Article

ISSN 0006-2979, Biochemistry (Moscow), 2026, Vol. 91, No. 5, pp. 688-712 © Pleiades Publishing, Ltd., 2026.

688

REVIEW

Hypothalamic Regulation of the Gonadal Axis

and Roles of Leptin and Insulin in It

Inna I. Zorina

1,a

*, Kira V. Derkach

, and Alexander O. Shpakov

Sechenov Institute of Evolutionary Physiology and Biochemistry

of the Russian Academy of Sciences, 194223 Saint-Petersburg, Russia

e-mail: zorina.inna.spb@gmail.com

Received February 11, 2026

Revised April 8, 2026

Accepted April 8, 2026

Abstract— The hypothalamic-pituitary-gonadal (HPG, gonadal) axis is responsible for regulating reproductive

functions, and its activity is regulated by numerous hormones, including leptin and insulin. Their primary

targets are hypothalamic neurons expressing gonadotropin-releasing hormone (GnRH), which regulate se-

cretion of gonadotropins and, thus, control puberty and fertility. The key function of leptin and insulin in

hypothalamus is to mediate functional relationship between the energy availability and expenditure, on the

one hand, and reproduction, which is determined, in part, by the activity of GnRH neurons, on the other.

The effects of leptin and insulin on the GnRH neurons are typically indirect and mediated through other

hypothalamic neurons, providing more specialized, multi-level regulation of their activity. The targets of

leptin and insulin are various types of kisspeptin (Kiss1)-expressing neurons, as well as neurons expressing

proopiomelanocortin (POMC, a precursor of anorexigenic melanocortin peptides), and the orexigenic factors –

agouti-related peptide (AgRP) and neuropeptide  Y (NPY). The Kiss1- and POMC-expressing neurons positively

regulate GnRH-neurons, while the AgRP/NPY neurons are primarily involved in their negative regulation.

The effects of leptin and insulin on the Kiss1-, POMC-, and AgRP/NPY-neurons, and consequently on the

GnRH-neurons and the HPG axis, depend on physiological state of the organism, including its metabolic

status, puberty, and gender. These effects are significantly altered in obesity and type  2 diabetes mellitus,

thereby contributing to etiology and pathogenesis of the associated reproductive disorders. This review

focuses on the current state of knowledge on the roles of insulin- and leptin-mediated regulation of the

hypothalamic HPG axis in health and disease, as well as on the unresolved issues in this area. Understanding

molecular basis of this regulation opens up broad prospects for the development of new pharmacological

approaches to restoring reproductive function in obesity and diabetes.

DOI: 10.1134/S0006297926600353

Keywords: leptin, insulin, hypothalamus, gonadal axis, kisspeptin, melanocortin, agouti-related peptide,

neuropeptide Y, insulin system, leptin signaling, reproduction, fertility, eating behavior

* To whom correspondence should be addressed.

INTRODUCTION

Historically, brain was considered as an organ

whose functioning was controlled by the peripheral

components of the endocrine system. Modern neuro-

endocrinology has shifted this paradigm, positioning

the central nervous system, primarily hypothalamus,

as the primary regulatory center, constantly analyz-

ing afferent signals coming from the periphery and

directing the endocrine orchestra to maintain homeo-

stasis throughout the body  [1]. Compelling evidence

has been obtained that eating behavior, glucose ho-

meostasis and lipid metabolism, and the amount,

proportion, and composition of adipose tissue in hu-

mans and experimental animals are directly linked

to the functional activity of the hypothalamic-pitu-

itary-gonadal (HPG) axis and reproductive processes.

In this regard, it is not surprising that the hormon-

al agents such as leptin and insulin, which control

energy metabolism and eating behavior, have come

to be considered the most important regulators of

various links in the male and female HPG axis  [1,  2].

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Fig. 1. Schematic diagram of the structure of hypothalamic-pituitary-gonadal axis and influence of insulin and leptin on it

under normal conditions and in metabolic dysfunctions. Detailed description in the text. Designations: FSH – follicle-stim-

ulating hormone; GnRH – gonadotropin-releasing hormone; LH – luteinizing hormone.

In recent years, much attention has been paid to the

insulin-like growth factor-1 (IGF-1), a structural and

functional homologue of insulin, which also has the

properties of a regulator of reproductive functions  [3].

The targets of leptin, insulin, and IGF-1 are both hy-

pothalamic neurons responsible for the synthesis and

secretion of gonadotropin-releasing hormone (GnRH),

which is a releasing factor for gonadotropins – lu-

teinizing hormone (LH) and follicle-stimulating hor-

mone (FSH), and the downstream links of the HPG

axis – gonadotrophs of the anterior pituitary gland,

which secrete gonadotropins in response to stimula-

tion by GnRH, and the gonads, where the processes

of steroidogenesis, spermatogenesis (in the testes in

men), oogenesis and folliculogenesis (in the ovaries in

women) are carried out under control of LH and FSH

(Fig.  1). In this review, we will focus on the role of

these hormones in regulating the hypothalamic links

of the HPG axis. The effects of these hormones on

its peripheral links have been described in detail in

our previous publications  [4,  5] and by other authors

[6-8]. Since the impaired insulin and leptin signaling,

including resistance to these hormones characteris-

tic of obesity, type  2 diabetes mellitus (T2DM), liver

steatosis, and some neurodegenerative diseases, also

lead to the development of reproductive dysfunctions,

ZORINA et al.690

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

including hypogonadotropic hypogonadism in men

and polycystic ovary syndrome (PCOS) in women

[9-11], the development of pharmacological approach-

es to normalize metabolic and hormonal status, as

well as to restore insulin and leptin signaling path-

ways in hypothalamus could become a platform for

creation and implementation of new strategies to

enhance reproductive potential in the patients with

these metabolic and endocrine disorders.

Insulin, secreted by the pancreas, and leptin,

produced by adipose tissue, enter the central ner-

vous system from the bloodstream via the specialized

transport systems. In hypothalamus, they regulate se-

cretion of GnRH, which activates secretion of LH and

FSH by gonadotrophs of the anterior pituitary gland.

These hormones control functioning of gonads and

reproductive system in men and women. At physio-

logical levels of insulin and leptin, they adequately

control release of GnRH and gonadotropins, maintain-

ing normal HPG axis activity. The GnRH secretion can

occur in several modes: pulsatile, which is the prima-

ry mode, and wave-like, which is observed only in

women  [4]. In the pulsatile mode, the GnRH release

occurs in a specific rhythm (every 60-90  min). The

pulsation rate is controlled by the “pulse generator”,

which is anatomically located in the mediobasal hypo-

thalamus, and its activity is regulated by the pituitary

LH and FSH according to the principle of negative

feedback. In obesity and T2DM, which are associated

with hyperinsulinemia, hyperleptinemia, insulin and

leptin resistance, as well as in conditions of insulin

and leptin deficiency due to starvation or genetic fac-

tors, the pulse frequency and intensity of the GnRH

release as well as the gonadotroph response are dis-

rupted, leading to the development of reproductive

dysfunction. Deficiency of the sex hormones estradiol

and testosterone, which have pronounced neuropro-

tective (through modulation of the Bcl-2 family pro-

teins) and anti-inflammatory properties, exacerbates

the diabetes-associated sexual dysfunction. Moreover,

changes in the insulin and leptin signaling caused by

both central resistance in T2DM and insulin deficien-

cy in type  1 diabetes mellitus (T1DM) lead to dysfunc-

tion of the gonadal axis in both its peripheral (go-

nads) and upstream (hypothalamus, pituitary gland)

links, and this leads to dysregulation of the gonadal

axis at the central level [1, 4].

MAIN LINKS OF HYPOTHALAMIC REGULATION

OF GONADOLIBERIN SECRETION AS POTENTIAL

TARGETS FOR LEPTIN AND INSULIN PEPTIDES

The main hypothalamic components of the HPG

axis are various types of kisspeptin (Kiss1)-express-

ing neurons  [12], as well as neurons localized in the

arcuate (ARC) nuclei of the hypothalamus expressing

proopiomelanocortin (POMC)/cocaine- and amphet-

amine-regulated transcript (CART) and agouti-re-

lated peptide (AgRP)/neuropeptide  Y (NPY) [13-15].

According to the modern concepts, these neuronal

populations are considered as a single entity that

provides integrated control of metabolism and re-

production [15]. They originate from a common em-

bryonic progenitor pool and differentiate under the

influence of sex hormones, insulin, leptin, and vari-

ous growth factors. In the postnatal period, estradiol

and other sex hormones regulate all three neuronal

populations. It is, therefore, not surprising that the

metabolic disorders are often comorbid with the re-

productive dysfunction, and that stress and starvation

impair sexual behavior and fertility.

