Adiponectin (ADIPOQ, ACRP30, apM1) was first described in the mid-1990s ^[1][2][3][4][3,4,5,6]. In 1995, Schrerer et al. ^[1][3] depicted a protein produced by adipocytes as the adipocyte complement-regulated protein of 30 kDa (ACRP30), the secretion of which increased under the influence of insulin. The concentration of adiponectin in plasma, reaching several dozen µg/mL, is many times (1000 times) higher than that of other peptide hormones and is inversely associated with body fat distribution ^[1][5][3,7]. The primary product of the adiponectin gene (AdipoQ), which is adiponectin (30 kDa in its full length), undergoes proteolytic cleavage to globular adiponectin, which can assemble into trimeric forms and higher-order structures ^[6][7][8,9]. In plasma, adiponectin occurs primarily in homomultimeric forms: trimers (low molecular weight), hexamers (medium molecular weight), and various high-molecular-weight multimers composed of 12 to 18 adiponectin molecules ^[8][9][10,11]. Initially, it was believed that the source of adiponectin was exclusively differentiating adipocytes ^[1][3]. Subsequent studies conducted in humans, rodents, pigs, and birds have shown that adiponectin is also synthesised by other cells and tissues, e.g., the skeletal muscles ^[10][11][12,13], hypothalamus, pituitary gland ^{[11][12][13][14][15]}[13,14,15,16,17], cardiomyocytes ^[16][18], osteoblasts ^[17][19], gonads ^{[11][13][18][19]}[13,15,20,21], uterus and placenta ^{[20][21][22][23][24]}[22,23,24,25,26], and adrenal glands and liver ^[11][25][13,27]. Adiponectin has pleiotropic effects. This adipokine can control energy homeostasis, insulin sensitivity, and feeding behaviour, and it plays an important role in the regulation of autonomic and neuroendocrine functions ^{[26][27][28][29][30]}[28,29,30,31,32]. Adiponectin exerts its biological effects mainly through two types of specific receptors, ADIPOR1 and ADIPOR2 (encoded by two distinct genes, ADIPOR1 and ADIPOR2, respectively), which were identified and characterised in 2003 by Yamauchi’s team ^[31][33]. ADIPOR1’s gene expression is high in the skeletal muscle, whereas the ADIPOR2 transcript is predominantly expressed in the liver. In subsequent experiments, high expression levels for both genes were also found in the pancreatic beta cells ^[32][34]. It is currently known that adiponectin receptors are universally expressed in human and animal bodies. The presence of ADIPOR1 and ADIPOR2 proteins or the mRNAs of their genes were found, among others, in the adipose tissue ^[33][35], central nervous system ^{[12][14][34][35]}[14,16,36,37], reproductive system ^{[13][18][20][22][23][24]}[15,20,22,24,25,26], heart, lungs, liver, kidneys ^[33][36][35,38], and endocrine glands ^[32][37][34,39]. The effects that adiponectin exerts through ADIPOR1 and ADIPOR2 are different. It has been shown that in mice, the action of adiponectin through ADIPOR1 appears to reduce glucose tolerance, motor activity, and energy expenditure and promotes an increase in adiposity. In turn, ADIPOR2 activation increases glucose tolerance, motor activity, and energy expenditure, reduces plasma cholesterol levels, and increases resistance to high-fat-diet-induced obesity ^[38][40]. In 2004, the extracellular protein T-cadherin was identified as the third adiponectin receptor, which may act as a coreceptor binding hexameric and high-molecular-weight adiponectin multimers ^[39][41]. This receptor most likely functions as an adiponectin-binding protein and does not directly participate in adiponectin intracellular signalling. It seems that T-cadherin/adiponectin interactions are of great importance in vascular homeostasis and cardioprotection ^[40][41][42,43].

