Adiponectin and Its Physiological Function in Ruminant Livestock
2022 Volume 10 Pages 115-122
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2022 Volume 10 Pages 115-122
Adiponectin is a hormone that belongs to a group known as adipokines that white adipose tissue is a primary source of it. This hormone has multiple functions in livestock, including lipid metabolism, energy regulation, immunity, and insulin sensitivity, with energy metabolism and ovarian function being the most important. Adiponectin’s action is determined by its interactions with its receptors, including AdipoR1 and AdipoR2. These receptors (AdipoR1 and AdipoR2) are found in multiple tissues, including adipose tissue, skeletal muscles, and other tissues. Besides, these receptors are expressed in the hypothalamus, pituitary, and gonadotropin-releasing glands. Accordingly, adiponectin and its receptors are believed to affect livestock productivity and reproduction. Adiponectin promotes skeletal muscle proliferation by interacting with the p38 mitogen-activated protein kinase (p38-MAPK) pathway, thereby influencing carcass characteristics (including meat marbling, ribeye muscle area, and carcass fat thickness). Besides, it appears to be related to mammal fertility because adiponectin is located on the hypothalamic-pituitary-gonadal (HPG) axis, which is involved in mammal reproductive functions. However, the physiological action of adiponectin in livestock needs to be clarified. It is crucial to investigate the association of adiponectin with productive and reproductive traits in livestock. This review summarizes the adiponectin effects on productivity along with reproductive traits in livestock.
Adipose tissue is a crucial endocrine organ that secretes hormones and cytokines called adipocytokines. The following are among them: adiponectin, apelin, chemerin, resistin, ghrelin, and visfatin [1]. Adiponectin is one of the largest adipokines, also known as AdipoQ, ACRp30, apM1, and GBP28 composed of 244 amino acids with a molecular weight of 30 kDa that belongs to the superfamily C1q/TNF-α (tumor necrosis factor-α) [2]. It comprises an N-terminal signal peptide, a collagenous domain, and a globular C1q-like domain at its C-terminus [3, 4] (Fig. 1). Serum adiponectin is composed of trimers (low molecular weight, LMW), hexamers (medium molecular weight), and multimers (high molecular weight) [4, 5]. In cattle, this hormone is encoded by the adiponectin gene located within the bovine chromosome 1 region [6], while sheep are located on chromosome 1q27 comprises three exons and two introns (Adopted from ncbi.nlm.nih.gov). Adiponectin is a hormone that is mainly produced by white adipose tissue (WAT) [4]. Along with WAT, this hormone is secreted by muscles, myocytes, the hypothalamus, the pituitary, and the ovaries [7, 8]. Adiponectin correlates negatively with fat mass and is implicated in the regulation of fat metabolism [9], immune system, glucose metabolism, insulin sensitivity, and reproduction [10]. The ovary and oocytes express both adiponectin and receptors in many livestock like chickens [11], bovine [12], and goats [13]. Additionally, adiponectin receptors are found on follicular and luteal cells in the ovary, making them potentially responsible for reproduction in farm animals [12, 14]. Nevertheless, the mechanisms of action and the active forms begin by binding to receptors [15].
Figure 1: Structure and specific forms of adiponectin after secreted from adipose tissue to serum
The effects of adiponectin occur because of the binding to its receptors, including AdipoR1 and AdipoR2. According to their ability to bind adiponectin, three putative adiponectin receptors have been described: adiponectin receptors 1 and 2 (AdipoR1 and AdipoR2) and T-cadherin recently [4]. The T-cadherin, also known as H (heart)-cadherin or cadherin 13 (CDH13), without transmembrane or cytoplasmic domains, is attached to the surface membrane through glycosylphosphatidylinositol (GPI) anchors [16]. There is evidence that T-cadherin competes with adiponectin receptors 1 and 2 to bind adiponectin or interfere with adiponectin signal transduction [4, 17]. The AdipoR1 and the AdipoR2 receptors have seven transmembrane domains that are distinct from all other G protein-coupled receptors by having an extracellular carboxy content and an intracellular amino content [18]. The AdipoR1 gene encodes 375 amino acids with a predicted molecular weight of 42.4 kDa, while the AdipoR2 gene encodes 311 amino acids with a predicted molecular weight of 35.4 kDa. Those two receptors share 67% amino acid sequence identity, proving their structural similarity [19]. Adiponectin binding to its receptors activates several transduction signals, with the transcription factor AMP-activated protein kinase (AMPK) and p38 mitogen-activated protein kinases (p38-MAPK) being the most important [20, 21] (Fig. 2).
