The body's proper function relies on hormonal balance, with white adipose tissue recognized as an endocrine organ due to its secretion of adipokines. These molecules, including vaspin (visceral adipose tissue-derived serine protease inhibitor), impact various bodily functions like lipid metabolism, inflammation, and reproduction. Imbalances in adipokine levels correlate with conditions such as infertility, diabetes, and increased food intake. Discovered in 2005, vaspin, also known as SERPINA12, is associated with insulin resistance, obesity, and inflammation, with notably higher levels found in obese individuals.
Related Products
Vaspin Structure and Expression
Vaspin, an adipokine classified under the serpin family, is also known as SERPINA12. It targets kallikrein 7 and 14, crucial for skin desquamation. Vaspin exhibits typical serpin structural domains with three β-sheets, nine α-helices, and a flexible reactive center loop (RCL). Its amino acid sequence shares 40.5% homology with α1-antitrypsin. Human, rat, and mouse vaspins differ slightly in amino acid composition. Interestingly, vaspin's glycosylation doesn't hinder its inhibitory activity against kallikrein 7. Vaspin's gene, SERPINA12, is located on chromosome 14 and its single nucleotide polymorphisms influence serum levels. Vaspin is expressed in various tissues like visceral and subcutaneous adipose tissue, liver, pancreas, placenta, skin, and ovaries. Its expression correlates with obesity, insulin resistance, and hormonal changes, suggesting its role as a compensatory molecule. Hormones like insulin and metformin influence vaspin expression, and their levels vary with gender, age, and circadian rhythm, implying intricate regulatory mechanisms in the body's physiology.
Vaspin Receptor GRP78 and the Mechanism of Vaspin Action
Vaspin interacts with the 78 kDa glucose-regulated protein (GRP78), also known as heat shock protein family A member 5 (HSPA5) or binding immunoglobulin protein, on the cell surface. GRP78, with its ATP binding domain (ABD) and substrate binding domain (SBD), shares homology with the HSP70 family and plays crucial roles in protein translocation across the endoplasmic reticulum (ER) membrane and intracellular calcium homeostasis. Its expression, regulated by factors like hormones, impacts cell proliferation, survival, and various physiological processes in tissues like the reproductive tract and adipose tissues. Additionally, dysregulation of GRP78 is linked to cancer, cardiovascular, and neurodegenerative diseases.
Studies have shown that vaspin binds to GRP78 via its helical domains in the N-terminus, initiating intracellular signaling pathways. However, the specific binding site and mechanism of signal transduction remain unclear. Vaspin also interacts with phospholipids, crucial for membrane trafficking, and modulates various kinase pathways like protein kinase B (AKT), AMP-activated kinase (PRKAA1), and mitogen-activated protein kinase (MAPK). These interactions regulate cellular functions such as apoptosis, inflammation, and endothelial nitric oxide synthase activity. Co-localization studies further reveal complex interactions between vaspin, GRP78, and other proteins like MTJ1 and voltage-dependent anion channel (VDAC), highlighting the intricate regulatory network through which vaspin influences cellular processes.
Fig. 1 Summary of mechanism of vaspin action (Kurowska P, et al. 2021).
Vaspin's Role in the Hypothalamus and Pituitary
Vaspin, a recently discovered adipokine, exerts significant influence within the hypothalamus and pituitary gland, pivotal areas for metabolic regulation and hormone secretion. Studies in mice and humans have revealed vaspin's presence in the hypothalamus and cerebrospinal fluid, suggesting its involvement in central metabolic control. Notably, administration of vaspin in rodents reduces food intake and blood glucose levels, akin to the effects of leptin, albeit with a transient nature.
Further investigations indicate that vaspin acts directly within the hypothalamus to modulate neuropeptide expression, favoring anorectic pathways while suppressing orexigenic signals. Moreover, central administration of vaspin correlates with decreased hepatic glucose production and enhanced insulin sensitivity, possibly mediated through the dorsal vagal complex and vagus nerve. Interestingly, vaspin levels in serum may also impact eating behavior in humans, although genetic polymorphisms associated with vaspin concentrations show no clear link to dietary habits.