In the pituitary gland, the expression of genes and proteins of the adiponectin system components (adiponectin, ADIPOR1, and ADIPOR2) has been examined in humans ^[12][14], pigs ^[15][35][17,37], rodents ^[30][37][42][32,39,44], and birds ^[11][13][43][13,15,45]. In humans, a high expression of adiponectin system proteins was observed in the anterior pituitary (in GH-, FSH-, LH-, and TSH-producing cells). Adiponectin and its receptors’ proteins were not colocalised with PRL- and ACTH-immunoreactive cells. In the intermediate lobe of the pituitary gland, adiponectin was detected in gonadotrophs (LH- and FSH-positive cells) and thyrotrophs, but neither the presence of ADIPOR1 nor ADIPOR2 was detected ^[12][14]. In turn, in pigs, the expressions of genes and proteins of adiponectin and its receptors were found in both the anterior and posterior lobes of the pituitary gland ^[15][35][17,37]. The expressions of proteins and genes of the adiponectin system components in the pituitary gland are related, among others, to the reproductive status of animals. In the beaver pituitary, the expressions of ADIPOR1 and ADIPOR2 were higher in males in relation to females and were the lowest during the reproductive season ^[37][39]. The expressions of genes and proteins of the adiponectin system in the pig pituitary changed during the oestrous cycle and were generally higher during the luteal phase than the follicular phase ^[15][35][17,37]. It has been shown that adiponectin can directly influence the secretion of pituitary hormones, although the results of these studies are ambiguous. In rat pituitary cell cultures, adiponectin inhibited GH and LH release ^[30][32]. On the other hand, it was observed that adiponectin stimulated GH secretion from isolated rat somatotroph cells ^[44][46]. Adiponectin did not affect basal LH secretion but increased basal FSH release by isolated porcine anterior pituitary cells ^[15][17]. In the murine AtT-20 pituitary corticotroph cell line and rat pituitary corticotroph cells, adiponectin stimulated basal ACTH secretion ^[45][47]. In turn, the pituitary cells isolated from macaques and baboons, under the influence of adiponectin, decreased ACTH and GH secretion and increased PRL secretion, with no changes in gonadotrophin and TSH release ^[46][48].

Resistin, also known as FIZZ3 (found in Inflammatory Zone 3) ^[47][49] or adipose tissue-specific secretory factor (ADSF), is encoded by the RETN gene, and was first described in the 2000–2001 period by three independent groups of researchers ^[47][48][49][49,50,51]. Resistin belongs to a group of cysteine-rich proteins generally referred to as resistin-like molecules (RELMs), four of which have been identified in mice (resistin, RELMα, RELMβ, and RELMγ). In humans, two proteins of the RELM family are known: resistin and RELMγ ^[50][52]. There is a fairly low similarity between human and mouse resistin (59%), and both proteins also differ in the main place of production; in mice, it is produced in the white adipose tissue, while in humans, the main sites of resistin synthesis are peripheral mononuclear blood cells, macrophages, and bone marrow ^[51][53].

Resistin is a secretory peptide that interacts with cells through a membrane receptor, although none of the postulated resistin receptors are specific for this adipokine. It has been suggested that these may be Toll-like4 receptors (TLR4) acting through the MAPK pathway, and the phosphorylation of ERK, P38, and JNK lead to an increase in the expression of NF-κB ^{[52][53][54][55]}[54,55,56,57]. Other signalling pathways associated with the TLR4 receptor are the PI3kinase/Akt—NF-κB pathway and the AMP-activated kinase (AMPK) pathway ^[56][58]. Another postulated receptor is an isoform of the extracellular matrix protein—delta-decorin—which is formed as a result of the proteolysis of decorin. The binding of resistin to delta-decorin activates the signalling cascade of protein kinase A and cyclic AMP, leading to the activation of the pro-inflammatory NF-κB transcription factor, as was found in murine progenitor adipocytes ^[57][59]. In mouse adipocyte progenitor cells, another putative receptor for resistin was found—receptor tyrosine kinase-like orphan receptor 1 (ROR1)—with the non-canonical WNT pathway with the WNT5a protein as an activating factor leading to the inhibition of ROR1 tyrosine phosphorylation, the modulation of the MAP kinase pathway, as well as Glut4 and Glut1 expression in 3T3-L1 cells ^[58][60]. In rodents, resistin inhibits AMP-activated kinase (AMPK) and induces an anti-inflammatory mediator suppressor of cytokine signalling-3 (SOCS-3). SOCS-3 may mediate resistin-induced insulin resistance and cytokine production, as it is a factor that reduces the insulin response of adipocytes ^[59][61].

