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Adipose Tissue‐Derived Omentin‐1 Function and Regulation

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ABSTRACT

Omentin‐1, also known as intelectin‐1, is a recently identified novel adipocytokine of 313 amino acids, which is expressed in visceral (omental and epicardial) fat as well as mesothelial cells, vascular cells, airway goblet cells, small intestine, colon, ovary, and plasma. The level of omentin‐1 expression in (pre)adipocytes is decreased by glucose/insulin and stimulated by fibroblast growth factor‐21 and dexamethasone. Several lines of experimental evidence have shown that omentin‐1 plays crucial roles in the maintenance of body metabolism and insulin sensitivity, and has anti‐inflammatory, anti‐atherosclerotic, and cardiovascular protective effects via AMP‐activated protein kinase/Akt/nuclear factor‐κB/mitogen‐activated protein kinase (ERK, JNK, and p38) signaling. Clinical studies have indicated the usage of circulating omentin‐1 as a biomarker of obesity, metabolic disorders including insulin resistance, diabetes, and metabolic syndrome, and atherosclerotic cardiovascular diseases. It is also possible to use circulating omentin‐1 as a biomarker of bone metabolism, inflammatory diseases, cancers, sleep apnea syndrome, preeclampsia, and polycystic ovary syndrome. Decreased omentin‐1 levels are generally associated with these diseases. However, omentin‐1 increases to counteract the acute phase after onset of these diseases. These findings indicate that omentin‐1 may be a negative risk factor for these diseases, and also act as an acute‐phase reactant by its anti‐inflammatory and atheroprotective effects. Therapeutic strategies to restore omentin‐1 levels may be valuable for the prevention or treatment of these diseases. Weight loss, olive oil‐rich diet, aerobic training, and treatment with atorvastatin and antidiabetic drugs (metformin, pioglitazone, and exenatide) are effective means of increasing circulating omentin‐1 levels. This review provides insights into the potential use of omentin‐1 as a biomarker and therapeutic target for these diseases. © 2017 American Physiological Society. Compr Physiol 7:765‐781, 2017.

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Figure 1. Figure 1. Favorable and unfavorable effects of novel adipocytokines on energy homeostasis, glucose metabolism, cardiovascular system, inflammation, and oxidative stress. Adiponectin, omentin‐1, vaspin, chemerin, resistin, and leptin are selected as novel adipocytokines. (+) indicates favorable effect and (−) indicates unfavorable effect on energy homeostasis, glucose metabolism, cardiovascular protection, anti‐inflammation response, and antioxidative stress.
Figure 2. Figure 2. Genomic structure of human omentin gene. (A) The genomic structure of the human omentin (intelectin) gene. (B) The exon‐intron junctions. Exons are indicated as square boxes and the open reading frame is indicated as black regions. The sequences and numbers of exon junctions are shown earlier the square boxes. The consensus sequences for splicing are underlined. The usage of this figure from the original paper () is permitted by the American Society for Biochemistry and Molecular Biology.
Figure 3. Figure 3. Comparison of amino acid sequences between human omentin‐1 and mouse omentin‐1. This figure illustrates the alignment of amino acid sequences of human omentin‐1 (GenBank AAS49907; intelectin‐1, BAA96094) and mouse omentin‐1 (intelectin‐1, BAA31992). The homologous amino acids are shown in outline characters on black backgrounds, which are 81.5% identical (255/313 amino acids). The usage of this figure from the original paper () is permitted by the Oxford University Press.
Figure 4. Figure 4. Comparison of amino acid sequence between human omentin‐1 and human omentin‐2. This figure illustrates the alignment of amino acid sequences of human omentin‐1 (GenBank AAS49907; intelectin‐1, BAA96094) and human omentin‐2 (intelectin‐2, EAW52685). The homologous amino acids are shown in outline characters on black backgrounds, which are 83.0% identical (264/318 amino acids). Alignment of amino acid sequences between human omentin‐1 and human omentin‐2 is from Basic Local Alignment Search Tool.
Figure 5. Figure 5. Expression of human omentin‐1 in human vascular cells. Aliquots of protein extracts (50 μg) derived from human monocytes, HMDMs, HUVECs, and HASMCs were separated by 10% sodium dodecyl sulfate‐polyacrylamide gel electrophoresis and then immunoblotted with antibodies against human omentin‐1 (upper). α‐Tubulin served as a loading control (beneath). Molecular size is expressed in kilodaltons (kDa).
Figure 6. Figure 6. Mechanisms underlying the atheroprotective effects of omentin‐1. This figure illustrates the suppressive effects of omentin‐1 on atherogenesis in the arterial wall. Omentin‐1 prevents atherosclerosis by suppressing the inflammatory responses in endothelial cells (ECs), the adhesion of monocytes (Mo) to ECs, oxidized low‐density lipoprotein (LDL)‐induced foam cell formation in Mo‐derived macrophages (Mφ), the migration and proliferation of vascular smooth muscle cells (VSMCs), and the production of extracellular matrix (ECM), such as collagen‐1 and collagen‐3, by VSMCs. Abbreviations: ACAT‐1, acyl‐coenzyme A:cholesterol acyltransferase‐1; ABCA1, ATP‐binding cassette transporter A1; DM, diabetes mellitus; HT, hypertension, ICAM‐1, intercellular adhesion molecule‐1; M‐CSF, macrophage colony‐stimulating factor; NO, nitric oxide; VCAM‐1, vascular adhesion molecule‐1.
Figure 7. Figure 7. Expression of human omentin‐1 in epicardial adipose tissue. These pictures (Alexa Fluor 488 confocal images) show fluorescent immunohistochemistry staining of human omentin‐1 (green) in epicardial adipose tissues in CAD and non‐CAD patients.
Figure 8. Figure 8. Intracellular signaling pathways for multiple beneficial effects of omentin‐1. This figure illustrates the secretion source, intracellular signals, and main beneficial effects of omentin‐1. Abbreviations: AMPK, AMP‐activated protein kinase; eNOS, endothelial nitric oxide synthase; ERK, extracellular signal‐regulated kinase; JNK, c‐Jun N‐terminal kinase; MAPK, mitogen‐activated protein kinase; NF‐κB, nuclear factor‐κB; PI3K, phosphoinositide 3‐kinase.