Mechanistically, vaspin's actions in the hypothalamus may be intertwined with its interaction with the glucose-regulated protein 78 (GRP78), known for its multifaceted roles in cellular homeostasis and signaling. Studies suggest that GRP78 overexpression in specific hypothalamic nuclei can reverse obesity-associated phenotypes, hinting at vaspin's potential involvement in these processes.
In contrast, research on vaspin in the pituitary gland remains limited, though changes in pituitary function appear to affect vaspin levels in peripheral tissues. Disruptions in pituitary hormone secretion correlate with alterations in vaspin expression, underscoring the intricate interplay between the pituitary and metabolic regulation. Further exploration is warranted to elucidate vaspin's role in pituitary function and its implications for overall metabolic homeostasis.
Vaspin's Function in Adipose Tissue
Vaspin's expression and action in adipose tissue underscore its multifaceted role in metabolic regulation and inflammation. Studies have detected vaspin mRNA and protein in various adipose depots, including visceral, subcutaneous, and brown adipose tissue, with differential expression observed in obese individuals.
Functionally, vaspin exerts insulin-sensitizing effects in adipocytes, promoting glucose uptake and attenuating inflammation by modulating the expression of pro-inflammatory cytokines. Additionally, vaspin appears to play a role in adipocyte differentiation and lipid accumulation, albeit with conflicting results in different experimental models.
Moreover, vaspin's actions extend beyond adipose tissue, impacting insulin signaling pathways in vascular endothelial cells and skeletal muscle, suggesting a systemic role in metabolic regulation. Notably, vaspin's effects on insulin sensitivity may vary between species and physiological conditions, warranting further investigation into its precise mechanisms of action.
Vaspin's Involvement in Pancreatic Function
Vaspin's expression and action in the pancreas highlight its importance in glucose metabolism and insulin secretion. Studies indicate vaspin's presence in pancreatic islets and its ability to enhance insulin sensitivity and secretion, potentially through the activation of signaling pathways involving AKT and mTOR.
Furthermore, vaspin appears to protect pancreatic β-cells from inflammation-induced damage, suggesting a potential therapeutic role in mitigating type 2 diabetes-associated β-cell dysfunction. Notably, vaspin's effects on insulin secretion may be modulated by factors such as lipid metabolism and thyroid function, indicating its integration into broader metabolic pathways.
Vaspin's Impact on Ovarian Function
In the ovaries, vaspin's expression and action coincide with various stages of follicular development and luteal function. Studies have demonstrated vaspin's presence in ovarian follicles, where it influences steroidogenesis and follicular growth through interactions with steroid hormones and growth factors.
Moreover, vaspin appears to play a crucial role in luteal function, modulating angiogenesis, steroid hormone synthesis, and cell survival within the corpus luteum. Its actions extend to granulosa cells, where it promotes proliferation and oocyte maturation, suggesting a regulatory role in fertility and reproductive health.
Vaspin's Involvement in Placental Function and Testicular Regulation
Vaspin's expression in the placenta suggests its involvement in maternal-fetal metabolic interactions, potentially influencing gestational weight gain and lipid metabolism. Studies indicate species-specific localization and expression patterns within the placenta, hinting at its diverse functions in pregnancy.
In the testes, vaspin's presence in Leydig cells suggests a role in steroidogenesis and reproductive function. Notably, serum vaspin levels correlate with testosterone and luteinizing hormone levels, implicating vaspin in the regulation of endocrine testicular function.
Conclusion
Vaspin emerges as a multifaceted adipokine with diverse roles in metabolic regulation, reproductive health, and endocrine function. Its expression and actions in various tissues underscore its systemic influence on metabolism, inflammation, and hormone secretion, implicating vaspin as a potential therapeutic target for metabolic disorders and reproductive health issues. Further research into vaspin's precise mechanisms of action and its clinical implications holds promise for understanding its role in health and disease.
Reference
- Kurowska P., et al. Vaspin (SERPINA12) expression and function in endocrine cells. Cells. 2021, 10(7): 1710.
.
