Adiponectin and Its Receptors Physiological Roles: History
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Contributor:
Mayank Choubey
,
Munichandra B. Tirumalasetty
,
Nalini S. Bora
,
Puran S. Bora

Tthere has been a captivating focus of interest in elucidating the intricate crosstalk between adiponectin (APN), a versatile fat-associated adipokine and ocular pathologies. Unveiling the intricate relationship between adipocytokine APN and its receptors (AdipoRs) with aging eye disorders has emerged as a fascinating frontier in medical research. 

  • obesity
  • adiponectin (APN)
  • adiponectin receptors (AdipoRs)
  • age-related macular degeneration (AMD)

1. Introduction

Adiponectin (APN), a hormone linked to obesity regulation weighing around 30 kDa, is produced by the ADIPOQ gene and primarily originates from white adipose tissue. APN plays a crucial central role in various vital bodily functions such as managing glucose and fatty acid metabolism [1][2]. It also contributes to maintaining glucose and lipid balance [3], overall energy regulation [4], immune responses [5], and the effects of aging and metabolism [6][7][8]. Notably, APN extends its safeguarding influence on ocular tissue [8][9]. The retina, a metabolically very active component often outpacing even the brain’s metabolic rate, triggers blood vessel growth and regression due to its high-energy needs. APN has also demonstrated protective effects against multiple retinal disorders, including diabetic retinopathy (DR) [9], choroidal neovascularization (CNV) arising from age-related macular degeneration (AMD) [10], and other additional retinal complications [11].
Neovascular AMD is a complex retinal condition where an individual’s genetic disposition is influenced by the effects of age and environmental stressors. These factors cascade in a series of signaling pathways that involve inflammation, oxidation, and/or angiogenesis within the retinal pigment epithelial (RPE) cells and choroidal endothelial cells (CECs) [8]. Ultimately, this process results in vision loss due to the advancement of CNV. Navigating the world of AMD, researchers encounter its dual personas: the wet and dry types. Unveiling its dramatic impact, the wet form takes the spotlight, emerging as a chief instigator of irreversible blindness and the complete eclipse of central vision among the elderly. The hallmark of this drama is CNV [8][10]. In contrast, the dry type, though not synonymous with total blindness, casts a shadow over central vision, posing challenges in reading, driving, and perceiving the world around. As the curtain rises on advanced stages, dry AMD can take a perilous turn, progressing into geographic atrophy (GA) or even evolving into its wet counterpart, both orchestrating a symphony of severe vision loss [10]. Initiating a cascade of events, retinal hypoxia triggers an upsurge in metabolic demands, setting off signaling pathways that endeavor to tap into new vascular resources, ultimately culminating in the eye’s neovascularization [10]. The literature hints at a shift in the balance of two predominant circulating adipokines, APN and leptin, pivotal players in metabolic modulation across diverse tissues. This dynamic duo might play a role in driving the progression of neovascular eye conditions [9]. Further insights point to the heightened release of leptin, a hormone originating from adipocytes, as a harbinger of disrupted energy equilibrium, increased oxidative stress on vascular endothelial cells (ECs), and consequent dysfunction of these cells, ultimately contributing to retinopathy [12]. In parallel, another metabolic influencer, primarily sourced from adipocytes, APN, joins the orchestra of metabolic irregularities in the retina. The levels of circulating APN are intricately tied to DR [13][14], the development and advancement of premature retinopathy [15], and age-related macular degeneration [16]. This correlation is underscored by research, including studies involving laser-induced choroidal neovascularization [17][18] and a rodent model of oxygen-induced proliferative retinopathy, where higher circulating APN levels correlate with suppression of pathological vascular proliferation [19]. 

2. Adiponectin and Its Receptors Physiological Roles

2.1. Unlocking the Mysteries of APN/AdipoRs: A Journey through Discovery, Structure, and Forms in Circulation

During the mid-1990s, APN’s discovery unfolded as a harmonized effort across four research laboratories [20][21][22][23]. In contrast, the identification of APN receptors denoted as AdipoRs, underwent a protracted gestation period, finally coming to fruition in 2003 through pioneering work by Yamauchi et al. [24]. This milestone was achieved by selectively extracting two strongly associated seven-transmembrane receptors isoform, AdipoR1 and AdipoR2, from human skeletal muscle [25]. The foundational architecture of APN is constructed with a carboxy (C)-terminal globular domain paired with an amino (N)-terminal collagen-like domain [26]. The AdipoRs adopt the form of integral membrane proteins, where the N-terminus faces internally, and the C-terminus faces externally—a distinctive arrangement that diverges from the topology and role of other recognized G protein-coupled receptors (GPCRs) [27]. In a pattern of ubiquity, APN and AdipoRs manifest their presence across diverse tissues [28]. In addition to the dynamic duo of AdipoRs, APN extends its influence through interaction with the receptor T-cadherin, although, at present, its role seems less pivotal in comparison to AdipoRs [29].
The obesity-related peptide APN assumes a complex structural configuration and circulates within the bloodstream in different molecular forms: a trimer, hexamer, and a higher molecular weight (HMW) oligomer. These diverse APN variants exhibit varying levels of biological activity, with HMW oligomer APN being identified as the biologically energetic iteration of this hormone [30]. Interestingly, in specific scenarios, the HMW form has demonstrated superior insulin-sensitizing properties when compared to trimers or hexamer forms. In addition to its intricate structural diversity, APN undergoes glycosylation, a crucial post-translational modification necessary for maintaining its functionality. Its concentration in circulation typically ranges from 3 to 30 µg/mL in both humans and rodents, making it one of the most abundant adipokines present in the plasma [31][32].