Figure 2: Adiponectin and signaling transduction via adiponectin receptors (AdipoR1 and AdipoR2) activation. Leucine zipper motif (APPL1), AMP-activated protein kinase (AMPK), p38 mitogen-activated protein kinases (p38-MAPK).
AMPK is a ubiquitous cellular energy sensor that is activated when the intracellular ratio of AMP to ATP is elevated [22]. Through the suppression of adiponectin, AMPK appears to promote acetyl-CoA carboxylase (ACC) phosphorylation, fatty acid oxidation, glucose uptake, and other productive and reproductive traits [18]. There is evidence that adiponectin receptors interact with a phosphotyrosine residue and a pleckstrin homology domain that is composed of a leucine zipper motif (APPL1) [23]. It has been confirmed that APPL1 modulates AMPK and p38-MAPK phosphorylation in response to adiponectin [24]. In addition to being essential for cell cycle initiation, activated p38-MAPK also plays a crucial role in cell proliferation and survival [25]. It appears that the proliferation, anti-inflammatory, and other physiological effects of adiponectin are mediated primarily by its activation of the PI3K-Akt pathway via APPL1 [17]. It has also been suggested that APPL1 interactions with androgen receptors are responsible for the effects of reproductive hormones on adiponectin signaling [23]. Numerous mammal organs express adiponectin and its receptors, indicating this hormone could be involved in productive and reproductive function in livestock [26, 27].
In livestock, adipose tissue releases numerous adipokines as well as adiponectin that contribute to energy homeostasis, glucose metabolism, and lipid metabolism [28]. By phosphorylating and activating AMPK in both skeletal muscle and liver, it increased insulin sensitivity by improving glucose utilization and fat oxidation, thus influencing carcass traits in Nanyang cattle [29]. Like in humans, because of combining adiponectin with insulin, glucose tolerance and insulin sensitivity are improved [30]. It enhances skeletal muscle glucose uptake and fatty acid oxidation by stimulating AMPK [31]. Human skeletal muscle proliferation is stimulated by adiponectin via the p38-MAPK pathway [32]. The adiponectin hormone increases adipocyte lipid storage for the human body as well as inversely correlates with plasma triglycerides levels and positively correlates with HDL cholesterol levels [33]. Therefore, it can play a vital role in determining the growth and productive traits of livestock.
In domestic animals, adiponectin polymorphisms are associated with live body weight and productive traits. Adiponectin gene polymorphism is known to affect the fat thickness, growth traits including birth weight, body weight, average daily gain, and body sizes, and carcass traits such as marbling, ribeye muscle area, and fat thickness in Angus cattle [29, 34], suggesting that this gene is a potential candidate for animal productivity. The adiponectin gene polymorphism is closely related to carcass and meat quality traits, and therefore can be used as a molecular marker for high-quality meat production [28, 29]. There is evidence that a C>T mutation within exon3 of the adiponectin gene is associated with carcass traits in Qinchuan beef cattle carrying the CD genotype. Cattle with the CD genotype had greater slaughter weight, fat thickness, back fat thickness, crural girth, and tenderness than cattle with the CC genotype [35]. Genetic variants in the ADIPOQ exhibited significant positive effects on marbling score (MAR) in Hanwoo cattle [36]. For goats, a novel mutation has been reported in the ADIPOQ 3’UTR. This locus did not show a significant statistical relationship with body weight traits in goats [37]. Besides, inherited traits such as growth traits (pre-weaning growth rate) and carcass traits (yield of leg-, loin-, and total-lean meat) are correlated positively with ADIPOQ haplotypes in New Zealand (NZ) Romney lambs [28]. Further, ADIPOQ polymorphisms in the ovine have been associated with sheep fatness [38]. The results of previous studies suggest that this gene plays a fundamental role in several productive traits among livestock.
