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Omentin Signaling Pathway

Figure 1. Omentin signaling pathway.

An overview of omentin Adipose tissue not only stores energy but also secretes a variety of inflammatory mediators and cellular factors. It secretes tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), leptin, retinol-binding protein, resistin, adiponectin, visfatin, etc., affecting carbohydrates and lipid metabolism and playing an important role in pathophysiological processes such as insulin resistance, type 2 diabetes, atherosclerosis, inflammatory response, and vascular endothelial dysfunction. Omentin is a new adipocytokine recently discovered, mainly produced by the secretion of visceral adipose tissue. In recent years, studies have shown that omentin is widely involved in a variety of pathophysiological processes such as obesity, insulin resistance, inflammatory response, atherogenesis, and regulation of vascular endothelial function. It has the functions of enhancing insulin sensitivity, anti-atherosclerosis, reducing inflammation, regulating vascular endothelial cell function, cardiovascular protection, and is closely related to various clinical diseases such as diabetes, cardiovascular diseases, autoimmune diseases, and tumors. Therefore, it is particularly important to study the omentin signaling pathway.

Omentin family

Sequence analysis of the omentin protein revealed that it is 1269 bp in length and encodes a 313 amino acid peptide chain containing a secreted signal sequence and a fibrinogen-associated region. The latter is a 296 amino acid globular structure with a molecular weight of 33 kD, including: β-chain and γ-chain of fibrinogen; Peroxisome proliferating protein-activated receptor γ-encoded angiogenin-related protein (PGAR); Binds to wrist protein. Compared to SAT, omentin has a highly selective expression in VAT. Real-time PCR assays showed that omentin mRNA was expressed in retinal adipose stromal vascular cells, but not in adipocytes, and was 150-fold higher than SAT. The results of hybridization experiments with nucleic acid molecules showed that in addition to high expression in omental adipose tissue, omentin is highly expressed in human placenta and ovary, low in small intestine, lung and heart, and is only detectable in muscle and kidney. In other organs or tissues, it is not detected at all.

