|
 
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| REVIEW ARTICLE |
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| Year : 2022 | Volume
: 7
| Issue : 4 | Page : 152-160 |
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Adiponectin: A reliable marker
Geetha Bhaktha1, Shivananda Nayak B2, Manjula Shantaram3
1 Multidisciplinary Research Unit, Shimoga Institute of Medical Sciences, Shivamogga, Karnataka, India
2 Department of Biochemistry, Subbaiah Institute of Medical Science, Shivamogga, Karnataka, India
3 Department of PG Studies and Research in Biochemistry, Mangalore University, Jnana Kaveri Post Graduate Centre, Kodagu, Karnataka, India
| Date of Submission | 09-Nov-2022 |
| Date of Decision | 08-Dec-2022 |
| Date of Acceptance | 09-Dec-2022 |
| Date of Web Publication | 07-Jan-2023 |
Correspondence Address:
Geetha Bhaktha
Multidisciplinary Research Unit, Shimoga Institute of Medical Sciences, Shimoga, Karnataka
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/jncd.jncd_77_22
The biological functioning of adiponectin (APN) has been well understood for two decades. Numerous clinical and animal studies have paved an understanding of the exposed physiological functions of APN in obesity and its related disorders. APN mediates its action through its receptors to achieve its function. Apart from its contribution to metabolism, APN also defends the cells from cell death and decreases the inflammation in various cell types through receptor-dependent mechanisms and also contributes to the reproductive function. APN communicates between adipose tissue and other organs and hence is a potential therapeutic target for obesity and its related pathogenesis.
Keywords: Adiponectin, bone, cancer, cytokine, diabetes, females
How to cite this article:
Bhaktha G, Nayak B S, Shantaram M. Adiponectin: A reliable marker. Int J Non-Commun Dis 2022;7:152-60 |
| Introduction | |  |
Adipose tissue is now considered an active endocrine tissue because of the secretion of biologically active molecules – adipokines (leptin and adiponectin [APN]), protein of acute inflammation (haptoglobin), growth factors (transforming growth factor-beta), cytokines (tumor necrosis factor-alpha, interleukin-6 [IL-6], and IL-8), lipid-metabolizing regulators (lipocalin-2 and retinol-binding protein), glucose metabolism regulators (visfatin, omentin, and resistin), vascular homeostasis, and angiogenesis-related proteins (plasminogen activator inhibitor and vascular endothelial growth factor). This is also observed to be involved in many physiological processes such as satiety feeling, immunity, regulation of blood pressure, metabolism, homeostasis, and energy expenditure.[1],[2]
The two types of adipose tissue present in humans are white adipose tissue (WAT) and brown adipose tissue (BAT) which not only have dissimilar functions but also different localization with cellular composition.
| Structure | | |
- APN also referred to by other names such as APN, ADIPOQ, and ACRP30 is synthesized exclusively from WAT;however, smaller quantity secretion is also observed from BAT[3]
- Studies also observed the biosynthesis and secretion in other tissues at much lesser concentrations, in several tissues such as skeletal muscle, cardiomyocytes, liver, bone marrow, and cerebrospinal fluid[4],[5],[6],[7],[8]
- APN is a 30 kDa multimeric glycoprotein comprising 244 amino acids[9]
- APN is encoded on human chromosome 3q27.3 by the ADIPOQ gene that spans 15,790 bp[10]
- The peptide domain of APN has three parts – a short signal peptide domain, a collagenous domain, and a C-terminal globular domain. A striking similarity has been observed with C1q[10]
- APN can exist in a variety of different isoforms[11],[12]
- As trimers – low molecular weight
- Two trimers can then form middle-molecular-weight hexamers
- The trimers then associate with 12-or 18-monomers to form high-molecular-weight (HMW) multimers
- A smaller part of the peptide domain-globular form (gACR) also exists in circulation.
The HMW form is known to elicit the most biological functions, the better indicator of glucose intolerance, thiazolidinedione treatment, and deviation of HDL levels during weight reduction in obese subjects.[13],[14],[15],[16] [Figure 1][17] shows the different forms of APN with its receptors. | Figure 1: APN with its receptor. Reproduced from Formolo DA et al.[17] APN - Adiponectin
Click here to view |
| Structure of Adiponectin Receptors | | |
AdipoR1 and AdipoR2 are transmembrane proteins with seven domains. Each has an external C-terminal and an internal N-terminal region.