Kisspeptin-expressing neurons. The Kiss1 neu-

rons are localized in various brain regions, which

made it possible to identify at least seven of their

populations, differing in their functional characteris-

tics and expression patterns of Kiss1 and other neu-

ropeptides  [16]. Kisspeptin secreted by the Kiss1 neu-

rons subsequently stimulates the G-protein-coupled

kisspeptin receptors GPR54, localized, among other

things, on the GnRH-expressing neurons. Depending

on their location and activity, the Kiss1 neurons in-

volved in regulation of the HPG axis are divided into

two types: those localized in the ARC of the hypo-

thalamus (Kiss1

ARH

neurons) and in the anteroventral

periventricular (AVPV) and periventricular preoptic

(PeN) nuclei (Kiss1

AVPV/PeN

neurons)  [17]. In addition

to Kiss1, the Kiss1

ARH

-neurons express two other

neuropeptides involved in regulation of the GnRH

secretion: neurokinin  B and dynorphin, which is

why these neurons are often referred to as KNDy

neurons  [18]. The Kiss1

ARH

neurons also express the

vesicular glutamate transporter vGLUT2, which gives

these neurons the ability to release glutamate upon

excitation  [19]. The most important regulator of both

types of Kiss1 neurons is estradiol, whose targets are

α-estrogen receptors (ERα) localized in them, and

this underlies functioning of the feedback regulato-

ry connections in the HPG axis [16,  17,  20]. Release

of Kiss1 and GnRH in the ovariectomized females

is reduced and desynchronized, and treatment with

estrogens restores secretion of these neuropeptides

[21]. The GnRH neurons do not contain ERα, and,

therefore, they cannot be directly involved in the

estrogen-mediated regulation of GnRH secretion [15,

17, 22]. Selective β-estrogen receptors (ERβ) agonists

do not significantly affect the Kiss1 neurons, which

indicates absence of ERβ in them  [23]. On the other

hand, the ERβ knockout animals have reduced fer-

tility and LH surge amplitude, which may indicate

an indirect effect of ERβ on activity of the Kiss1 and

GnRH neurons  [24]. Androgens are able to modulate

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activity ofthe Kiss1 neurons and stimulation of GnRH

secretion mediated by them  [21,  23]. This is due to

the differentiated expression levels of the androgen

receptors in different types of Kiss1 neurons, includ-

ing its high level in the Kiss1

AVPV/PeN

neurons  [16].

Forthe Kiss1 neurons localized in the amygdala, colo-

calization of ERα and androgen receptors with GPR54

was shown, which indicates their sensitivity to vari-

ous sex steroids and the possibility of auto/paracrine

regulation by Kiss1  [25].

Regulatory effects of estradiol on the Kiss1

ARH

and Kiss1

AVPV/PeN

neurons differ. Estradiol excites the

Kiss1

AVPV/PeN

neurons by stimulating conductance ac-

tivity of various types of ion channels – voltage-de-

pendent calcium (Cav3.1) and sodium (Nav1.1, Navβ2)

channels, as well as hyperpolarization-activated and

cyclic nucleotide-gated HCN channels, and TRPC5 cat-

ion channels. This results in the release of Kiss1 and

stimulation of GnRH neurons, leading to the secretion

of LH by gonadotrophs in the anterior pituitary [26].

When estradiol acts on the Kiss1

ARH

neurons, its ef-

fects are more complex. On the one hand, estradiol

increases expression of the vGLUT2 transporter and

cation channels (Cav3.1, HCN), causing increased glu-

tamate release, and, on the other hand, suppresses

expression of all three neuropeptides – Kiss1, neu-

rokinin  B and dynorphin, and the cation channel

TRPC5, negatively affecting the pulsatile secretion

of GnRH  [27]. In  this regard, it should be noted that

neurokinin  B, acting on the tachykinin receptors

type  3 located on the Kiss1

ARH

and neighboring neu-

rons, depolarizes the Kiss1

ARH

neurons, inducing slow

excitatory postsynaptic currents and enhancing secre-

tion of Kiss1  [28]. Dynorphin has the opposite effect

by stimulating the G  protein-gated inward-rectifier

potassium channels (GIRKs) through activation of

the presynaptic κ-opioid receptors, thus causing re-

polarization and suppression of the slow excitatory

postsynaptic currents in the Kiss1

ARH

neurons  [27].

This provides fine modulation of the Kiss1 release

by these neurons, determining both direct stimulation

of the GnRH neurons due to the Kiss1 release into

the external zone of the median eminence and indi-

rect stimulation of the Kiss1

AVPV/PeN

neurons through

glutamate release from the terminals of the Kiss1

ARH

neurons [27,  29]. Both processes provide a powerful

preovulatory surge of GnRH and LH. At low estradiol

levels, such as in ovariectomized female rats, high-fre-

quency activity of the Kiss1

ARH

neurons has been re-

corded, which correlates with the moderate pulsatile

release of GnRH and LH, while at the elevated estra-

diol levels transition to a volley, glutamate-mediated

activation of the Kiss1

AVPV/PeN

neurons occurs, result-

ing in a powerful peak of GnRH, which, in rodents,

is observed in the proestrus stage, preceding ovula-

tion [27,  30].

POMC/CART and AgRP/NPY neurons. In hypo-

thalamus, the Kiss1

ARH

neurons are functionally con-

nected to both POMC/CART neurons expressing POMC,

a precursor of α-melanocyte-stimulating hormone

(α-MSH) with anorexigenic activity, and AgRP/NPY

neurons expressing orexigenic factors AgRP and NPY.

α-MSH stimulates melanocortin receptors types 3

and 4 (MC

R, MC

R), while AgRP is an antagonist of

these receptors. In the hypothalamic ARC, projections

of the POMC/CART neurons are in close contact with

the cell bodies of Kiss1

ARH

neurons expressing MC

and MC

R, thus the release of α-MSH by POMC/CART

neurons leads to rapid depolarization and activation

of the Kiss1

ARH

neurons and Kiss1-mediated GnRH

peak, while the MC

R and MC

R antagonists prevent

this effect [31]. The ability of melanocortin peptides

to activate Kiss1 and GnRH neurons is determined

by the degree of sexual maturity. Administration of

the MC

R/MC

R agonist melanotan-II to the sexually

mature female rodents leads to the intense release

of GnRH and LH after just 15 min, while treatment

of immature animals does not affect these parame-

ters [31]. The most important regulator of the POMC/

CART neuron activity is estradiol, which, like α-MSH,

has anorexigenic properties. This effect of estradiol

is realized primarily through stimulation of secre-

tion of the melanocortin peptides, which is one of

the components of the intersection of the regulatory

pathways between metabolic and reproductive pro-

cesses  [20]. In hypothalamus, estrogens enhance me-

lanocortin signaling both by increasing expression of

the Pomc gene and sensitivity of MC

R to the melano-

cortin peptides  [32], and by increasing excitability of

the POMC/CART neurons, which is due to the chang-

es in expression and ratio of different types of ion

channels in them  [33,  34]. The POMC/CART neurons,

acting through MC

R on the Kiss1

ARH

neurons, stimu-

late the GnRH “pulse generator” and limit activation

of the Kiss1

AVPV/PeN

neurons depending on duration of

estrogen action during ovulation  [35].

The action of AgRP is based on its inhibitory al-

losteric effect on the melanocortin signaling in the

Kiss1 neurons, since the terminals of the AgRP/NPY

neurons contact the cell bodies of the MC

R/MC

R-ex-

pressing Kiss1

ARH

neurons  [36]. However, instead of

the expected increase in the GnRH release upon sup-

pression of AgRP secretion, mice exhibit decreased

fertility and delayed sexual development  [37]. This is

believed to be due to imbalance of the stimulatory

and inhibitory effects on the Kiss1 and GnRH neu-

rons, which ensures normal pulsatile release of GnRH

and LH. This conclusion is based on the study of fe-

male mice with the knockout of the Kiss1 gene in the

Kiss1

ARH

neurons with preservation of maintaining

the expression of neurokinin  B. In these animals, in

adulthood, the LH pulsation is disrupted, amplitude

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BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

of the basal and preovulatory LH peaks decreases,

and the levels and ratio of sex steroid hormones

change, which leads to premature ovarian failure and

an early decline in fertility  [28].

Activity of the AgRP/NPY neurons is largely de-

termined by the reciprocal interactions between them

and the Kiss1

ARH

and POMC/CART neurons. Under

conditions of starvation and excessive physical ex-

ertion, increase in the activity of AgRP/NPY neurons

is observed, which is associated with both weight

loss and decrease in the HPG axis activity and fer-

tility  [16,  38]. In this case, estradiol is a key media-

tor between the metabolic and reproductive process-

es  [20]. At high levels, for example, during proestrus

or during estrogen therapy, expression of the extra-

synaptic metabotropic glutamate receptors mGluR7

increases in the AgRP/NPY neurons. Their activation

enhances calcium signaling and negatively affects

secretory activity of these neurons  [19]. This is due

to the increased glutamate release by the terminals

of the Kiss1

ARH

and POMC/CART neurons resulting

from the estradiol-induced increase in the expres-

sion of glutamate transporters in them. Moreover,

high concentrations of estradiol change the pattern

of site-specific POMC proteolysis products, increas-

ing proportion of β-endorphin, an agonist of µ-opi-

oid receptors, which suppresses activity of the AgRP/

NPY neurons. Under conditions of low estradiol lev-

els or its absence (for example, during ovariectomy),

the reverse process is observed. Activity of the AgRP/

NPY neurons is stimulated by the relatively low dos-

es of glutamate, which, in this case, exerts its effects

through the ionotropic glutamate AMPA receptors.