Figure 1. Favorable and unfavorable effects of novel adipocytokines on energy homeostasis, glucose metabolism, cardiovascular system, inflammation, and oxidative stress. Adiponectin, omentin‐1, vaspin, chemerin, resistin, and leptin are selected as novel adipocytokines. (+) indicates favorable effect and (−) indicates unfavorable effect on energy homeostasis, glucose metabolism, cardiovascular protection, anti‐inflammation response, and antioxidative stress.


Figure 2. Genomic structure of human omentin gene. (A) The genomic structure of the human omentin (intelectin) gene. (B) The exon‐intron junctions. Exons are indicated as square boxes and the open reading frame is indicated as black regions. The sequences and numbers of exon junctions are shown earlier the square boxes. The consensus sequences for splicing are underlined. The usage of this figure from the original paper () is permitted by the American Society for Biochemistry and Molecular Biology.


Figure 3. Comparison of amino acid sequences between human omentin‐1 and mouse omentin‐1. This figure illustrates the alignment of amino acid sequences of human omentin‐1 (GenBank AAS49907; intelectin‐1, BAA96094) and mouse omentin‐1 (intelectin‐1, BAA31992). The homologous amino acids are shown in outline characters on black backgrounds, which are 81.5% identical (255/313 amino acids). The usage of this figure from the original paper () is permitted by the Oxford University Press.


Figure 4. Comparison of amino acid sequence between human omentin‐1 and human omentin‐2. This figure illustrates the alignment of amino acid sequences of human omentin‐1 (GenBank AAS49907; intelectin‐1, BAA96094) and human omentin‐2 (intelectin‐2, EAW52685). The homologous amino acids are shown in outline characters on black backgrounds, which are 83.0% identical (264/318 amino acids). Alignment of amino acid sequences between human omentin‐1 and human omentin‐2 is from Basic Local Alignment Search Tool.


Figure 5. Expression of human omentin‐1 in human vascular cells. Aliquots of protein extracts (50 μg) derived from human monocytes, HMDMs, HUVECs, and HASMCs were separated by 10% sodium dodecyl sulfate‐polyacrylamide gel electrophoresis and then immunoblotted with antibodies against human omentin‐1 (upper). α‐Tubulin served as a loading control (beneath). Molecular size is expressed in kilodaltons (kDa).


Figure 6. Mechanisms underlying the atheroprotective effects of omentin‐1. This figure illustrates the suppressive effects of omentin‐1 on atherogenesis in the arterial wall. Omentin‐1 prevents atherosclerosis by suppressing the inflammatory responses in endothelial cells (ECs), the adhesion of monocytes (Mo) to ECs, oxidized low‐density lipoprotein (LDL)‐induced foam cell formation in Mo‐derived macrophages (Mφ), the migration and proliferation of vascular smooth muscle cells (VSMCs), and the production of extracellular matrix (ECM), such as collagen‐1 and collagen‐3, by VSMCs. Abbreviations: ACAT‐1, acyl‐coenzyme A:cholesterol acyltransferase‐1; ABCA1, ATP‐binding cassette transporter A1; DM, diabetes mellitus; HT, hypertension, ICAM‐1, intercellular adhesion molecule‐1; M‐CSF, macrophage colony‐stimulating factor; NO, nitric oxide; VCAM‐1, vascular adhesion molecule‐1.


