricular thalamic nucleus; TRH, thyrotropin-releasing hormone; VTA, ventral tegmental area.

ARH neurons projecting to the LHA

ARH neurons expressing both AgRP and NPY project to the LHA [132], and optogenetic stimulation of this projection can evoke feeding behavior in mice [133].

ARH neurons projecting to the DMH

ARH^Kiss1+ neurons project to DMH neurons. When activated optogenetically, they release glutamate, thus regulating energy expenditure in female mice [134]. Moreover, ARH^NPY+ neurons project to DMH neurons expressing NPY1R. These in turn project to the nucleus raphe pallidus, resulting in the inhibition of sympathetic outputs for BAT thermogenesis, mean arterial pressure, and heart rate [127].

ARH neurons projecting to the anterior BNST (aBNST)

ARH^AgRP+ neurons project to two distinct parts of the aBNST: the dorsomedial part (aBNST_dm) and the ventrolateral part (aBNST_vl). ARH^AgRP+ projections to the aBNST_dm and aBNST_vl induce feeding and peripheral insulin resistance, respectively [133, 135].

ARH neurons projecting to the paraventricular thalamic nucleus (PVT)

ARH^NPY+ and ARH^CART+ neurons project to the PVT. As NPY and CART are orexigenic and anorexigenic, respectively, these two antagonistic circuits suggest that the PVT may integrate orexigenic and anorexigenic inputs [136].

ARH neurons projecting to the central nucleus of the amygdala (CEA)

The amygdala is involved in emotional responses including fear, anxiety, and aggression as well as the regulation of energy balance [137, 138]. Reciprocal projections exist between ARH^NPY+/CART+ neurons and CEA neurons [24, 139]. Infusion of insulin into the CEA increases the immunoreactivity of c-Fos, a neuronal activity marker, in the ARH, suggesting that insulin mediates anorexia via this circuit [137, 140]. Alcohol activates ARH^POMC+ neurons projecting primarily to the amygdala, which may be implicated in rewarding effect responsible for alcohol use disorders [141].

ARH neurons projecting to the periaqueductal gray (PAG) in the midbrain

Retrograde labeling has revealed the projection of POMC neurons in the ARH to the PAG [142]. During electroacupuncture, glutamatergic reciprocal projections between ARH neurons and ventrolateral PAG neurons become activated [143]. Galanin activates projections from ARH^{β–endorphin+} neurons to PAG neurons, thereby triggering anti-nociceptive effects [144].

ARH neurons projecting to the parabrachial nucleus (PBN)

ARH neurons co-expressing AgRP, NPY and GABA project to the PBN in the pons, thus inhibiting the GABAA receptor in neurons expressing calcitonin gene-related peptide (CGRP). This inhibition delays meal termination [145, 146].

ARH neurons projecting to the ventral tegmental area (VTA)

ARH^POMC+ neurons project to the VTA, inhibiting dopamine neurons in this region. In mice under chronic restraint stress, optogenetic inhibition of this circuit increases body weight and food intake, and suppresses depression-like behaviors and anhedonia [147].

ARH neurons projecting to the nucleus raphe obscurus

Optogenetic stimulation of aBNST neurons expressing glutamate decarboxylase 2 (aBNST^Gad2+) in mice activates the nucleus raphe obscurus in the MO via projections from ARH^Gad2+ neurons, thereby mobilizing glucose rapidly [148].

ARH neurons projecting to the NTS

Activation of ARH^Gad2+ neurons through projections from aBNST^Gad2+ neurons in mice stimulates projections to the NTS, eliciting anxiety-like behavior [148].

ARH neurons projecting to the nucleus accumbens (NAc)

ARH^{β-endorphin+} neurons project to the GABAergic neurons in the NAc, which are associated with ethanol reinforcement [149, 150]. Chang et al. [151] demonstrated that acupuncture stimulates this projection and thus attenuates alcohol dependence in rats.

Projections from the PVH^TRH/PACAP+ to the ARH^AgRP+ neurons

PVH afferent neurons expressing thyrotropin-releasing hormone (TRH) and pituitary adenylate cyclase-activating polypeptide (PACAP), provide excitatory input to ARH^AgRP+ neurons, thereby inducing intense feeding [152].

Projections from the ventral compartment of the DMH (vDMH) to the ARH^AgRP+ neurons

In the fasted state, food detection rapidly activates GABAergic vDMH^{LepR/pDYN+ →} ARH^AgRP+ neurons, which in turn inhibit ARH^AgRP+ neurons [153].

Projections from the NTS to the ARH^POMC+ neurons

GLP-1 neurons in the NTS project to ARH^POMC+ neurons expressing GLP-1R. This circuit is involved in the suppression of food intake [154].