It is observed that AdipoR1 has a high affinity for the globular form of APN gACRp, whereas AdipoR2 has a moderate affinity for both forms.[18] The receptors are ubiquitously expressed, but AdipoR1 is abundant in skeletal muscle and endothelial cells while AdipoR2 is abundantly present in the liver.[19] A study by Kodwaki et al. showed that AdipoR1 and AdipoR2 mediate pleiotropic biological actions such as metabolic and anti-apoptotic action.[20] Hence, a decrease in receptors of APN can cause a variety of obesity-related diseases.
T-cadherin, another identified receptor for the HMW form of APN,[8] is deficient in the intracellular structural domain and has been suggested as the binding protein for APN and hence is important in APN signaling.[21],[22],[23],[24]
APPL1 is an adaptor protein with multiple interaction domains. It is involved in APN signaling and its effects on metabolism, in an insulin-signaling pathway, in APN-dependent insulin sensitization in skeletal muscle.[25] APPL1 binds to AdipoR1 and AdipoR2 and is involved in its anti-inflammatory and cytoprotective effects on endothelial cells. APPL1 is also known to exert roles in cell proliferation, apoptosis, cell survival, endosomal trafficking, and chromatin remodeling.
| Adiponectin-associated Roles | | |
Metabolic syndrome (MetS) is a collection of abdominal obesity, hypertension, dyslipidemia, and hyperglycemia. APN is considered an adipokine that is important as a therapeutic tool for type 2 diabetes mellitus (T2DM) and MetS because it exerts multiple key functions such as antidiabetic and anti-atherogenic activity.[19],[26],[27] In contrast to other adipokines, APN is produced in high levels by adipose tissue and enters circulation. Although the circulating levels are detrimental to metabolic effects, levels in humans range variedly with an average of around 3–30 μg/mL.[28],[29],[30] Observational studies have shown that APN can prognosticate the development of T2DM through insulin resistance. A decrease in levels of APN declines the protective role against risk factors associated with MetS.[31],[32],[33] Animal experimental evidence has provided insight into the functioning of APN, where the administration of APN in a recombinant form in mice with a high-fat diet was able to demonstrate weight loss by fat oxidation and energy expenditure regulation.[34] Several literature reviews have expressed an inverse relationship between MetS and APN levels which have shown that a rise in body mass index (BMI) decreases this hormone level, as observed in overweight individuals than in lean persons.[35],[36] Presuming that hypoadiponectin might be a critical aspect in the development of various diseases, the mechanism has been represented as an important therapeutic target through recombinant APN. A study about the recombinant APN has been shown to reduce the abortion rate in mice by regulating Th17/Treg ratio.[37] The damage-diminishing effects in the experimental acute pancreatitis model through recombinant APN were observed through nuclear factor-kappa B;[38] further, the effects of exogenous intraperitoneal administration of APN molecules have shown an increase in the survival rates of rats with a decrease in levels of inflammatory cytokine and intra-abdominal adhesion.[39] The results of the study by Rothan et al. have shown that the bioactivity of recombinant APN is beneficial as a therapeutic agent for diabetic tendinopathy.[40]
[Figure 2] depicts the effect of APN on major organs and its role.[41] | Figure 2: APN showing potent antidiabetic, anti-atherogenic, cardioprotective, and anti-inflammatory functions. Reproduced from Ye R et al.[41] APN - Adiponectin
Click here to view |
| Adiponectin and Major Organs | | |
Apart from the roles that are significant in the regulation of metabolism and homeostatic control of the body's energy balance, it is now understood that APN also contributes to other functions of other target cells, namely liver and muscle.