Omentin signaling pathway

  1. Omentin signaling pathway cascade
    In recent years, studies have shown that omentin is widely involved in various pathophysiological processes such as obesity, insulin resistance, inflammatory response, atherogenesis, and regulation of vascular endothelial function. Therefore, the cascade is introduced for different physiological effects: the occurrence of cardiovascular disease is closely related to the formation of atherosclerosis and vascular endothelial dysfunction. The current study found that omentin has an anti-atherosclerotic effect. Omentin induces NO synthesis by activating AMPK-eNOS phosphorylation and increases endothelial function. Omentin inhibits multiple TNF-α-mediated signaling pathways, down-regulates the expression of vascular adhesion molecules and reduces the production of reactive oxygen species, reducing the infiltration of inflammatory cells into the vascular wall, thereby providing anti-inflammatory and anti-atherosclerotic effects. Omentin inhibits the expression of alkaline phosphatase and osteocalcin mRNA by selectively activating the Akt, an effector molecule downstream of PI3K, and inhibits the differentiation of arterial vascular smooth muscle cells into osteoblasts, thereby inhibiting arterial vascular calcification. In addition, omentin also has a protective effect on cardiomyocytes. In a mouse model of ischemia-reperfusion and in vitro cultured cardiomyocytes, omentin was shown to reduce myocardial infarct size and cardiomyocyte apoptosis by enhancing AMPK and Akt phosphorylation and to protect the myocardium from ischemic injury. There are few reports on the relationship between omentin and tumors, and the concentration of omentin serum varies among patients with different types of tumors. In patients with renal cell carcinoma, omentin serum concentrations were significantly lower than that in the control group, while serum omentin concentrations were elevated in prostate and colon cancer patients, and serum omentin levels were also higher in patients with stage III colon cancer after surgery and chemotherapy than that in the control group. In a study of two types of human hepatoma cells HepG2 and HuH-7, omentin-1 inhibited the proliferation of these two tumor cells at a concentration of 1-2 μg/mL. Annexin staining method and TUNEL analysis showed that omentin induced apoptosis in both cells. Further studies have found that omentin up-regulates P53 protein levels by decreasing P53 deacetylation, thereby increasing the stability of the P53 protein. The p53 gene is an important tumor suppressor gene, and P53 protein has the function of inhibiting DNA replication and cell division. Whether omentin can up-regulate P53 protein levels and has an indirect anti-cancer effect requires further observation in other tumor cells. In incubated human omental adipose tissue, the non-adipocyte cells mainly found in adipose tissue are up-regulated, and albumin can enhance the up-regulation of inflammatory factors such as TNF-α, IL1β, and IL8. Moreover, hypoxia-inducible factor 1α (HIF1α), nuclear factor κB (NF-κB) and upregulation of inflammatory response in adipocytes and non-adipocytes are not affected by paracrine effects. Due to the reduced concentration of hemoglobin in obese people, it is possible to prevent and control the arteriosclerosis process by virtue of its effect on vascular endothelial inflammation. Human umbilical vein endothelial cells (HUVEC) were used to detect the effect of omentin on TNF-α-induced inflammatory response, and it was observed that reticulin is mediated by 5'-AMP-activated protein kinase (AMPK)-mediated endothelial nitric oxide synthase (eNOS) whose phosphorylation causes NO production, and NO derived from retina inhibits TNF-α-mediated cyclooxygenase 2 (COX2) production by inhibiting the activation of CJun N-terminal kinase (JNK). In addition, omentin activation of AMPK directly inhibits p38-mediated induction of E-selectin and ultimately lymphocyte adhesion to vascular endothelial cells. These results explain, at least in part, the relationship between obesity and cardiovascular disease such as arteriosclerosis.
  2. Pathway regulation
    According to the role of omentin, it can be known that proper up-regulation of omentin in vivo can effectively inhibit the corresponding diseases, so the regulation of the reticulin signaling pathway can be achieved mainly through aerobic exercise, an effective intervention. Aerobic exercise can reduce body fat content and reduce the volume of fat cells. 18 overweight and obese people were divided into an obese exercise group and the obese control group, 9 in each group. In addition, 8 normal-weight people were classified as a normal control group, and the exercise group had 5 days of aerobic exercise per week for 12 weeks. The results showed that hemoglobin levels of normal-weight people were significantly higher than that of overweight and obese people, and the same to omentin-1 levels and waist circumference, fasting plasma glucose levels, insulin resistance, high-density lipoprotein, total cholesterol, triglycerides and contraction. The pressure was negatively correlated, and the level of hemoglobin was significantly increased after aerobic exercise, and negatively correlated with insulin resistance, waist circumference and aerobic adaptation. Serum omentin levels are decreased in patients with type 2 diabetes, and liraglutide (long-acting glucagon-like peptide analogs) can up-regulate their omentin levels. Tan et al found that serum reticulin levels were significantly decreased in patients with metabolic syndrome, accompanied by elevated serum cell migration and pro-angiogenic activity (inflammatory response). After treatment with metformin, omentin levels are elevated, and serum migration and angiogenic activity are decreased. Omentin may mediate the anti-inflammatory effects of metformin via nuclear factor-κB (NF-κB) and serine/threonine kinase (Akt) pathways. Li Na et al found that reconstituted insulin-secreting hormone treatment significantly increased fasting plasma reticulin levels and significantly reduced fasting insulin levels and insulin resistance at 12 weeks.
  3. Relationship with disease
    Polycystic ovarian syndrome
    A study to estimate the level of ometin-1 in omental fat in women with PCOS and matched control groups showed that the level of omentin-1 in women with PCOS was significantly lower than that in the control group. Omentin 1 mRNA and protein were significantly lower than the latter. In isolated omental adipose tissue, insulin and glucose have a significant dose-dependent reduction in omentin 1 mRNA expression and its protein levels as well as its secretion. In addition, the induction of hyperinsulinemia in healthy individuals can significantly reduce omentin-1 levels. Insulin and sugar down-regulate omentin 1, which may partly explain the decline in the level of omentin 1 in overweight PCOS women. Treatment of patients with PCOS with metformin (MET) for 6 months significantly increased omentin-1 levels, and it was important that changes in high-sensitivity C-reactive protein (hs-CRP) were significantly and negatively correlated with omentin-1 levels. Inflammation and angiogenesis were significantly increased in the serum of women with PCOS compared to the matched control group. These effects were significantly attenuated by treatment with MET, which appears to regulate omentin-1 levels by virtue of NF-kB and Akt signaling pathways. In vitro experiments showed that CRP and VEGF induced endothelial cell migration, while omentin 1 significantly reduced angiogenesis. In conclusion, the effect of increasing omentin 1 levels is not sufficient to explain the reduction of inflammatory and angiogenic effects in serum from PCOS women treated with MET. Importantly, MET also regulates angiogenesis via the vascular endothelial growth factor (VEGF) system, which in turn reduces VEGF levels in MET in patients with T2DM.
    Gestational diabetes (GDM)
    GDM is characterized by insulin resistance and pro-inflammatory status, which may be related to the expression of adipokines. A study of 20 patients with GDM and 23 age- and BMI-matched NGT pregnant women showed no significant difference between omental and thrombospondin-1 (TSP1). TSP1 is not associated with HOMA or insulin resistance index (RII). However, there was a significant positive correlation between omentin and TSP1, and only a positive correlation between the hemoglobin level in the control group and the blood glucose levels at 60 and 90 min after oral glucose in the oral glucose tolerance test (OGTT). However, there was no difference in omentin levels and TSP1 levels between NGT and GDM patients. The latter two are also independent of HOMA and IRI, suggesting that increased insulin resistance associated with pregnancy is unlikely to act directly through changes in omentin or TSP1 levels, which regulates the concentration of these adipokines in pregnant women compared with non-pregnant women and is regulated by different mechanisms.

References

  1. Rao S S, Hu Y, Xie P L, et al. Omentin-1 prevents inflammation-induced osteoporosis by downregulating the pro-inflammatory cytokines. Bone Research. 2018, 6(1):9.
  2. Bakry O A, El S F, Ghanayem N, et al. Serum Omentin-1 in Psoriasis. Indian Journal of Dermatology. 2018. 63(1):85.
  3. Yıldız S S, Sahin I, Cetinkal G, et al. Usefulness of Serum Omentin-1 Levels for the Predictions of Adverse Cardiac Events in Patients with Hypertrophic Cardiomyopathy. Medical Principles & Practice. 2018.
  4. Franz M, Polterauer M, Springer S, et al. Maternal and neonatal omentin-1 levels in gestational diabetes. Archives of Gynecology & Obstetrics. 2018, 297(4):885-889.
  5. Zhou J Y, Chan L, Zhou S W. Omentin: linking metabolic syndrome and cardiovascular disease. Current Vascular Pharmacology. 2014, 12(1):136-143.

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