Resistin was named due to its ability to block insulin and, consequently, impair glucose homeostasis in rodents ^[48][50]. As a result of obesity in mouse experimental models, the production of resistin in the adipose tissue increases. Silencing the resistin gene in mice alleviates symptoms of metabolic syndrome, such as hepatic steatosis, increased serum cholesterol, and very low-density lipoprotein levels. On the other hand, in mice expressing human resistin, glucose tolerance and hepatic insulin resistance have been demonstrated under chronic inflammatory conditions, as well as an increased production of pro-inflammatory cytokines (TNF-α, IL-1, and MCP-1) ^[60][62]. The pro-inflammatory effects of human resistin have been confirmed in other tissues, suggesting its association with diseases such as type 2 diabetes, rheumatoid arthritis, chronic kidney disease, sepsis, and coronary atherosclerosis ^[61][62][63,64]. The main effort in the study of resistin action is concentrated on its peripheral influences on the metabolic and inflammatory state of different organs. However, the influence of resistin on metabolic homeostasis mechanisms cannot be excluded through its influence on the activity of metabolic control centres in the hypothalamus and pituitary gland, as the presence of resistin and the possibility of its synthesis have been found in rodents ^[63][64][65,66]. The immunolocalisation of the protein showed its highest presence in the arcuate nucleus of the hypothalamus and the anterior and intermediate pituitary gland. In the pituitary gland, resistin expression has been shown to be dependent on the arcuate nucleus of the hypothalamus and changes with age. The destruction of the neurons of the arcuate nucleus significantly diminishes the expression of resistin in the pituitary gland ^[63][65]. In the hypothalamus, a shorter form of resistin (s-resistin), which is the intracellular form and is not secreted, was found ^[65][67]. The inhibition of s-resistin synthesis resulted in an increase in the activity of leptin signalling pathways and an insulin pathway in the rat hypothalamus. As a result, improvements in glycemia and insulin sensitivity and a decrease in inflammatory parameters were found in rats. Resistin administered intraventricularly or directly into the hypothalamus causes an increase in blood glucose levels, liver insulin resistance, and the production of cytokines TNF-α, IL-6, and SOCS-3 ^[66][68].

An increase in the secretion of GH and ACTH by resistin has been demonstrated in vitro in cultures of primary cells of the anterior pituitary gland of macaques and baboons ^[46][48] and a somatotroph cell line ^[67][69], and this effect is caused by intracellular signalling pathways similar to GHRH. These findings further strengthen the involvement of the hypothalamo-pituitary system in the development of the metabolic syndrome. The inhibition of LH secretion by resistin was found in the mouse cell line of LβT2 gonadotrophs by increasing the phosphorylation of AMP1K and Erk1/2 ^[68][70]. Peripherally administered resistin has a much greater effect on the secretion of hormones in the anterior pituitary gland. For example, in sheep, during a long day, the administration of resistin causes an increase in the secretion of LH, FSH, and PRL, while during a short day, the decreased secretion of LH and increased FSH and PRL secretion were found ^[69][71].

Apelin (apelin-17 and apelin-36) was observed in the anterior pituitary cells as well as in the pituitary intermediate lobe (apelin-17) ^[70][83] and in the posterior pituitary (apelin-36) ^[71][95]. In the pituitary gland of male rats, apelin was detected in the anterior part, mainly in corticotrophs, and to a lesser extent in somatotrophs ^[70][83]. In a few cells, the colocalisation of apelin and LH was observed, but FSH-, PRL-, and TSH-immunoreactive cells are devoid of apelin ^[70][83]. APLNR mRNA has been detected in the pituitary of rats and mice ^{[70][72][73][74]}[83,88,94,96]. APLNR was highly expressed in the rat anterior and intermediate pituitary ^[70][74][83,96], and it was expressed in lower amounts in the posterior lobe ^[70][83]. A high expression of APLNR was found in rat corticotrophs ^[70][83]. In the mouse pituitary, the expression of this gene and the density of apelin binding sites were high in the anterior part, moderate in the posterior part, and lowest in the intermediate part ^[72][88].

Apelin (apelin-17) in an ex vivo perfusion system increased ACTH secretion by rat corticotrophs ^[70][83]. In turn, in mice and rats, the i.c.v. administration of pyr-apelin-13 resulted in increases in the ACTH and corticosterone plasma levels, and in rats, it resulted in decreases in the prolactin, FSH, and LH plasma concentrations ^[75][76][97,98]. The authors of both of these publications suggested that the effect of apelin on the secretion of pituitary hormones may be mediated by hypothalamic CRH and AVP. In other studies in rats, a decrease in plasma FSH, LH, and testosterone was also observed after the intraperitoneal administration of apelin-13 ^[77][99]. Similar results were obtained in studies on ruminants. In sheep, apelin-13 (administered i.v.) induced significant increases in the concentrations of ACTH, aldosterone, and cortisol in plasma ^[78][100].