ARH ASSOCIATED GENETIC DISEASES

Hypothalamic obesity syndrome (HOS)

Obesity, a chronic inflammation disorder, is associated with diverse diseases such as cardiovascular diseases, type 2 diabetes mellitus, certain types of cancer, and CNS diseases [155]. Characterized by overweight and disrupted energy homeostasis, obesity results from an imbalance between energy storage and expenditure, and excessive food intake [156]. The hypothalamus is the main brain region controlling energy homeostasis [157]. Specifically, neurons in the ARH including ARH^AgRP/NPY+, ARH^POMC+ and ARH^CART+ play a critical role in energy homeostasis [158]. In obese condition, hyperglycemia and insulin resistance can lead to hypothalamic inflammation, POMC neuronal loss and microglia activation in the ARH [159, 160]. While various factors including anatomic lesions, can caused HOS [161, 162], here we focus solely on genetic causes in the ARH.

Leptin, an anorexigenic hormone, is primarily produced in adipose cells and binds to its cognate receptor, the leptin receptor. This binding in AgRP/NPY neurons reduces expression and release of AgRP and NPY. However, this binding in CART/POMC neurons increases expression and release of CART and POMC. As a result, appetite reduction is suppressed, and locomotion, thermogenesis, and lipolysis are enhanced [163, 164]. Mutations in the leptin receptor are known to cause HOS [165, 166].

MC4R mutations negate the satiating effect of α-MSH in the ARH, and thus elicit hyperphagia and a higher satiety threshold. Once stimulated by leptin, ARH^POMC+ neurons produce α-MSH, which in turn binds to MC4R in PVH neurons. These mutations are the most common cause of monogenic obesity [167-170].

A heterozygous missense mutation in the CART gene (Leu34Phe) in ARH^CART+ neurons is responsible for obesity with a reduced metabolic rate [171, 172].

Homozygous or compound heterozygous mutations in the POMC gene in ARH^POMC+ neurons cause early-onset obesity, hyperphagia, blunted satiety, secondary adrenal insufficiency, and pigmentary changes [173, 174].

Prohormone convertase 1 (PC1, also referred to as proprotein convertase subtilisin/kexin type 1 [PCSK1]) splices POMC in ARH^POMC+ neurons to liberate various biologically active peptides including ACTH and α-MSH. Compound heterozygous mutations in PC1 lead to early-onset obesity, hypoadrenalism, and reactive hypoglycemia [175, 176].

Age-related progressive weight gain typically develops in middle age, which is followed by anorexia (sarcopenia and/or cachexia) in old age. This phenomenon is primarily linked to a decrease and increase in ARH^POMC+ neuronal tone in middle age and old age, respectively [177-179].

Neurogenin 3 (Ngn3 or Neurog3) is a basic helix-loop-helix transcription factor implicated in the development of pancreatic β-cells and the hypothalamus. The conditional knockout of hypothalamic Ngn3 in mice elicits hyperphagia and reduced energy expenditure leading to obesity. This is primarily due to a decrease in the number of ARH^POMC+ neurons and an increase in the number of ARH^NPY+ neurons [180, 181].

Nescient helix-loop-helix 2 (NHLH2) is a transcription factor that promotes the transcription of PC1/3 [182], and is a downstream target gene of leptin signaling [183]. Mutations in NHLH2 are associated with obesity [184-186].

Islet 1 (ISL1), a LIM-homeodomain transcription factor, augments expression of POMC, thereby promoting the terminal differentiation of ARH^POMC+ neurons in the developing hypothalamus. Conditional ISL1 knockout in mice ARH^POMC+ neurons induces hyperphagia and obesity [187, 188].

Tubby (Tub) is expressed in the human hypothalamus including the ARH and adipose tissue. Homozygous mutations in human Tub are associated with retinal dystrophy and early-onset obesity. However, the molecular function of Tub is still under debate [189, 190].

Orthopedia homeobox (Otp), a homeodomain transcription factor, is expressed in several hypothalamic nuclei including the ARH, and plays an important role in the development of hypothalamic neuroendocrine cell lineages in mice. Heterozygous missense mutations in Otp results in obesity, glucose intolerance and anxious behavior in mice [31, 191].

Given that obesity can ensue from various genetic mutations in the ARH neurons, investigation of genes associated with HOS followed by editing of a causative mutation(s) may offer a way to alleviate obesity.

Puberty and sexual maturation disorders

Homozygous or compound heterozygous mutations in Kiss1 or Kiss1R (also called GPR54) lead to hypogonadotropic hypogonadism, resulting in pubertal failure [85, 192-195]. Activating mutations in Kiss1 or Kiss1R cause central precocious puberty (CPP) [194, 196]. Mutations in NHLH2 also lead to hypogonadotropic hypogonadism [185, 186]. Furthermore, homozygous mutations in TAC3 or TACR3 elicit hypogonadotropic hypogonadism [197-200]. Loss-of-function mutations in the makorin ring finger protein 3 (MKRN3) and deletion mutations in the delta-like 1 homolog (DLK1) result in CPP [201, 202].

CONCLUSION

Various types of ARH neurons, their neuropeptides, and their projections play an important role in the regulation of nutrition/metabolism and reproduction. However, their precise roles remain unclear. Advanced manipulation of these neuropeptides and their cognate receptors in the ARH through genetics, optogenetics and chemogenetics could shed more light on the molecular mechanism by which the ARH regulates nutrition/metabolism and reproduction.