Figure 7. Expression of human omentin‐1 in epicardial adipose tissue. These pictures (Alexa Fluor 488 confocal images) show fluorescent immunohistochemistry staining of human omentin‐1 (green) in epicardial adipose tissues in CAD and non‐CAD patients.


Figure 8. Intracellular signaling pathways for multiple beneficial effects of omentin‐1. This figure illustrates the secretion source, intracellular signals, and main beneficial effects of omentin‐1. Abbreviations: AMPK, AMP‐activated protein kinase; eNOS, endothelial nitric oxide synthase; ERK, extracellular signal‐regulated kinase; JNK, c‐Jun N‐terminal kinase; MAPK, mitogen‐activated protein kinase; NF‐κB, nuclear factor‐κB; PI3K, phosphoinositide 3‐kinase.
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Teaching Material

T. Watanabe, K. Watanabe-Kominato, Y. Takahashi, M. Kojima, R. Watanabe. Adipose Tissue-Derived Omentin-1 Function and Regulation. Compr Physiol 7 2017, 765-781.

Didactic Synopsis

 

Major Teaching Points:

     

  • Omentin-1, also known as intelectin-1, is a recently identified novel adipocytokine that is mainly expressed in visceral fat.

 

     

  • Omentin-1 is downregulated by glucose/insulin and upregulated by fibroblast growth factor-21 and dexamethasone.
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  • Omentin-1 exerts suppressive effects on insulin resistance, atherosclerosis, and inflammation via AMP-activated protein kinase/Akt/nuclear factor-κB/mitogen-activated protein kinase (ERK, JNK, and p38) intracellular signaling pathways.
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  • Circulating omentin-1 is used as a biomarker of obesity, diabetes, metabolic syndrome, atherosclerosis, ischemic heart disease, inflammatory disease, and cancer.
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  • This review provides insights into the potential use of omentin-1 as a biomarker and therapeutic target for these diseases.
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Didactic Legends

The figures-in a freely downloadable PowerPoint format-can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

 

 

Figure 1. Teaching points: Understanding the favorable (+) and unfavorable (-) effects of novel adipocytokines (adiponectin, omentin-1, vaspin, chemerin, resistin, and leptin) on energy homeostasis, glucose metabolism, cardiovascular protection, anti-inflammation response, and antioxidative stress.

Figure 2. Teaching points: Understanding the genomic structure of human omentin gene (A) and the exon-intron junctions (B). Exons are indicated as square boxes and the open reading frame is indicated as black regions. The sequences and numbers of exon junctions are shown above the square boxes. The consensus sequences for splicing are underlined.

Figure 3. Teaching points: Understanding the alignment of amino acid sequences between human omentin-1 and mouse omentin-1. The homologous amino acids are shown in outline characters on black backgrounds, which are 81.5% identical (255/313 amino acids).

Figure 4. Teaching points: Understanding the alignment of amino acid sequence between human omentin-1 and human omentin-2. The homologous amino acids are shown in outline characters on black backgrounds, which are 83.0% identical (264/318 amino acids).

Figure 5. Teaching points: Understanding the expression of human omentin-1 in human vascular cells: human monocytes, human monocyte-derived macrophages (HMDMs), human umbilical vein endothelial cells (HUVECs), and human aortic smooth muscle cells (HASMCs). α-tubulin served as a loading control. Molecular size is expressed in kilodaltons (kDa).

Figure 6. Teaching points: Understanding the mechanisms underlying the atheroprotective effects of omentin-1 in the arterial wall. Omentin-1 prevents atherosclerosis by suppressing the inflammatory responses in endothelial cells (ECs), the adhesion of monocytes (Mo) to ECs, oxidized low-density lipoprotein (LDL)-induced foam cell formation in Mo-derived macrophages, the migration and proliferation of vascular smooth muscle cells (VSMCs), and the production of extracellular matrix (ECM), such as collagen-1 and collagen-3, by VSMCs.

Figure 7. Teaching points: Understanding the expression of human omentin-1 in epicardial adipose tissue in coronary artery disease (CAD) and non-CAD patients. Pictures show that omentin-1 expression (green color) in epicardial adipose tissue is decreased in a CAD patient compared with a non-CAD patient.

Figure 8. Teaching points: Understanding the intracellular signaling pathways for multiple beneficial effects of omentin-1. This figure illustrates the secretion source, intracellular signals, and main beneficial effects of omentin-1.

 


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How to Cite

Takuya Watanabe, Kaho Watanabe‐Kominato, Yui Takahashi, Miho Kojima, Rena Watanabe. Adipose Tissue‐Derived Omentin‐1 Function and Regulation. Compr Physiol 2017, 7: 765-781. doi: 10.1002/cphy.c160043