2.2. Tissue Distribution, Mechanism, Physiological and Pathological Relevance of APN/AdipoRs Pathway

Primarily originating from adipocytes, APN is expressed in various locations in addition to plasma and imparts favorable influences on several metabolically demanding organs and cell types [33][34]. These include liver parenchymal cells (PCs), such as hepatocytes [35], skeletal muscle and myocytes [36], the brain [37], blood vessels [38], and reproductive organs in both males and females [6][39], as well as ocular tissues [9][40]. AdipoR1 and AdipoR2 exhibit broad and abundant expression, not limited to skeletal muscle and liver tissues but also extending to macrophages [41], the hypothalamus [42], white adipose tissue [43], reproductive tissues [44][45], and the retina [46]. In both in vitro and in vivo studies, AdipoRs have emerged as pivotal mediators of APN signaling [8]. APN engages with its two well-established, distinct cell-surface receptor variants, AdipoR1 and AdipoR2 [24]. Furthermore, AdipoR1 plays a more prominent role in initiating the AMP-activated protein kinase (AMPK) pathway, leading to the inhibition of hepatic glucose production and an increase in fatty acid oxidation. On the other hand, AdipoR2 is primarily associated with activating the peroxisome proliferator-activated receptor alpha (PPARα) nuclear receptor pathways, which in turn promote fatty acid oxidation and mitigate tissue inflammation and oxidative stress [47]. In metabolic organs targeted by insulin, such as the liver and skeletal muscle, the expression of AdipoRs significantly increases during fasting conditions compared to refed conditions in rodent models. Additionally, in vitro studies have revealed that insulin reduces the expression of AdipoRs through the phosphoinositide 3-kinase/FoxO1-dependent pathway [48]. The levels of APN in circulation and the presence of AdipoR1/R2 expression in metabolically active organs remain lower in obese and diabetic individuals as compared to healthy and lean individuals [49][50][51]. There is a significant reduction in APN concentrations among obese patients with Type 2 diabetes (T2D) and infertility [52]. In most cases, insulin acts as a stimulating factor, while tumor necrosis factor-alpha (TNF-α) serves as an inhibitor of APN signaling and secretion [53]. Additionally, it exerts a controlled influence on inflammatory responses by mitigating the production and functional activity of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) within macrophages through the inhibition of NF-κB activation, as elaborated earlier [54]. Furthermore, APN is recognized for its specific actions in regulating metabolism and developing insulin sensitivity.
APN also plays a vital role in managing multiple physiological processes, including glucose utilization, lipid biosynthesis, energy homeostasis, and inflammatory and retinal function [15][55]. Lack of APN secretion and expression globally or locally leads to insulin resistance, glucose intolerance, and hyperlipidemia in rodents [56][57]. APN along with other adipocytokines plays a primary pathophysiological function in the interaction between metabolism and reproduction and may be associated with the detrimental effect of aging on male reproductive actions [7][39]. The use of APN supplementation could potentially serve as a crucial therapeutic approach for addressing reproductive disorders associated with obesity, such as male and female infertility [6][58]. Knockdown experiments involving the ADIPOQ gene in skeletal muscles demonstrate the pivotal function of AdipoR1 in orchestrating various processes, including but not limited to β-oxidation, AMPK and PPAR pathway activation, glucose uptake [59]. AdipoR1 plays a role in elevating the phosphorylation of AMPK within the liver, consequently affecting the gluconeogenesis process. Concurrently, AdipoR2 is accountable for the removal of reactive oxygen species (ROS) and the initiation of nuclear receptor PPAR activation, along with the downstream modulation of target genes associated with β-oxidation. The emergence of nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) accompanied by fibrosis and inflammation in obese rats fed a high-fat/high-cholesterol diet highlights the involvement of AdipoRs in regulating hepatic fatty acid metabolism. The decreased expression of AdipoRs isoforms during NASH was linked to lower levels of PPARα and AMPKα 1/2. Furthermore, specific tissues played a crucial role in determining these effects. AdipoR1 in the liver played a role in activating AMPK, while AdipoR2 was actively engaged in activating PPARα, resulting in heightened insulin sensitivity [60][61]. Due to their proficiency in establishing cross-organ communication and its lipid sequestration capabilities, APNs assumes an essential role in the preservation of lipid and glucose homeostasis. In a particular investigation, the overexpression of adiponectin and its associated receptors (AdipoRs) yielded numerous favorable outcomes, notably the reduction of visceral adiposity, amelioration of inflammatory responses, and mitigation of hepatic fibrosis [62].

This entry is adapted from the peer-reviewed paper 10.3390/biomedicines11113044

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