The expression of the gene encoding chemerin (TIG2, tazarotene-induced gene 2) was initially detected in psoriatic skin lesions in humans ^[79][101]. Currently, this gene is also called RARRES2 (retinoic acid receptor responder 2) ^[80][102]. Chemerin, a product of RARRES2, was identified in 2003 as an endogenous ligand of chemokine-like receptor 1 (CMKLR1), also called ChemR23 or chemerin receptor 1 ^[81][82][103,104]. Additionally, chemerin is a ligand of two other receptors, GPR1 and CCLR2 ^[83][84][105,106]. Originally, chemerin was described as the factor recruiting leukocytes to inflammatory sites and regulating the immune response and was classified as a chemokine ^[81][103]. Later, Goralski et al. ^[85][107] observed an unexpectedly high level of chemerin and CMKLR1 expression in human and mouse adipocytes, as well as the regulatory role of the adipokine in adipogenesis, and adipocyte lipid and glucose metabolism. This suggests that chemerin can be classified as a biologically active adipokine. The expressions of RARRES2 mRNA and chemerin protein are not limited to the skin and adipose tissue. Chemerin expression was also found in the endocrine tissues, gonads, liver, pancreas, and cardiovascular system in humans, rodents, pigs, cows, and turkeys. The expression of chemerin receptors is similarly widespread in the body (for a review, see ^[80][102]).

Nicotinamide phosphoribosyltransferase (NAMPT) is a protein that has the activity of both an intracellular enzyme (iNAMPT) and an extracellular cytokine/adipokine (eNAMPT) ^[86][112]. The adipokine eNAMPT, originally referred to as pre-B-cell colony-enhancing factor (PBEF), was originally isolated as a presumptive cytokine that enhances the maturation of B-cell precursors ^[87][113]. Fukuhara et al. ^[88][114] identified PBEF gene mRNA in human visceral fat and named its product visfatin. Visfatin is a 52 kDa protein secreted in mammals not only from adipose tissue ^[89][90][115,116] but also from a number of other tissues, including the central nervous system and gonads ^[91][92][93][117,118,119]. To date, specific receptors for visfatin have not been definitively identified, and published research results are often contradictory. It has been shown that visfatin can bind to the insulin receptor ^[88][94][114,120] or TLR4 ^[95][121]. Additionally, more and more studies indicate that visfatin binds to C-C motif chemokine receptor type 5 ^[96][97][122,123].

Irisin, named after the Greek messenger goddess Iris, is a novel 12.5-kDa polypeptide hormone with 112 amino acids, which was identified in 2012 by Boström et al. ^[98][129]. The adipokine is the product of type 1 membrane protein cleavage encoded by the fibronectin type III domain-containing 5 (FNDC5) precursor gene ^[98][129]. Until now, no specific receptor for irisin has been identified. The results of recent studies have demonstrated that in fat cells and osteocytes, irisin exerts its action by binding to the members of the αv integrins family, with the highest affinity to αv/β5 integrins. The treatment of osteocytes with irisin significantly stimulated the phosphorylation level of focal adhesion kinase (FAK), the major intracellular signal molecule responsible for integrin signalling. It is also known that irisin treatment in several cell types activates various signalling pathways, including cAMP/PKA, AMPK, Akt/PI3K, MAPK/ERK1/2, p38, and IKK/NF-κB ^{[99][100][101][102][103][104][105]}[130,131,132,133,134,135,136].

In addition to skeletal muscle as well as subcutaneous and visceral adipose tissue, irisin is expressed in tissues of the hypothalamic–pituitary–gonadal (HPG) axis, including the rat and tilapia pituitary ^{[103][106][107]}[134,137,138]. It is suggested that FNDC5 gene expression can be controlled by tissue- and sex-specific regulatory mechanisms. In monkeys, the FNDC5 transcript levels were significantly higher in the female muscles, posterior hypothalamus, and whole pituitary than in the corresponding male tissues ^[108][139]. Similarly to other adipokines, irisin is likely to have pleiotropic properties.