In turn, γ-aminobutyric acid (GABA), released from

the terminals of the AgRP/NPY neurons onto the cell

bodies of Kiss1

ARH

and POMC/CART neurons, interacts

with the GABA

receptors localized there and inhibits

secretion of Kiss1 and melanocortin peptides [20].

The inhibitory effect of NPY on the GnRH neu-

rons was first described more than 15  years ago in

the experiments on suppression of GnRH release

by the selective agonist of the type  5 NPY receptor

(Y5R)  [39]. It was subsequently shown that this effect

of NPY is based on its interaction with the Y1R and

Y5R receptors on the cell bodies of Kiss1

ARH

neurons

[38,  40], and selective antagonist of only one of them

did not abolish the inhibitory effect of NPY on the

neurokinin B-induced calcium currents in the GnRH

neurons  [40]. Using an optogenetic approach, it was

established that the inhibitory effect of NPY on the

GnRH neurons could be realized through both types

of Kiss1 neurons, Kiss1

ARH

and Kiss1

AVPV/PeN

, which is

consistent with the neuroanatomical connections be-

tween them and the AgRP/NPY neurons  [38]. A direct

effect of NPY on the GnRH neurons expressing Y1R is

also possible, with this effect prevalent in the early

stages of ontogenesis  [41]. Long-term administration

of NPY disrupts sexual development and estrous cy-

cle in the female rats, reducing their fertility  [42].

The effect of NPY on the secretion of GnRH and LH

is largely determined by the hormonal status of the

HPG axis. Thus, intracerebral administration of NPY

to the ovariectomized female rats increased the LH

levels under conditions of combined administration

of progesterone, and caused the opposite effect in its

absence, which is associated with the different effects

of progesterone on the Y1R- and Y5R-mediated signal-

ing in the Kiss1 neurons  [43].

LEPTIN SIGNALING PATHWAYS

Leptin, a product of the ob gene, is secreted pri-

marily by adipocytes in white adipose tissue, regu-

lates eating behavior and energy metabolism, and

its signaling pathways are significantly altered in

obesity, T2DM, and endocrine disorders [44,  45]. Pos-

itive correlation has been shown between the body

weight, proportion of fat relative to the body weight,

and blood leptin levels  [45]. Its main targets in hu-

mans and animals are hypothalamus and a number

of other brain regions, where leptin penetrates from

the bloodstream bypassing the blood–brain barri-

er (BBB) via the receptor-mediated endocytosis  [46].

Enhanced leptin transport into the brain could be

mediated by 17β-estradiol, demonstrating a relation-

ship between the leptin levels in the CNS and HPG

axis activity  [47].

In hypothalamic neurons, the leptin system close-

ly interacts with other signaling systems, including

insulin and IGF-1  [48-50]. Under conditions of hyper-

leptinemia in obesity and T2DM, leptin levels in hy-

pothalamus could decrease as a result of impaired

transport across the BBB  [51-53]. Weakening of the

leptin signaling in the CNS has been demonstrated

under conditions of central leptin resistance, which

leads to the decrease of the neuroprotective effect of

leptin and is characteristic of Alzheimer’s disease and

a number of other neurodegenerative diseases  [54].

The leptin-activated signaling cascades not only

regulate energy balance but also serve as key links

in the transmission of metabolic signals to the hy-

pothalamic centers that control reproductive func-

tion. Through these pathways, leptin modulates ac-

tivity of the GnRH neurons, determining timing of

puberty, pulsatile rhythm of gonadotropin secretion,

and fertility. The leptin signaling pathway is shown

in Fig.  2. The target of leptin in the central nervous

system and in the periphery is the full-length leptin

receptor (OBRb), which belongs to the cytokine re-

ceptor family. Along with the full-length form, trun-

cated forms have been detected, formed as a result

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Fig.  2. Leptin signaling pathways including in hypothalamus. Detailed description in the text. Designations: OBRb – full-

length leptin receptor; JAK2 – non-receptor tyrosine kinase; IRS1/2 – insulin receptor substrates 1 and 2; SH2B1 – adapter

SH2-domain-containing protein; PI-3K – phosphatidylinositol 3-kinase; PIP3 – phosphatidylinositol-3,4,5-triphosphate; AKT–

serine/threonine protein kinase  B; TSC1, TSC2 – adapter proteins hamartin (TSC1) and tuberin (TSC2); mTORC1 – complex

including serine/threonine protein kinase mTOR; p70S6K – ribosomal S6 kinase p70; FoxO1 – transcription factor of the

FOX family FOXO1; AMPK – 5′-AMP-activated protein kinase; ACC – acetyl-CoA carboxylase; SHP2 – SH2-domain-containing

protein tyrosine phosphatase  2; GRB2 – growth factor receptor-bound protein  2; SOS – GDP/GTP exchange factor; Ras –

small G-protein of the Ras family; Raf – Ser/Thr-specific protein kinase; MEK – mitogen-activated protein kinase kinase;

ERK1/2 – extracellular signal-regulated kinases 1 and 2; STAT3, STAT5 – types  3 and 5 signal transducers and activators

of transcription; PTP1B – protein phosphotyrosine phosphatase 1B-subtype; SOCS3 – suppressor of cytokine signaling 3;

TCPTP– T-cell protein phosphotyrosine phosphatase; PTEN – phosphoinositide-specific phosphatase; NF-κB – nuclear tran-

scription factor κB; AgRP – agouti-related protein; NPY – neuropeptide Y; POMC – proopiomelanocortin.

of alternative splicing of the mRNA transcript of the

Lepr gene. Moreover, expression of these forms has

been detected in hypothalamus, and the level of ex-

pression depends on physiological state of the body

and changes during puberty, pregnancy, and lactation

[55,  56]. All of them retain the ability to bind leptin,

but lack functional activity of the full-length recep-

tor, and their function is believed to be transport of

leptin, including through the BBB, and binding of the

excess of leptin in hyperleptinemia [57, 58]. OBRb

is intensively expressed in those tissues and cells

where leptin exerts its regulatory effects, including

hypothalamic neurons, while truncated forms are ex-

pressed mainly in the tissues and cells involved in

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BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

the transport, redistribution of leptin between tissues,

and its release [56].

The non-receptor tyrosine kinase JAK2 plays a

key role in the leptin signaling. In complex with the

ligand-activated OBRb, it is first autophosphorylated

at the tyrosine residue (Tyr), and next carries out

Tyr-phosphorylation of OBRb at Tyr

985

, Tyr

1077

, and

Tyr

1138

[59,  60]. This determines two main patterns

of leptin signaling pathways. Some are mediated

through the phospho-Tyr-containing sites of OBRb,

which specifically interact with the SH2-domain-con-

taining proteins, and others are mediated through

the JAK2 kinase independently of these sites, through

interaction of the Tyr-phosphorylated JAK2 with the

proteins that are substrates of the insulin receptor

(IRS)  [60,  61].

Phospho-Tyr

985

OBRb interacts with the SHP2

phosphatase, which targets the mitogen-activated

protein kinase (MAPK) cascade, including its effec-

tor component, ERK1/2 kinase [62,  63] (Fig.  2). In hy-

pothalamic neurons, ERK1/2 mediates the effects of

leptin on eating behavior and thermogenesis; and

expression of the mutant OBRb (Tyr

985

Phe) in these

neurons, Shp2 gene knockout, and ERK1/2 inhibitors

lead to hyperphagia and obesity  [62,  64]. At the same

time, it has been shown that the SHP2 phosphatase is

associated with ERα and is necessary for synergistic

activation of ERK1/2 by estrogens and leptin during

the HPG axis regulation  [64].

Phospho-Tyr

1077

and phospho-Tyr

1138

interact

with the transcription factors STAT5 and STAT3,

which control eating behavior, metabolism, and neu-

roendocrine functions [61,  65] (Fig.  2). When phos-

pho-Tyr

1138

binds to STAT3, the OBRb–STAT3–JAK2

complex is formed, after which JAK2 phosphorylates

STAT3, promoting its dimerization and translocation

into the nucleus. There, the STAT3-STAT3 dimer regu-

lates expression of numerous STAT3-dependent genes,

enhancing Pomc gene expression in the POMC/CART

neurons, which leads to production of the anorex-

igenic melanocortin peptides, and stimulating ex-

pression of the suppressor of cytokine signaling-3

(SOCS3) gene, negative regulator of the leptin signal-

ing  [66,  67]. Tyr

1138

substitution in the OBRb and Stat3

gene knockout in the hypothalamic neurons lead to

hyperphagia and obesity  [68]. This indicates that dis-

ruption of the STAT3 pathways makes a decisive con-

tribution to the central leptin resistance  [56,  69].