Podocyte loss also occurs in diabetic nephropathy, Adiponectin stimulates AMPK in podocytes,A study by Rutkowski et al. was able to show the podocyte of the kidney was protected from cell death under diabetic conditions.[42] In addition, APN is known to show action on the endothelial cell by inhibiting endothelial dysfunction and decreasing atherosclerotic function.[43] Studies have also supported the data that the deficiency of APN contributes largely to cardiac hypertrophy.[44] The mechanism understood at this level is that stimulation of AMP-activated protein kinase (AMPK) causes inhibition of extracellular signal-regulated kinases. It is also known that induced overproduction of APN caused improvement in the functioning of cardiac cells. This effect was partially mediated by the cyclooxygenase 2-dependent production of prostaglandin E2. Shabita R and his colleagues were able to demonstrate the APN-COX-2 regulatory axis in the protection of the heart cells from ischemia-reperfusion injury.[45]
The understanding of APN receptor-associated ceramidase has identified certain diverse actions of the cytokine. Studies from Holland et al. found that the hepatocyte content of ceramide is increased in both high-fat diet-induced obese animals and genetically obese mice. Insulin sensitization was observed along with decreased ceramide content in the hepatocyte.[46]
| Adiponectin and Cancer | | |
APN has been shown to play a critical role in a wide variety of processes including the pathogenesis of obesity and its associated malignancies. Several interactions through its receptor and its interactions in regulating cell survival, cell death, and metastasis are noted. The most notable notion is that hypoadiponectinemia is connected with a bigger risk of having cancer and its poor prognosis. [Figure 3] represents the mechanism of the protein in cancer cells of respective organs.[47] | Figure 3: Summary of mechanism of APN in cancer. Reproduced from Di Zazzo E et al.[47]
Click here to view |
The action of APN in reducing the risk of cancer is understood to be through the AMPK pathway.[48] Activation of AMPK is also seen during exercise and starvation. This is known to be a controller of cellular energy also. It is well studied that cancer-protective action is played through the inhibition of cell cycle growth and progression.[49] APN is known to inhibit the growth of macrophage precursors and hence suppresses the phagocytic activities of mature macrophages in vitro and TNF synthesis.[50],[51] In addition, APN is known to decrease the secretion of adhesion of molecules such as intercellular adhesion molecule 1 and vascular cell adhesion molecule, inhibit IL-6 and IL-8 production, and be associated with inducing the anti-inflammatory cytokines IL-10 and IL-1 receptor antagonists.[52],[53],[54],[55]
APN is mostly confined to be inversely associated with BMI/body weight and obesity-associated cancer. Of further interest, the isoform of the receptors (AdipoR1 and AdipoR2) is seen to be expressed in both ER+ and ER− breast cancer cell lines.[56],[57] This adipose tissue-derived protein, when added to human breast cancer cell lines, shows decreased proliferation of these cell lines, suggesting clearly that estrogen and APN interact through some signaling pathways.[58],[59]
Further, insulin resistance/hyperinsulinemia along with obesity has been associated with the pathophysiology of colorectal cancer (CRC). An inverse correlation between blood levels of APN and CRC risk has been observed in several studies and meta-analyses.[60],[61],[62] Ishikawa et al., in their study, were able to show that APN levels are decreased in patients with gastric cancer along with an inverse correlation with the depth, stage, and size of the tumor.[63]
| Adiponectin and the Female Reproductive System | | |
The mechanistic action of APN over the reproductive system is studied via the hypothalamus–pituitary–gonadal axis and also through hormonal actions. Females have higher circulating APN than males during the progression of puberty.[64],[65] The APN system is supposed to influence the reproductive process. Studies by Archanco et al. have confirmed that rat oviduct has shown the expression of the APN gene and the expression of this gene varied throughout the estrous cycle.[66] Further, expression of APN in reproductive parts such as human endometrial epithelial and stromal cells, porcine myometrium, endometrium, and trophoblasts is seen.[67],[68] Surprisingly, it is seen that APN is involved in cross-talk between embryo and mother. Further, a study was also shown that a higher rate of failure of implantation in females with endometriosis had lower levels of APN than in normal individuals.[69] The serum concentration of APN is known to be decreased in disorders associated with ovarian steroidogenesis as seen in polycystic ovary syndrome.[70]
Nearly 5%–10% of females of reproductive age are affected by polycystic ovary syndrome (PCOS).[70] Genomic evidence has revealed that SNPT45G at an APN gene is more commonly observed in females with PCOS.[71] The data concerning levels of APN in preeclampsia are controversial, but evidence from the genetic study has shown an association of preeclampsia with SNP in the APN gene.[72]
Nearly 1%–10% of overall pregnancies are affected by gestational diabetes (GDM). Patients with GDM are reported to have lower APN levels than normal which was independent of BMI and insulin sensitivity.[73] Several studies imply that the deficiency of APN may be a convincing explanation for the abnormalities identified in intrauterine growth restriction in children.[74] Studies have also linked APN with in vitro fertilization success and hence a marker for fertility.[75],[76] Taken together, failure in implantation or loss due to either PCOS or diabetes or endometriosis is due to irregular expression of APN gene.
| Adiponectin in Storage and Release of Glucose | | |
Adiponectin expression was up-regulated in ConA-mediated acute liver failure. Therefore, adiponectin might play a role in the control and limitation of inflammation in the liver.Animal experimental evidence from Wolf AM et al. has shown that adiponectin levels have increased during inflammation and damage to the hepatocyte.[77] It is observed that APN can be induced in mouse liver which has been subjected to hepatic fibrosis by CCl4. Furthermore, the levels of protein and mRNA were detected in the normal liver of mice and levels of expression were upregulated in ConA-mediated acute liver failure.