In animal production based on economic principles, reproductive traits are four times more influential than productive traits [39]. Additionally, sheep’s reproductive potential and fertility are also associated with health conditions and biological characteristics (e.g., growth) [40]. Reproductive traits are complex traits due to genetic factors and endocrine signal transpositions between the pituitary, ovary, and adipose tissues in sheep [41, 42]. Adipose tissue and its secreted factors have been implicated in all aspects of mammal reproductive functions [43]. The human adipose tissue contains signaling proteins such as adipocytokines and adipokines [1]. Some domestic animals, like cows, goats, and ewes, express adipokines in their ovarian cells, which modulate ovarian physiology [44]. Recent evidence suggests that adiponectin plays a crucial role in mammal reproductive function. Adiponectin inhibits basal- and GnRH-stimulated LH secretion by gonadotrope cells through phosphorylation of AMPK [45]. Besides, pituitary AMPK is known to act as a sensor of energy, controlling bovine gonadotropin secretion and reproduction [46]. It has been shown that animals of all species express adiponectin and its receptors [14], and it affects ovarian steroidogenesis [47]. Additionally, adiponectin regulates mammal oocyte nutrient sensing via AMP-activated protein kinase (AMPK) pathways [48]. According to data regarding adiponectin's role in ovarian function, adiponectin exerts its effects through the hypothalamic-pituitary-ovarian axis. These peripheral effects of adiponectin are mediated primarily by AdipoR1 and AdipoR2. These receptors have been found in the brain and ovaries. Therefore, adiponectin could affect livestock reproduction.
Adiponectin has been shown to regulate mammal gonadoliberin (GnRH) in the hypothalamus [49] (Fig. 3). AMPK is activated by adiponectin to inhibit human GnRH release and cause hyperpolarization of plasma membranes as well as calcium influx [50]. The number of GnRH immunoreactive neurons decreased with adiponectin mutations, suggesting that adiponectin could control GnRH secretion in the mammal hypothalamus [51]. As well, human adiponectin is present in pituitary cells that produce the luteinizing hormone (LH), follicle-stimulating hormone (FSH), thyroid-stimulating hormone, and growth hormone [52]. FSH-induced progesterone secretion by the mammal granulosa cells has been reported to be mediated by the MAPK pathway [53, 54]. In addition, there is growing evidence that adiponectin and AMPK work in concert to control mammal ovarian cell function [55].
Figure 3: The adiponectin roles in ovarian physiology in livestock. Luteinising hormone receptor LHR, P450 side-chain cleavage enzyme (CYP11A1), cytochrome P450c17 (CYP17A1), IGF-1: insulin-like growth factor-1, P4: progesterone, E2: oestradiol, gonadotropin-releasing hormone (GnRH), luteinising hormone (LH), follicle-stimulating hormone (FSH). ↑ increase, ↓ decrease,
Adiponectin is a hormone that can be produced by ovarian cells, as demonstrated by AdipoR1 and AdipoR2 mRNA and/or proteins present in the bovine ovary [12, 14] and cumulus cells and the oocyte [14]. Additionally, adiponectin is accumulated in mammal follicular fluid from the local circulation and/or the local tissues [56]. Dupont et al. [55] demonstrated that adiponectin is a vital signal for follicles growth and oocytes, suggesting it is involved in follicular dominance and oocyte survival in rodent, bovine, ovine, and human ovaries. In small bovine follicles, adiponectin stimulates the proliferation of cells induced by IGF-1 (insulin-like growth factor-1) [14, 21]. Besides, increased adiponectin gene expression in granulosa cells in large bovine follicles has been associated with higher levels of estradiol in the follicular fluid [12, 21]. In sheep, the highest levels of adiponectin expression are found in granulosa cells [57]. Additionally, mammal antral follicles exhibited significantly greater levels of adiponectin protein than primitive, primary, small, and large preantral follicles [58].
There has been little research regarding the association between genetic polymorphisms in the ADIPOQ gene and reproductive traits in livestock. Only one study investigated the relationship between ADIPOQ gene polymorphisms and reproductive performance in domestic pigs. A new SNP (c. 1138G > A) is associated positively with litter size in the Wannan Black pig [59]. The ADIPOQ/TasI genotypes at nucleotide position 1431C>T also indicated that cows with TT genotypes had a longer calving interval (CI), a prolonged lactation period (LP), and greater milk yield (TMY) than CC or CT cows in Indian Sahiwal cows [6]. Except for this, there is little literature on the relationship between this gene’s polymorphism and sheep reproductive performance.
Adiponectin, a hormone derived from adipocytes, plays a vital role in the regulation of livestock energy metabolism, productive and reproductive traits. By activating AMPK of skeletal muscle and liver, adiponectin improves insulin sensitivity and increases glucose utilization and fat oxidation, influencing growth, carcass composition, and meat quality traits. In addition, it affects the reproductive system by exerting central effects on the highest branch of the hypothalamic-pituitary-ovarian axis, inhibiting GnRH and GnRH-induced LH secretion. Regulation of phenotypic traits concerning the adiponectin gene suggested that this gene is fundamentally linked to several phenotypic traits among livestock.