The STAT5 activation occurs via the phos-

pho-Tyr

1077

-containing site of OBRb, after which

STAT5 dimerizes and the STAT5-STAT5 complex

translocates into the nucleus, leading to activation

of the STAT5-dependent genes [61,  70]. The female

mice with the mutant OBRb with the Tyr

1077

Phe

substitution expressed in hypothalamus, along with

obesity, have a disrupted estrous cycle, which em-

phasizes importance of the STAT5 pathways for repro-

duction [71].

Among the mechanisms independent of Tyr

phosphorylation of OBRb, the most significant is the

3-phosphoinositide cascade (Fig.  2), which includes the

IRS protein (in hypothalamus, predominantly IRS2),

phosphatidylinositol 3-kinase (PI-3K), protein kinase

AKT, and effector proteins, AKT targets, including ri-

bosomal p70-S6 kinase, glycogen synthase kinase-3β

(GSK3β), mTOR (mammalian target of rapamycin), and

transcription factor FoxO1 [54, 72, 73]. To activate IRS

proteins, an oligomeric complex is first formed, in-

cluding the leptin-bound OBRb, phosphorylated JAK2,

and the SH2-domain-containing protein SH2B1  [74].

Leptin activation of the 3-phosphoinositide pathway

in hypothalamic neurons mediates regulation of ap-

petite, metabolism, and neuroendocrine functions, as

well as interactions between the leptin and insulin/

IGF-1 signaling, significantly contributing to neuro-

protective effects of leptin, including in neurodegen-

eration [54]. Furthermore, knockout of the IRS2 gene

in hypothalamus leads to the development of central

hypogonadism [75].

In hypothalamus, the AKT-induced phosphoryla-

tion of FoxO1 reduces its activity, changing the ratio

of expression of orexigenic and anorexigenic factors in

favor of the latter, thereby reducing appetite and nor-

malizing carbohydrate and lipid metabolism  [76]. This

effect is mimicked by knockout of the gene encoding

FoxO1 in the hypothalamic ARC [77,  78]. The AKT-reg-

ulated mTOR and ribosomal p70-S6 kinase are also

involved in the effects of leptin on appetite, energy

metabolism, and neuroendocrine function, with these

effects occurring primarily in the hypothalamic ARC

[79]. Considering that the p70-S6 kinase is a negative

regulator of the AMP-activated protein kinase (AMPK),

the most important cellular energy sensor, its activa-

tion by leptin leads to phosphorylation of the Ser

491

in the α2-subunit of AMPK and decrease in its activity

[80,  81]. This enhances anorexigenic effect of leptin

in hypothalamic neurons, preventing obesity [72, 82].

The key components of leptin signaling are its

negative regulators, SOCS3 and phosphotyrosine phos-

phatases PTP1B and TCPTP, as well as NF-κB factor,

which activates proinflammatory pathways in the cell

[50, 83-85] (Fig.  2). PTP1B dephosphorylates JAK2 and

prevents leptin stimulation of the 3-phosphoinositide

pathways; SOCS3 inhibits the SHP2- and STAT3-medi-

ated signaling by dephosphorylation of phospho-Tyr

985

and phospho-Tyr

1138

, and TCPTP blocks leptin activa-

tion of STAT3- and STAT5-transcription factors, pre-

venting expression of the STAT3/5-dependent genes.

Increased activity of negative regulators of leptin sig-

naling is one of the primary causes of central and

peripheral leptin resistance, including in T2DM and

obesity  [50,  83].

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LEPTIN REGULATION OF HYPOTHALAMIC

LINKS OF THE GONADAL AXIS

Decreased leptin levels, including those observed

during prolonged starvation and excessive physical

exertion, indicate lack of energy resources, which is

a signal for their conservation and inhibition of the

HPG axis, especially since, under conditions of acute

energy deficiency, pregnancy and gestation are asso-

ciated with significant risks  [86] (Fig.  1). As expected,

exogenous leptin, in the context of its deficiency re-

sulting from starvation or leptin gene knockout (as

in ob/ob mice), promotes activation of hypothalam-

ic components of the HPG axis, which is manifested

as elevated levels of LH, FSH, and sex steroids  [87].

In conditions such as obesity, T2DM, and metabolic

syndrome, leptin resistance develops, which leads

to both disruption of the leptin transport across the

BBB, which may be accompanied by the decrease in

its level in hypothalamus and other brain structures

[51-53], and to the development of systemic leptin

resistance, including in the CNS, which is character-

ized by the disruption of the downstream stages of

leptin signaling and decrease in the number of active

forms of OBRb in neurons and glial cells  [88]. This

also leads to the decrease in activity of the HPG axis

and fertility, which could be either transient or lead

to the persistent weakening of reproductive functions

and infertility  [86]. Intranasal administration of the

leptin fragment 116-122 (endowed with the activity

of full-length leptin) to the male rats with diet-in-

duced obesity and leptin resistance not only positive-

ly modulated testicular steroidogenesis but also en-

hanced human chorionic gonadotropin stimulation of

Fig. 3. Influence of leptin and insulin on the hypothalamic links of the hypothalamic-pituitary-gonadal axis. The figure shows

major populations of neurons in the arcuate nucleus (ARC) of hypothalamus (POMC/CART, KNDy(Kiss1

ARC

) and AgRP/NPY

neurons), Kiss1(Kiss1

AVPV/PeN

) and GnRH neurons located in the preoptic area and the anteroventral periventricular nucleus

(POA/AVPV), as well as the ventral premamillary nucleus (PMv), which contains populations of neurons sensitive to leptin

and insulin. Leptin receptors (OBRb) and insulin receptors (INSR) are differentially expressed on these neurons, which

mediates the direct and indirect effects of insulin and leptin on generation of pulsatile GnRH secretion. In GnRH neurons,

the leptin receptors OBRb are absent, while expression of INSR is at a low level, and direct stimulation of these neurons

by insulin has not yet been proven and is possibly realized through the receptors of IGF-1, which are intensively expressed

in the GnRH neurons. Green arrows indicate stimulatory effects, red arrows indicate inhibitory effects, and the dotted

arrow indicates modulatory effects. α-MSH – α-melanocyte-stimulating hormone; GnRH – gonadotropin-releasing hormone.

ZORINA et al.696

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

testosterone production [89,  90]. A scheme integrating

the action of leptin and insulin on the hypothalamic

links of the HPG axis is shown in Fig.  3.

Ability of leptin to regulate the HPG axis is de-

termined by the significant density of the OBRb leptin

receptors in the hypothalamic nuclei. The neuron-spe-

cific knockout of the OBRb gene leads to the delayed

sexual development and sterility in the mice of both

sexes  [91]. In the ARC neurons expressing POMC/

CART and AgRP/NPY, integration of nutritional sta-

tus and HPG axis activity is mediated by the leptin

signaling [8,  92]. OBRb is localized on the surface of

more than half of the POMC/CART neurons, and using

immunohistochemical methods, we have shown that

their density on the POMC/CART neurons is several

times higher than on the ARC neurons of other neu-

rotransmitter phenotypes  [51]. It should be noted that

OBRb is absent in the GnRH neurons, which indicates

the possibility of only an indirect effect of leptin on

the synthesis and secretion of GnRH [91,  93,  94].

POMC/CART neurons. Leptin stimulation of the

POMC/CART neurons leads to the increased activity

of the GnRH neurons, which results in the increased

HPG axis activity, which could be realized through

several mechanisms. These mechanisms involve a

leptin-induced increase in the secretion of α-MSH

by the POMC/CART neurons. α-MSH is a product of

POMC hydrolysis, whose action on the Kiss1 or GnRH

neurons leads to the release of GnRH and increase of

LH levels in the blood. Intrahypothalamic administra-

tion of leptin to the ovariectomized female rats fasted

for three days synchronously increases the levels of

α-MSH, GnRH, and LH, supporting coordinated acti-

vation of the leptin signaling in the POMC/CART neu-

rons and increased melanocortin peptide production.

Moreover, this does not depend on whether leptin is

injected into the medial preoptic area, where most

of the bodies of GnRH neurons are located, or into

the median eminence and ARC complex, where their

axonal endings are localized  [95]. Administration of

leptin to the satiated rats did not have a significant

effect on the level of α-MSH and release of GnRH,

while melanotan-II, a synthetic analogue of α-MSH,

mimicked stimulation of the GnRH neurons by leptin

and release of GnRH by them  [96]. It should be noted

that under conditions of stimulation with melanocor-

tin peptides, at least 70% of the GnRH neurons are

activated, which is significantly higher than in the

case of their activation by leptin  [97]. This indicates

a more moderate, “physiological” stimulation of the

HPG axis by leptin compared to its pharmacological

activation by melanocortins, which is due to the prev-

alence of a multistage mechanism including sequen-

tial activation of the POMC/CART, Kiss-1, and next of

the GnRH neurons. Presence of a complex neuronal

network of the HPG axis regulation by leptin in the

ARC is supported by the data obtained with animals

with the Lepr gene knockout in the POMC/CART neu-

rons, which does not lead to the pronounced repro-

ductive disorders  [98].