Levels of APN in the fatty liver are well documented and suggest that APN plays a protective role against fatty liver in animal as well as human observational studies. In the rodent model, the levels of APN were reduced, and a similar effect was observed in alcohol-induced steatosis in ob/ob mice.[78],[79] The results were expectedly similar in humans with chronic hepatitis with liver steatosis but were not in a positive correlation with the grading of steatosis.[80] Since genetic polymorphism studies were able to substantiate the cause of liver fibrosis and fatty liver, more insight needs to be documented.
APN molecule has shown a protective effect in pancreatic cells. APN-deficient mice were presented with lower plasma insulin levels during a hyperglycemic state which links APN with insulin secretion.[81] Also reported that the levels of expression of of mRNAs for the adiponectin receptors (AdipoR1 and AdipoR2) were similar in both human and animal pancreatic beta cells. With a further level up, it revealed that recombinant APN increased insulin secretion which was through increased AMP phosphorylation.[82],[83]
The insulin-sensitizing effect of APN molecules is well documented. A study by Hara et al. reported that the HMW ratio to the total APN level is a better factor in representing insulin resistance.[13] Hence, polymorphism associated with the multimerization of APN molecule has led to the presented development of T2DM.
More clear insight into APN and the glucose-lowering effect was given by APN knockout mice. It was seen that in these mice, the circulating insulin was normal, but the glucose-lowering effect was lost.[84] The use of recombinant APN in these mice through injection restores the condition.[34] A similar observation was seen in diabetic pigs.[85] Thus, results of several studies have come to consider similar results that hypoadiponectinemia is associated with a diabetic state.
These studies depict that APN molecules decrease glucose production independent of insulin levels. A study by Combs et al. has shown that APN suppresses gluconeogenesis.[86] Hence, APN molecules can act as a messenger between energy release and metabolically relevant organs.
| Adiponectin Involved in Hypertension | | |
Changes in APN levels have been well related to hypertension though there are several risk factors associated with it. Clinical studies have shown that an increase in levels of APN is evident during exposure to angiotensin II injection.[87] More insight was given when renal sympathetic nerve activity was seen to be depressed when APN was given in a dose-dependent manner.[88] Taken together, it suggests that APN can show an immediate effect on blood pressure.
| Adiponectin and Exosomes | | |
The extracellular vesicles generated inside the cells are termed exosomes, which are also secreted from adipocytes. Adipose-derived extracellular vesicles are known to exercise the metabolic functions in cells, namely hepatocytes, skeletal cells, etc., by transporting microRNAs to their target cells and modulating the gene expression. A study by Kita et al. has shown that exosome biogenesis is accelerated by APN in adipocytes. The molecular mechanisms of APN are mediated by cells expressing T-cadherin. During the process, multivesicular bodies are synthesized and released as exosomes.[89] Stimulation of exosomes through APN was detected in muscle cells and associated with improved muscle regeneration. These findings have opened novel insights into the importance of APN.[90]
| Adiponectin and Bone | | |
The APN's actions on bone turnover have been comprehensively explored in both in vivo and in vitro studies. APN studies concerning age and bone mineral density (BMD) are been reported. Among the male gender, in a population of age above 60 years, an inverse relationship between serum levels of APN and BMD was observed. Similar results were also found in middle-aged Korean men, Chinese men, and also in subjects with an age group of 20–29 years.[91],[92],[93],[94] Association among the women about serum APN and BMD varied in both pre- and postmenopause states. In postmenopause subjects, decreased BMD with increased serum levels of APN was observed in most of the studies.[95],[96],[97] Further, APN emerged to exert an independent effect on BMD in perimenopausal women or was not correlated with BMD.[99] Bone mass remodeling and its mechanism are known to be regulated through estrogens. Studies show that the cytokine inhibits bone resorption.[100],[101] Further, it is understood that estrogen is important for the maintenance of bone formation and hence may be the reason for bone loss with aging.[102] The mechanism may be by direct initiation of apoptosis of the cells involved in bone-resorbing through the estrogen receptor mechanism.
| Conclusion | | |
Hypoadiponectinemia is now considered a risk factor for obesity and its related disorders. More understanding of the mechanism of action of this cytokine can provide new thought into the pathology associated with it. Overall, the evidence indicates that monitoring the levels of APN may be considered a useful tool for predicting or early detection of obesity-related pathologies and hence can be an effective therapeutic target. Overall more in-depth basic and clinical research is needed to precisely identify the efficiency of APN.
Ethical approval
This review paper is not currently being considered for publication elsewhere and the review paper has no interaction with animal nor did human but purely collected from various journals sources. Henceforth no ethical consent form necessary.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
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