Fat tissue is one of the sites where lipid deposition occurs, and in recent years, it has been discovered to have endocrine functions. Fat tissue can secrete various hormones or cytokines through autocrine, paracrine, or endocrine mechanisms, collectively referred to as adipocytokines. Currently identified adipocytokines mainly include adiponectin, leptin, resistin, visfatin, interleukin-6 (IL-6), and tumor necrosis factor α (TNF-α). Among them, adiponectin is one of the adipocytokines found to be negatively correlated with obesity. Understanding the structure and tissue distribution of adiponectin, and exploring its role in regulating lipid metabolism, is a hot topic in the research of nutrition and energy metabolism.
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Discovery and Structure of Adiponectin
Adiponectin, formerly known as Acrp30, AdipoQ, GBP28, or apM1, was initially identified and isolated from humans and rodents. In 1995, Scherer et al. screened a cDNA fragment with digoxin labeling from 3T3-L1 adipocytes, which encoded 249 amino acids. The protein structure resembled complement factor C1q, leading to its designation as adipocyte complement-related protein of 30 ku (Acrp30). Hu et al. isolated a new fat gene from human, rat, and mouse adipose tissues, naming it the AdipoQ gene. Meada et al. identified a gene abundantly expressed in adipose tissue in the abdominal subcutaneous and visceral fat, naming it apM1 (adipose most abundant gene transcript 1). Nakano et al. isolated a 28 ku gelatin-binding protein from human plasma encoded by apM1, calling it gelatin-binding protein of 28 ku (GBP28). It was not until 1999 that Arita et al. officially unified the name of the substance discovered by these teams as adiponectin. Researchers have identified this gene in various domestic animals such as pigs, cows, sheep, chickens, and ducks, as well as aquatic animals, but there are no reports in reptiles and amphibians.
There are differences in the number of exons, chromosomal localization, types, and quantities of encoding nucleotides and amino acids in the adiponectin gene among different species. Mammalian adiponectin consists of 3 exons and 2 introns, while the avian gene contains 2 exons and 1 intron, both encoding 240-250 amino acids. Adiponectin is mainly composed of an N-terminal signal peptide, a non-homologous region, a collagenous structure domain, and a C-terminal globular structure domain. The presence of the N-terminal signal peptide suggests that adiponectin is a secretory protein, and the C-terminal globular structure domain is relatively conserved. Recent studies have found that small peptide fragments in the C-terminal globular structure domain of adiponectin have functions similar to adiponectin. In vivo, adiponectin exists in the forms of full-length adiponectin (fAd) and globular adiponectin (gAd), with gAd exhibiting stronger biological activity.
Tissue Distribution of Adiponectin
In the early stages of research, scientists initially identified the expression of mammalian adiponectin exclusively in adipose tissue. However, advancements in research methodologies and technologies have unveiled a broader scope of adiponectin expression, extending beyond adipose tissue to encompass the placenta, muscles, blood, and embryonic cells. Surprisingly, in non-mammalian species like chickens, zebrafish, and rainbow trout, adiponectin has been detected in diverse tissues such as the brain, pituitary gland, and liver.
Furthermore, the expression levels of adiponectin in various tissues exhibit correlations with factors such as species, gender, and growth stages. This widespread distribution of adiponectin across different animal tissues hints at its potential involvement in a myriad of biological functions. Scientific confirmation has established that adiponectin serves diverse roles, including but not limited to enhancing insulin sensitivity, mitigating atherosclerosis, safeguarding vascular endothelial cells, participating in appetite regulation, and promoting glucose uptake.
Noteworthy is the observation that the heightened expression of adiponectin in adipose tissue in both mammals and birds suggests a pivotal role in lipid metabolism. Numerous studies have delved into its regulatory functions in lipid metabolism, shedding light on the intricate mechanisms through which adiponectin contributes to metabolic processes in these organisms. This evolving understanding underscores the intricate web of connections between adiponectin and various physiological functions, unveiling its potential as a key player in maintaining metabolic homeostasis.
Adiponectin Signaling Adaptor Proteins
After adiponectin first binds to the C-terminus of the adiponectin receptor, the N-terminus of the adiponectin receptor is recognized by associated signaling adaptor proteins, activating downstream signaling factors such as AMPK and PPAR, thereby exerting biological functions. Adiponectin receptors mainly include adiponectin receptor 1 (AdipoR1), adiponectin receptor 2 (AdipoR2), and T-cadherin. Studies have shown that AdipoR1 and AdipoR2 can mediate various biological effects of adiponectin, while T-cadherin is mainly involved in anti-atherosclerosis. There is relatively less research on T-cadherin-mediated lipid metabolism.