Increased production of melanocortin peptides

upon stimulation of the POMC/CART neurons with

leptin is based on the enhanced expression of the

Pomc gene. This is due to both the OBRb-mediated

phosphorylation of the STAT3 transcription factor and

nuclear translocation of its dimeric complex, which

functions as a positive transcription factor for this

gene, and the leptin-induced suppression of the activi-

ty of the FoxO1 factor, negative regulator of the Pomc

gene expression  [56]. Inactivation of the leptin (ob/ob

mice) and its receptor (db/db mice) genes leads to the

changes in the architecture of the POMC/CART neu-

rons in the neonatal mice, including changes in their

axon projections. It has been shown that the leptin-ac-

tivated OBRb–SHP2–MAPK(ERK1/2) and OBRb–STAT3

signaling pathways are involved in this process  [99].

AgRP/NPY neurons. The effect of leptin on AgRP/

NPY neurons, which negatively modulates activity of

the GnRH neurons, reduces the expression of AgRP

and NPY by two mechanisms  [83] (Fig.  3). The first in-

volves increasing the activity of STAT3, which reduc-

es expression of these orexigenic factors, while the

second consists of suppressing the activity of FoxO1

factor, an activator of expression of the Agrp and Npy

genes  [56,  83]. Total suppression of leptin signaling

could cause changes in the morphology of the AgRP/

NPY neurons, which, as assumed, could alter the en-

tire integrative neuronal network responsible for the

regulation of the Kiss1 and GnRH neurons. Thus, in

the early stages of ontogenesis in the hypothalamus

of the mutant mice of the ob/ob and db/db lines, as

in the case of the POMC/CART neurons, changes in

the axon projections of the AgRP/NPY neurons were

demonstrated, which were caused by the change

in the OBRb–SHP2–MAPK(ERK1/2) cascade, but not

by the STAT3-dependent pathway  [99]. Knockout of

the Agrp and Npy genes did not affect morphology

of the AgRP/NPY neurons, indicating crucial role of

the components of leptin system in their morpho-

genesis  [100]. The key role of AgRP/NPY neurons in

the control of reproduction is supported by the fact

that complete inactivation of the AgRP/NPY neurons

in the ARC of the hypothalamus under conditions of

impaired leptin signaling resulted in restoration of

fertility in both male and female ob/ob and db/db

mice  [101]. Knockout of the Lepr gene exclusively in

the AgRP/NPY neurons resulted in the delayed puber-

ty in mice, which is believed to be due to the weak-

ening of GABAergic transmission from the terminals

of the AgRP/NPY neurons to the Kiss1 neurons  [37].

It has also been shown that disruption of leptin sig-

naling in all populations of the GABAergic neurons

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BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

containing OBRb, including AgRP/NPY neurons, leads

to the decrease in the number of the Kiss1

ARH

and

Kiss1

AVPV/PeN

neurons and reproductive dysfunctions

[102]. Surprisingly, the simultaneous knockout of the

Lepr gene in the AgRP/NPY and POMC/CART neurons

in the mutant mice resulted in obesity, but without

significant impairment of reproductive function  [103].

This phenomenon highlights the existence of paral-

lel pathways of the leptin-mediated regulation of the

HPG axis, which will be discussed below.

In the hypothalamus of the leptin-deficient ob/ob

mice, the Npy gene expression is increased, and treat-

ment of these mice with leptin normalizes the level of

this neuropeptide, which indicates a role for leptin in

the control of NPY production and its signaling path-

ways  [104]. In contrast to AgRP, whose effect on the

HPG axis is considered mainly in terms of its inhibi-

tory effect on MC

R in the Kiss1 and GnRH neurons,

the data on the mechanisms of NPY regulation of this

axis are less clear. The effects of NPY on the HPG

axis, including the one mediated by leptin, largely de-

pend on sexual maturity, gender factors, and specific

action of NPY on the GnRH neurons– directly  [41] or

indirectly, through the Kiss1

ARH

neurons  [38,  40]. This

has been indirectly confirmed by the data obtained

in the study of the lizard Hemidactylus flaviviridis,

in which, at the different stages of reproductive cy-

cle, different pattern of regulation of neuropeptide

production in the diencephalon by leptin and other

adipokines was observed, including NPY and its re-

ceptor, which are involved, among other functions, in

the control of reproduction  [105]. This confirms im-

portance of the hypothalamic leptin and NPY systems

in implementation of the relationships between the

metabolic status and reproductive functions  [42], and

indicates early formation of these relationships in the

evolution of vertebrates  [105].

It should be noted, however, that the stimulating

effect of leptin on androgen production, due to in-

hibition of the NPY expression and increased GnRH

secretion, may also have negative consequences,

for example, in the development of PCOS  [88]. The

main pathogenetic factors of this disease, along with

obesity and hyperinsulinemia, are elevated LH lev-

els, increase in the LH/FSH ratio, and persistent hy-

perandrogenism. Accordingly, pharmacological NPY

preparations may be useful in the correction of PCOS

by reversing the stimulating effect of leptin on the

Kiss1 and GnRH neurons  [88].

Kisspeptin-expressing neurons. As noted above,

leptin activation of various populations of Kiss1 neu-

rons, primarily Kiss1

ARH

neurons, is mediated by the

leptin-mediated regulation of the POMC/CART and

AgRP/NPY neurons expressing OBRb  [13] (Fig.  3).

Inaddition, regulation of the Kiss1 neurons by leptin

depends on the developmental stage of the ani-

mal [106]. Before puberty, no response to leptin was

detected in the Kiss1 neurons, which is confirmed by

the absence of a stimulatory effect of this adipokine

on the content of the phosphorylated form of STAT3.

Leptin signaling in the Kiss1 neurons is activated

only after the completion of puberty, as illustrated

by the coordinated increase in the OBRb and Kiss1

expression in the Kiss1

ARH

and Kiss1

AVPV/PeN

neurons

and decrease in the Kiss1 expression in the Kiss1

neurons with the Lepr gene knockout  [106].

However, in addition to the mechanism described

above, other pathways of the leptin action on Kiss1

and GnRH neurons are possible, including those me-

diated by the neurons of the ventral premammillary

nucleus of hypothalamus (PMv). They have been

found to contain OBRb receptors and high levels of

STAT3 phosphorylation, and also express the vGLUT2

transporter (PMv

vGLUT2

neurons), which ensures secre-

tion of glutamate, and the adenylate cyclase-activating

polypeptide (PACAP) (PMv

PACAP

neurons) [107]. The

PMv neurons project to the cell bodies of the GnRH

neurons in the adjacent areas of the median eminence

[108,  109], as well as to the Kiss1

ARH

and Kiss1

AVPV/PeN

neurons [109]. Thus, a close functional relationship is

established between the activation of PMv neurons

and stimulation of the Kiss1 and GnRH neurons  [107,

110]. The OBRb-expressing PMv neurons are current-

ly considered a key link integrating metabolic signals

with the onset of puberty at the hypothalamic level

[111-113]. Restoration of leptin signaling only in PMv

is sufficient for the normal course of puberty [109].

Blocking the leptin signal in the PMv

vGLUT2

neu-

rons did not result in disruption of puberty [102],

whereas deletion of the gene encoding vGLUT2 in

the OBRb-expressing neurons slowed down pubertal

development  [110]. Selective knockout of the Pacap

gene in the PMv

PACAP

neurons caused delay in the

sexual development in the female mice, decrease in

the frequency and amplitude of LH secretion, disrup-

tion of the estrous cycle and ovulation, and, when

pregnancy occurred, decrease in the number of pups

in a litter and their survival  [107]. Knocking out the

Pacap gene in the adult female rats also resulted in

reproductive dysfunctions manifested as an extension

of the estrous cycle, decrease in the number of cor-

pora lutea, and decrease in fertility.

INSULIN SIGNALING PATHWAYS

In the postnatal period, insulin is synthesized

and secreted mainly by the pancreatic β-cells and is

subsequently transported into the CNS by transcytosis

through endothelial and epithelial cells of the BBB, as

well as by penetration through the fenestrated capil-

laries and ependymal cells of the median eminence,

ZORINA et al.698

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

Fig. 4. Major insulin signaling pathways, including in hypothalamus. Detailed description in the text. Legend: INSR – insulin

receptor; SHC – Src-domain-containing adapter protein2; SHIP2 – SH2-containing 5′-inositol phosphatase2; JNK1 – JunN-ter-

minal kinase 1; GSK3β – glycogen synthase kinase-3β. Other legends as in Fig. 2.

which is in many ways similar to the transport of

leptin  [114]. Insulin transport across the BBB is be-

lieved to be saturable  [114] and is mediated by bind-

ing not only to the insulin receptor (INSR), but also

to the IGF-1 receptors (IGF1R) and hybrid INSR/IGF1R

receptors  [115]. Alternative insulin transport path-

ways independent of INSR also exist, as well as the

possibility of de  novo insulin synthesis in some brain

structures  [116]. Hypothalamic mechanisms, based on

the principles of negative feedback, may make a cer-

tain contribution to the regulation of insulin transport

into the brain  [117]. A generalized diagram of insulin

signal transmission into the cell is shown in Fig.  4.

Since insulin in the brain can bind not only to

INSR, but also to IGF1R and the hybrid INSR/IGF1R

receptors, which are widely present in the CNS, this

determines a wide variety of neuronal responses to

insulin and existence of a complex network of insulin/

IGF-1-regulated cascades in the brain structures  [115].

Binding of INSR to the ligand leads to the change in

the receptor conformation and activation of its tyro-

sine kinase domain with autophosphorylation of three

residues: Tyr

1158

, Tyr

1162

, and Tyr

1163

. The phosphory-

lated INSR is able to interact with the IRS1/2 proteins,

which subsequently activate a number of regulatory

and adapter proteins containing phospho-Tyr-binding

domains  [118]. One such protein is the p85 regulatory

subunit of PI-3K, an enzyme that catalyzes formation

of the second messenger PI-3,4,5-P3. Binding of the

IRS protein to the p85 subunit releases the catalytic

HYPOTHALAMIC REGULATION OF THE GONADAL AXIS 699

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

p110 subunit of PI-3K, which ensures its translocation

to the plasma membrane and synthesis of PI-3,4,5-P

followed by activation of AKT kinase, a key effector

component of both insulin and leptin signaling. One

of the targets of AKT is glycogen synthase kinase  3β

(GSK3β), whose phosphorylation at Ser

leads to its

inactivation and ensures regulation of a large num-

ber of transcription factors, their coactivators, and

corepressors, including NF-κB, Snail, Notch, BAD,

and transcription factors of the FOX family. Thus,

the effects of insulin on gene expression, apoptosis,

autophagy, and cellular differentiation are realized

[119]. Another target of insulin is the MAPK cascade

(Ras–Raf–MEK–ERK1/2), which is responsible for ac-

tivation of numerous transcription factors (NF-κB,

MYT1, Elk-1, CREB, c-Fos, c-Jun, STAT1/3, etc.) and a

number of effector proteins that control many funda-

mental cellular processes, including those in neurons

[120]. At the level of the MAPK cascade, cross-inter-

action occurs between the insulin and other signaling

systems of the brain, including the leptin system.

Activation of INSR, as in the case of leptin, leads

to initiation of the negative feedback mechanisms that

are aimed at preventing hyperactivation of the insu-

lin system (Fig.  4). The most important among them

is activation of the tyrosine phosphatases PTP1B and

TCPTP, which dephosphorylate and inactivate INSR

and IRS proteins [118,  121]. Along with this, activity

of the IRS proteins can be inhibited by their phos-

phorylation at the serine residues with the help of

c-Jun N-terminal kinase-1 (JNK1)  [122]. Another nega-

tive feedback mechanism is aimed at inactivating the

3-phosphoinositide pathway, among which the most

important are phosphatases PTEN and SHIP2, which

inactivate PI-3,4,5-P

, and whose expression has been

shown in various parts of the brain [123, 124].

Recently, a new mechanism of negative regula-

tion of cellular sensitivity to insulin/IGF-1 was de-

scribed using a transmembrane protein called the in-

ceptor, which forms a complex with INSR and IGF1R

and inhibits their activity  [125]. Previously, the in-

ceptor, designated as the estrogen-regulated protein

ELAPOR1, was considered mainly in the context of

tumor development. It contains a mannose-6-phos-

phate-containing domain similar to that of the IGF-2

receptor. It has been established that in pancreatic

β-cells, the inceptor is localized in the clathrin-con-

taining vesicles near the plasma membrane, provid-

ing endocytosis of receptors  [125]. In addition, in the

pancreas, it could function as a sorting receptor in

the trans-Golgi network and in secretory granules,

directing proinsulin and insulin to the site of their

degradation in lysosomes  [126]. Expression of the in-

ceptor protein has also been shown in the brain neu-

rons (but not in glial cells), predominantly in the ARC

and paraventricular nuclei of hypothalamus, and its

expression is higher in females than in males [127,

128]. Insulin resistance in obesity is positively cor-

related with expression of the inceptor protein in the

ARC, and its neuron-specific knockout is associated

with the improved glucose tolerance  [128], however,

the detailed mechanisms of its action in the CNS have

not yet been studied.

Wide possibilities exist in terms of elucidating the

role of the inceptor protein expressed in the brain in

the regulation of reproductive functions. It has now

been established that the inceptor is expressed in

both male and female reproductive organs, and male

mice with knockout of its gene are infertile due to

impaired spermatogenesis  [129]. Considering that in-

sulin and IGF-1 are involved in the control of the

HPG axis through the Kiss1 and GnRH neurons, and

that this process is often disrupted in metabolic dis-

orders, the inceptor, which is a negative regulator of

INSR/IGF1R, may play a decisive role in modulating

sensitivity of the hypothalamic links of the HPG axis

to the metabolic signals. It could be assumed that

high expression of this protein in hypothalamus lim-

its the regulatory effects of insulin and IGF-1 on the

Kiss1 and GnRH neurons, making a significant con-

tribution to the dynamics of sexual development and

resistance of the HPG axis to the metabolic stress.

Although there is no data yet on the involvement of

inceptor in the regulation of Kiss1 or GnRH neurons,

it could be considered as a promising target for cor-

rection of reproductive dysfunctions in conditions

of insulin resistance and hyperinsulinemia.

Thus, insulin, like leptin, activates several con-

verging signaling pathways that fine-tune hypotha-

lamic neurons. Disruption of signaling at any of these

stages could cause gonadal axis dysfunction, especial-

ly in conditions of insulin resistance characteristic of

obesity and T2DM. Role of these signaling cascades

in regulating specific hypothalamic neuronal popula-

tions responsible for reproductive control is discussed

below.

HYPOTHALAMIC MECHANISMS OF INSULIN

REGULATION OF THE HPG AXIS

Connection between the insulin-dependent sig-

naling cascades and reproductive function has been

convincingly demonstrated in the models of neu-

ron-specific knockout of the components of these

cascades. Involvement of insulin in the control of

reproduction was first clearly demonstrated in the

study of the NIRKO mice with neuron-specific knock-

out of Insr and was confirmed in the further studies

with animals with knockout of this gene in different

neuronal populations. These mice exhibited impaired

spermatogenesis and folliculogenesis due to impaired

ZORINA et al.700

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

hypothalamic regulation of LH secretion  [130], with

insulin administration leading to normalization of

the pulsatile LH release  [131]. It was subsequently

shown that, at physiological concentrations, insulin

maintains normal pulsatile rhythm of the GnRH and

LH release, participating in integration of the signals

about nutritional status with the functional state of

the reproductive system. The stimulating effect of in-

sulin on GnRH secretion is indirect and is realized,

as in the case of leptin, through three main hypo-

thalamic mechanisms (Fig.  3): (i)  through activation

of the Kiss1 neurons, (ii)  through activation of the

POMC/CART neurons, and (iii)  through inhibition of

the AgRP/NPY neurons [15, 132]. All components of

the insulin system are present in all neurons that are

targets of insulin, including INSR and the hybrid re-

ceptors INSR/IGF1R, and INSR is also found, albeit in

relatively small quantities, in the GnRH neurons. This

suggests their direct regulation by insulin, although

this possibility has not yet been proven. Leptin uses

similar mechanisms to stimulate GnRH secretion, be-

ing a synergist of insulin at the level of the hypotha-

lamic links of the HPG axis, although, unlike INSR,

leptin receptors are absent in the GnRH neurons, as

a result of which direct effect of leptin on these neu-

rons is not even hypothetically feasible  [2].

Accordingly, it is logical to suggest that function-

al impairments of insulin signaling in the CNS and

peripheral nervous system in the context of T2DM,

obesity, and other metabolic disorders are among the

causes, and in some cases, the key cause, of repro-

ductive dysfunction and reduced fertility. Importantly,

as with leptin, insulin targets could include various

components of the HPG axis. Consequently, impair-

ments of the insulin signaling affect activity of vari-

ous components of the reproductive system, including

the hypothalamic components, which are involved in

the complex regulatory system of the synthesis and

secretion of neuropeptides regulating reproductive

functions. Restoring insulin levels and activity of the

insulin signaling system in the brain could normalize

the insulin-mediated hypothalamic regulation of the

HPG axis  [133,  134]. This is supported by our data

on the restorative effect of intranasal insulin admin-

istration on reproductive system functions both in

the rats with T1DM, which have systemic insulin de-

ficiency  [135], and in the animals with the neonatal

model of T2DM with severe insulin resistance [136].