Fig.1 Overall structures of AdipoR1 and AdipoR2 (Tanabe H., et al., 2015).
Four signaling adaptor proteins that can directly interact with AdipoR1 and AdipoR2 have been discovered, namely adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1 (APPL1), casein kinase II (CK2), receptor for activated C kinase 1 (RACK1), and endoplasmic reticulum protein 46 (ERp46). APPL1 can bind to both AdipoR1 and AdipoR2, while CK2, RACK1, and ERp46 only bind to AdipoR1. In the regulation of lipid metabolism by adiponectin, signaling adaptor proteins APPL1 and CK2 play important roles. Among them, APPL1 is the first identified signaling adaptor protein that can bind to adiponectin receptors and contains BAR, PH, and PTB domains. In C2C12 cells, adiponectin can induce the binding of the PTB domain of APPL1 to AdipoR1, leading to the interaction of the BAR domain of APPL1 (5~270 aa) with liver kinase B1 (LKB1), thereby activating AMPK, promoting ACC phosphorylation, and enhancing fatty acid oxidation. In addition, in C2C12 myoblasts, the regulatory subunit of the signaling adaptor protein CK2 (CK2β) can bind to the N-terminus of AdipoR1, and CK2 inhibitors can significantly inhibit the effect of globular adiponectin (gAd) in promoting ACC phosphorylation. Furthermore, it is still unclear whether there are other signaling adaptor proteins involved in the lipid metabolism process.
Adiponectin Regulates Lipid Metabolism
Adiponectin, a pivotal hormone central to lipid metabolism regulation, exerts profound lipid-lowering effects through a myriad of pathways. Its primary mechanisms encompass the facilitation of fatty acid oxidation and the inhibition of lipid synthesis.
In the realm of promoting fatty acid oxidation, adiponectin assumes a pivotal role by binding to AdipoR1/2 receptors, thereby instigating the activation of the AMPK signaling pathway. This activation triggers the phosphorylation of ACC in muscle and liver cells, culminating in the stimulation of fatty acid oxidation. The intricacies of this process involve upstream factors, including APPL1, CK2, and LKB1, and variations in the response of target genes within the AMPK-PPARα signaling pathway across diverse cell types. Notably, adiponectin, acting through the SIRT1-AMPK axis mediated by AdipoR1/2, exerts an influence on fatty acid oxidation, particularly under pathological conditions.
Conversely, in the inhibition of lipid synthesis, adiponectin takes a proactive stance by activating the AMPK signaling pathway. This activation suppresses the transcriptional activity of SREBP-1c and diminishes the expression of downstream target genes (such as ACCα, SCD1, and FAS), effectively thwarting lipid synthesis. Moreover, adiponectin, through the regulation of the AMPK and PPARα signaling pathways by AdipoR1/2, significantly impacts the expression of factors like SREBP-1c, Acox1, and Ucp2, thereby further impeding lipid synthesis. Recent research has brought to light additional factors, namely ATGL and HSL, which may serve as downstream effectors mediating adiponectin's lipid-lowering effects via the AMPK pathway.
To encapsulate, adiponectin assumes a pivotal role in both promoting fatty acid oxidation and inhibiting lipid synthesis, exerting its influence on lipid metabolism through a plethora of pathways. This multifaceted hormone holds promising therapeutic implications for obesity and related metabolic disorders. However, a comprehensive understanding of adiponectin's specific regulatory mechanisms in diverse tissues and under various pathological conditions necessitates further in-depth research.
References
- Tanabe H.; et al. Crystal structures of the human adiponectin receptors. Nature. 2015, 520(7547): 312-316.
- Karbowska J.; Kochan Z. Role of adiponectin in the regulation of carbohydrate and lipid metabolism. Journal of Physiology and Pharmacology. 2006, 57: 103.
- Scherer P. E.; et al. A novel serum protein similar to C1q, produced exclusively in adipocytes. Journal of Biological Chemistry. 1995, 270(45): 26746-26749.
- Hu E.;et al. AdipoQ is a novel adipose-specific gene dysregulated in obesity. Journal of Biological Chemistry. 1996, 271(18): 10697-10703.
- Maeda K.; et al. cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (AdiPoseMost abundant Gene transcript 1). Biochemical and Biophysical Research Communications. 1996, 221(2): 286-289.
- Nakano Y.; et al. Isolation and characterization of GBP28, a novel gelatin-binding protein purified from human plasma. The Journal of Biochemistry. 1996, 120(4): 803-812.
- Arita Y.; et al. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochemical and Biophysical Research Communications. 1999, 257(1): 79-83.
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