When used in combination with semaglutide, a glu-

cagon-like peptide-1 agonist, and metformin, widely

used antidiabetic drugs, potentiation of the restor-

ative effect of intranasal insulin administration on

the HPG axis is observed, which may be a conse-

quence of both a systemic improvement in metabolic

and hormonal status under antidiabetic therapy and

the result of synergistic action of insulin, metformin,

and semaglutide on neuronal signaling [137-139]. In-

teresting results were obtained in the male rats that

were subjected to breastfeeding restriction on postna-

tal days 19-21, which developed metabolic syndrome

and reproductive dysfunctions as adults. Activation of

the brain insulin system during the initial period of

postnatal development (days 28-55) using intranasal

insulin resulted in the improved testicular response

to GnRH and normalization of testicular steroidogen-

esis in the adult animals [140].

GnRH neurons as potential insulin targets.

Insulin and its structural homologue IGF-1 are the

most important modulators of the functional activi-

ty of GnRH neurons (Fig.  3), which has been directly

demonstrated in in  vitro experiments, including the

effect of insulin on its key targets, AKT kinase and

ERK1/2 [131, 141, 142], and is indirectly confirmed

by the data from studies of the genetically modified

animals and clinical results. It should be noted, how-

ever, that histochemical methods did not reveal co-

localization of GnRH and INSR in the preoptic area

of the hypothalamus  [143], which may be due to the

low level of INSR expression in the GnRH neurons

and small number of these neurons themselves [115].

However, presence of a significant number of IGF1R

has been shown in the cell bodies of the GnRH neu-

rons  [115]. Since IGF1R and its heterodimers with

INSR could be targets for insulin, which, although

with low affinity, is able to bind to the ligand-bind-

ing site of IGF1R, some effects of insulin in the GnRH

neurons may be due to the presence of IGF1R and

INSR/IGF1R heterodimers. This may be a molecular

basis for complex patterns of regulation of the GnRH

neurons by the peptides of insulin family. Indirect ev-

idence in favor of this suggestion has been provided

by the data of DiVall et al. [144], who found that the

specific knockout of the Insr gene in the GnRH neu-

rons has little effect on the timing of puberty and

fertility in the mutant mice, while knockout of the

gene encoding IGF1R leads to the delay in puberty,

and this is accompanied by the changes in morphol-

ogy of the GnRH neurons and decrease in the level

of LH in the blood. Insulin effects are characterized

by the marked sexual dimorphism, since its adminis-

tration to women causes a surge in LH  [145], while

this effect is absent in men  [146], and this is believed

to be due to the modulating effect of estrogens on

insulin signaling in the GnRH neurons.

Under physiological conditions, a moderate post-

prandial increase in insulin maintains reproductive

functions, while deficiency in the insulin signaling

leads to hypogonadism, impaired spermatogenesis,

and follicle maturation  [130]. At the same time, in

obesity and T2DM, hyperinsulinemia leads to hyper-

stimulation of the HPG axis, causing increase in the

GnRH pulsation frequency, LH hypersecretion, and

HYPOTHALAMIC REGULATION OF THE GONADAL AXIS 701

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

ovarian androgenization in the female rats  [147].

Under the diet-induced obesity, knockout of the gene

encoding INSR in the GnRH neurons of the mutant

GnIRKO mice resulted in retention of fertility, nor-

mal GnRH secretion patterns, and blood LH levels

compared to the obese mice with normal Insr gene

expression  [147]. It is noteworthy that the pituitary

response to GnRH did not change in all of the studied

groups of animals. Thus, blocking insulin signaling in

obesity could significantly reduce negative impact of

the excess insulin on the GnRH neurons, while main-

taining ability of insulin to exert its effects through

IGF1R.

Kisspeptin-expressing neurons. Only about 5%

of the hypothalamic Kiss1 neurons express INSR [148],

and expression of this receptor varies significantly

in different localizations of the Kiss1 neuron types.

For example, in the Kiss1

AVPV/PeN

neurons, the level

of Kiss1 colocalization with INSR is much lower than

in the Kiss1

ARH

neurons, and this regional specificity

suggests significant differences in the insulin signal-

ing in these populations of Kiss1 neurons  [149]. Insu-

lin signaling in the Kiss1 neurons is mainly required

for the timely activation of the HPG axis during the

prepubertal period of the development, but its func-

tions begin to decrease in adulthood, which is con-

firmed by the results of the study of mice with knock-

out of the Insr gene in the Kiss1 neurons  [149]. Thus,

no significant differences in the estrous cycle and fer-

tility were found in the mutant animals compared to

the wild-type mice  [148]. Moreover, double knockout

of the Insr/Lepr genes in the Kiss1 neurons also had

little effect on reproductive functions, although it sig-

nificantly increased the timing of puberty onset  [150].

The relatively mild phenotype of the mice with the

Insr gene knockout in the Kiss1 neurons may be due

to the fact that some of the INSR functions could be

redistributed to IGF1R, which are also expressed in

the Kiss1 neurons and could be activated by insulin,

although at higher concentrations  [151]. It is possible

that suppression of the insulin-dependent pathways

in the Kiss1 neurons upon the Insr gene knockout

could be partially compensated by the IGF-1–IGF1R

signaling, especially since intraventricular admin-

istration of IGF-1 could cause depolarization of the

Kiss1

ARH

neurons and increase of LH secretion by the

anterior pituitary gland [151].

POMC/CART and AgRP/NPY neurons. POMC/CART

and AgRP/NPY neurons, like Kiss1 neurons, express

INSR and IGF1R, which allows them to act as key

components in the translation of insulin/IGF-1 sig-

nals to the GnRH neurons (Fig.  3). Insulin is able to

influence activity of the POMC/CART neurons in dif-

ferent directions and inhibit activity of the AgRP/NPY

neurons  [121], which provides a functional relation-

ship between the pulsatile rhythm of GnRH release

and food stimuli  [36]. Importantly, attenuation of the

insulin signaling in either POMC/CART or AgRP/NPY

neurons does not significantly affect reproductive

functions, which indicates the possibility of switch-

ing the insulin regulation of the HPG axis mediated

through them from one type of neuron to anoth-

er  [152]. Moreover, simultaneous deletion of the Insr

and Lepr genes in the POMC/CART neurons not only

caused hyperinsulinemia, hyperleptinemia, insulin

and leptin resistance, but also reduced fertility and

caused hyperandrogenism in the female mice, which

is a characteristic feature of PCOS  [153]. This indicates

the need for close interaction between the leptin and

insulin systems in the POMC/CART neurons in order

to perform their function of regulating the HPG axis.

As with the GnRH neurons, sexual dimorphism

has been observed in the insulin regulation of the

hypothalamic POMC/CART neurons. In particular, the

obesity-induced hyperinsulinemia leads to the de-

crease in the insulin-induced depolarization of the

POMC/CART neurons in the male rats without affect-

ing it in the females, which is due to the elevated

estrogen levels in females, which maintain insulin

sensitivity of the POMC/CART neurons  [33].

In addition to insulin, possible involvement of

IGF1 in the regulation of POMC/CART and NPY/AgRP

neurons has been postulated in recent years, includ-

ing in the aspect of relationship between metabolism

and reproduction  [154]. This is due to expression of

IGF1R in these neurons, which is a potential target

for both IGF-1 and insulin; moreover, in the POMC/

CART neurons its expression is significantly higher,

which is consistent with the pronounced anorexigenic

effect of IGF-1, which is not inferior to that of insulin.

There is evidence of a decrease in the IGF1-mediated

signaling in the POMC/CART neurons during hyperin-

sulinemia, which could weaken production of α-MSH

in them and, as a consequence, decrease activation

of the Kiss1 and GnRH neurons  [35]. Knockout of the

gene encoding IGF1R in the AgRP/NPY neurons re-

sulted in attenuation of the insulin signaling but did

not cause a significant weakening of the reproductive

functions  [155], which is similar to the effect of knock-

out of the Insr gene in the same neurons  [152]. This

may be due to the switch in the insulin/IGF-1-mediat-

ed regulatory pathways from the AgRP/NPY to POMC/

CART neurons, but does not exclude contribution of

interactions between the insulin and IGF-1 signaling

in the AgRP/NPY neurons.

Glial cells. Glial cells, microglia and astrocytes,

constitute up to half of all cells in the nervous tissue.

They are involved in the control of eating behavior,

energy expenditure, and reproductive functions to

no less extent than the hypothalamic neurons  [156].

Knocking out of the Kiss1 receptors in glial cells dis-

rupts interaction between the GnRH neurons and

ZORINA et al.702

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

glial cells and reduces the Kiss1-mediated LH surge,

accompanied by the delayed sexual development

[157]. Knockout of the Insr gene in astrocytes caused

delayed sexual development, impaired gonadal func-

tion, and reduced the number of pups per litter  [158].

Knockout of the Insr gene in microglia led to the pro-

gression of obesity in the mutant female mice kept

on a high-fat diet, and in the males it caused de-

crease in the number of POMC/CART neurons, which

may significantly contribute to the disruption of re-

productive functions, which, however, were not stud-

ied by the authors [159].

CROSS-TALK BETWEEN THE LEPTIN

AND INSULIN SYSTEMS AT THE LEVEL

OF HYPOTHALAMIC REGULATION

OF THE GONADAL AXIS

A key link between the metabolic dysfunctions

and reproductive health impairment is deregulation

of the leptin and insulin signaling pathways at the

level of specific hypothalamic neurons. Both excess

of hormonal stimuli, which occurs in obesity and

T2DM, and deficiency associated with the reduced

food availability at any stage of development could

lead to the reduction in reproductive potential. Leptin

and insulin regulate activity of the POMC/CART and

AgRP/NPY neurons synergistically, largely due to the

presence of common links in their signaling cas-

cades and cross-talk between these cascades. Thus,

both hormones, via the IRS proteins, stimulate AKT

kinase, a key effector in neuronal and glial cells,

and the MAPK cascade. Their signaling pathways are

negatively regulated by the same tyrosine phospha-

tases (PTP1B, TCPTP), which dephosphorylate active

Tyr-phosphorylated forms of the receptors and IRS

proteins, as well as serine/threonine protein kinas-

es, which block signal transduction through the IRS

proteins by phosphorylating them at the “inhibitory”

sites. As a result, weakening of the insulin cascade

could be compensated to a certain extent by the in-

crease in leptin signaling, and vice  versa, and this is

of great importance in diabetes, metabolic syndrome,

and obesity, which are characterized by the changes

in activity of leptin and insulin signaling, including in

hypothalamic neurons [49,  133]. In the case of POMC/

CART neurons, the targets of leptin and insulin could

be different populations of these cells, as a result of

which consistency and synergy of their effects is de-

termined not only by the interaction of the leptin and

insulin signaling systems in the individual neurons,

but also at the level of the integrative networks they

form [160].

Functioning of PI-3K, which is located at the in-

tersection of the insulin and leptin signaling cascades,

makes a significant contribution to the effects of these

hormones on the HPG axis. However, contributions of

these hormonal agents to the activation of PI-3K and

the downstream AKT kinase in different populations

of neurons involved in the control of GnRH secretion

and reproductive functions are not the same  [161].

Compensatory influences could also be observed be-

tween the leptin and IGF-1 systems, as demonstrat-

ed in the ob/ob mice deficient in the leptin gene.

Administration of IGF-1 to these mice normalized

metabolic processes, synaptic plasticity, and memo-

ry, as well as improved activity of the leptin targets

in hypothalamic neurons via the AKT–GSK3β–BDNF

signaling pathway, which may also be involved in

the control of reproduction  [162]. Existence of com-

pensatory switching of the signal between the insu-

lin and leptin signaling pathways in the POMC/CART

neurons is supported by the fact that in the mutant

female mice with knockout of either the Lepr gene

(Pomc-Cre, Lepr

flox/flox

line) or the Insr gene (Pomc-Cre,

flox/flox

) fertility was slightly changed (INSR knock-

out) or moderately decreased (OBRb knockout) [153].

At the same time, the female mice with the POMC/

CART neurons lacking both receptors (Pomc-Cre,

Lepr

flox/flox

) were characterized by the pro-

nounced hyperandrogenism, ovarian dysfunction,

and very low fertility  [153]. Deficiency of the leptin

signaling in the POMC/CART neurons caused by the

OBRb shutdown was accompanied by the compensa-

tory increase in the INSR expression and led to res-

toration of the activity of GnRH neurons and of the

entire HPG axis  [163].

CONCLUSION

Puberty, along with pregnancy and breastfeeding,

is considered a metabolic challenge that requires the

body to quickly adapt to the increased energy expen-

diture. Insulin and leptin play a key role in the in-

teraction between the metabolic and hormonal status

and functional state of the reproductive system. They

coordinate functioning of the integrative neural net-

works in the CNS that control and monitor eating be-

havior and energy metabolism, and the hypothalamic

links of the HPG axis  [134,  164]. At the molecular and

cellular levels, this is manifested by the changes in

STAT3 phosphorylation, disruption of the PI3K/AKT

cascade activation, increased expression of the nega-

tive regulators of insulin and leptin signaling (SOCS3,

PTP1B), and changes in the balance between the ac-

tivity of anorexigenic (POMC/CART) and orexigenic

(AgRP/NPY) neurons. While the transient physiological

insulin resistance develops at the onset of puberty

as an adaptive mechanism for rapid growth and de-

velopment of the reproductive system, the excessive

HYPOTHALAMIC REGULATION OF THE GONADAL AXIS 703

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

insulin levels contribute to fat accumulation and in-

creased leptin production. With the reduced energy

expenditure and unbalanced diet in adolescents, this

could lead to obesity with its characteristic insulin

and leptin resistance, which, in turn, could have an

extremely negative impact on the function of the HPG

axis during a critical period of reproductive system

development  [2]. In boys, adolescent obesity leads to

hypogonadotropic hypogonadism  [10,  11], while in

girls, although it accelerates puberty, it increases the

risk of PCOS, one of the triggers of which is hyperin-

sulinemia  [11]. In both cases, such changes in insulin

and leptin signaling could lead to infertility.

Although leptin and insulin target various com-

ponents of the HPG axis, including gonads and nearly

all reproductive tissues, their hypothalamic mecha-

nisms make the most significant contribution to the

regulation of reproductive functions. These mecha-

nisms involve a complex, multi-stage integrative net-

work of interactions between the various populations

of hypothalamic neurons (POMC/CART, AgRP/NPY, var-

ious types of Kiss1), which mediate dynamic, multi-

factor-dependent regulation of GnRH secretion and,

consequently, control activity of the entire HPG axis.

Deciphering the mechanisms of the leptin- and insu-

lin-regulated hypothalamic networks is a key area in

understanding formation and regulation of the HPG

axis, including relationship between metabolism and

its hormonal status, as well as the role of disruptions

of these mechanisms in the development of repro-

ductive dysfunctions, including those associated with

obesity and T2DM. Moreover, considering the above,

the use of leptin and insulin preparations, including

intranasal administration, as well as selective regula-

tors of leptin and insulin signaling in the CNS, could

be considered a promising pharmacological approach

for prevention or correction of reproductive dysfunc-

tions, including during the pre- and pubertal periods.

Therefore, preclinical studies aimed at identifying

optimal doses and durations of hormone administra-

tion to prevent development of central insulin and

leptin resistance are necessary. Furthermore, the use

of insulin/leptin during critical periods of develop-

ment, when the body is most sensitive to hormonal

changes, requires special caution. Long-term effects

of such therapy and its impact on reproductive poten-

tial, neurodegenerative processes, and carcinogenesis

remain poorly understood.

Abbreviations

AgRP agouti-related peptide

ARC arcuate nucleus of the hypothala-

mus

AVPV anteroventral periventricular

nucleus

BBB blood-brain barrier

CART cocaine- and amphetamine-

regulated transcript

ERα, ERβ estrogen receptors of the types α

and β

FSH follicle-stimulating hormone

GABA γ-aminobutyric acid

GnRH gonadotropin-releasing hormone

HPG axis hypothalamic-pituitary-gonadal axis

IGF-1, IGF1R insulin-like growth factor-1

and its receptor

INSR insulin receptor

IRS insulin receptor substrate

Kiss1 kisspeptin

Kiss1

ARH

neurons

neurons expressing kisspeptin

and localized in the ARC of the

hypothalamus

Kiss1

AVPV/

PeN

-neurons

neurons expressing kisspeptin and

localized in the AVPV/PeN of the

hypothalamus

LH luteinizing hormone

R, MC

R melanocortin receptors of the

types 3 and 4

α-MSH α-melanocyte-stimulating hormone

NPY neuropeptide Y

OBRb full-length leptin receptor

PCOS polycystic ovary syndrome

PeN periventricular preoptic nucleus

PI-3K phosphatidylinositol 3-kinase

PMv ventral premamillary nucleus

of the hypothalamus

POMC proopiomelanocortin

T1DM/T2DM type 1 and 2 diabetes mellitus

Acknowledgments

The authors express their gratitude to Zorina  A.I. for

assistance in preparing illustrations.

Contributions

Z.I.I., D.K.V., and Sh.A.O. – writing and editing the

text of the article; Z.I.I. and D.K.V. – preparation

of illustrations; Sh.A.O. – concept and supervision

of the work.

Funding

The work was financially supported by the Minis-

try of Science and Higher Education of the Russian

Federation, state assignment no.  075-00264-26-00

(IEPhB RAS).

Ethics approval and consent to participate

This work does not contain any studies involving hu-

man and animal subjects.

Conflict of interest

The authors of this work declare that they have no

conflicts of interest.

ZORINA et al.704

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

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