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Adipocytokine Signaling Pathway

Figure 1. An overview of adipocytokine signaling pathway

Adipocytokine signaling pathway overview

The adipocytokine signaling pathway refers to the sum of all proteins, factors, and all proteins responsible for the regulation in the adipocytokine signaling pathway. Fat cells are an active endocrine and paracrine organ that secretes a variety of cytokines and biologically active substances that not only regulate energy balance in the body, but also participate in the process of inflammation, coagulation, fibrinolysis, insulin resistance, diabetes and atherosclerosis. A growing number of obesity, diabetes, atherosclerosis and related diseases have drawn people’s attention to adipose tissue, which is no longer considered only as a passive reservoir of triglycerides (TG) and a source of free fatty acids. It is a broad and active endocrine organ. Fat cells secrete dozens of cytokines, such as leptin, adiponectin, acylation stimulating proteins, omentin and cytokines, collectively referred to as adipokines. Under physiological conditions, adipokines act mainly on adipose tissue (paracrine or autocrine) or circulate through blood circulation to distant target organs, regulating their growth and development, metabolism and tissue remodeling. However, under pathological conditions (such as obesity and metabolic syndrome), the synthesis and secretion of adipokines are disordered. The endocrine function of obese adipose tissue is focused on the negative metabolic effects caused by excess adipose tissue; the main consequence is the promotion of diabetes. The occurrence of obesity-related diseases is such as atherosclerosis (Figure 2). Obesity is closely related to insulin resistance, hyperglycemia, low inflammation, dyslipidemia and metabolic syndrome (MS).

Schematic interaction between adipocytes and immune cells

Figure 2. Schematic interaction between adipocytes and immune cells

Adipocytokine family

The factors secreted by fat cells mainly include APN, leptin, IL-6, TNF-α and resistin. These adipocytokines regulate lipid metabolism through various signaling pathways, thereby affecting lipid metabolism, and there are also complex interactions:

APN is a cytokine synthesized and secreted by mature fat cells, which is one of the proteins with abundant gene expression in adipose tissue. Qiao et al. pointed out that APN can directly regulate lipid metabolism by inhibiting lipid breakdown in fat cells. Anthonsen et al. believe that APN can inhibit the hydrolysis of triglyceride (TG), mainly because its protein kinase A. (protein kinase A, PKA) is involved in the activation of hormone sensitive lipase (HSL).

Adiponectin: an adipocytokine secreted by adipose tissue, plays an important regulatory role in the energy metabolism of cell glucose, sugar and fatty acids, and participates in the regulation of cell proliferation and immune function. Serum adiponectin has three forms: a. a low molecular weight complex composed of two trimers; b. a high molecular weight complex composed of 6 trimers, c. a spherical trimer. Human adiponectin consists of 244 amino acids and acts on the corresponding target tissues in the blood circulation. Adiponectin is currently the most clear and important adipocytokines associated with insulin resistance and is involved in sugar and lipid metabolism. The human adiponectin gene is localized to 3q27, which is closely related to type 2 diabetes and metabolic syndrome, so it has anti-diabetic characteristics.

Leptin: one of the adipocytokines secreted by animal fat cells, is a protein hormone, mainly produced by white adipose tissue, and can participate in the regulation of fat metabolism in animals. A large number of studies have indicated that leptin inhibits the adipocytokine signaling pathway by acting on the brain signal center, inhibiting food intake and increasing energy consumption. Recent studies have shown that leptin can also directly inhibit fat synthesis and promote the decomposition of fat.

IL-6 is another fat cytokine related to fat metabolism produced by fat cells. Obesity increases the circulating IL-6 level and adipose tissue IL-6 secretion. Ruderman et al. showed that IL-6 is mainly present in adipose tissue and the center of the hypothalamus and regulates the body composition. Deletion of IL-6 gene in mice leads to obesity and insulin resistance.

TNF-α is a non-glycosylated protein secreted by fat cells. Adipose tissue is the main organ producing endogenous TNF-α, which is tissue-specific, in which visceral fat expresses more TNF-α than subcutaneous fat, and macrophages secrete more than lipoblastin.

Resistin is a cysteine-rich peptide found in the inflammation zone 3 (FIZZ3). It is a hormone secreted by fat cells that promotes insulin resistance, promotes inflammatory responses and adipocyte differentiation.

Adipocytokine signaling pathway

  1. Adipocytokine signaling pathway cascade

    Because of the different signaling pathways of different adipocytokines, we describe the adipocytokine signaling pathway based on the above-mentioned major adipocytokines:

    APN: Studies have found that AMP-activated protein kinase (AMPK) is a key signaling molecule in the APN signaling pathway. APN inhibits fat synthesis and promotes fatty acid oxidation in liver and muscle tissues through the AMPK pathway. AMPK is a key sensor of cellular energy status and is the main regulator of liver and body lipid homeostasis. Activation of the AMPK signaling pathway in liver tissue can cause direct phosphorylation of acetyl-coA carboxylase (ACC) downstream to inactivate activity, thereby inhibiting the conversion of acetyl-coenzyme to malonyl-coenzyme and inhibiting botulinum Alkali palmitoyltransferase 1 (CPT1)activity, therefore, activation of the AMPK pathway causes the transport of long-chain acetyl fatty acids to mitochondria, which inhibits the oxidation of fatty acids; malonyl-coenzyme is a key enzyme of fatty acid heavy synthase, therefore, AMPK activation of the pathway inhibits the adipocytokine signaling pathway.

    Leptin: Li et al. found that leptin up-regulates the mRNA expression of adipose triglyceride lipase (ATGL) in pig adipocytes, and down-regulates the protein expression of ATGL, and leptin mainly passes Janus kinase ( JAK) signaling and transcriptional activator (STAT) signaling pathway. PPARγ regulates ATGL mRNA and protein expression. ATGL is a PPARγ transcriptional target gene, and PPARγ can up-regulate the mRNA and protein expression of ATGL in vivo or in vitro, while leptin can promote the expression of PPARγ, indicating that leptin can promote the hydrolysis of TG. The JAK-STAT signaling pathway is an important intracellular signal transduction pathway. It also transduces lipid metabolism-related signals to the animal body to maintain homeostasis. STAT mainly includes STAT1, 2, 3, 4, 5A, 5B and 6 members. The major transcription factor in the JAK-STAT signaling pathway is cell and tissue specific. Cernkovich et al. knocked out the fat-specific gene seipin, which promotes fat storage in mice, causing a loss of STAT3 gene in adipose tissue. Compared with mice without STAT3 gene deletion, the body weight and adipose tissue of mice lacking STAT3 gene were significantly increased. Cell hypertrophy, but no fat cell proliferation, overfeeding or reduced energy consumption, these results indicate that STAT3 promotes lipolysis and inhibits adipocyte differentiation.

    IL6 promotes lipid breakdown, glycolysis and fatty acid oxidation in skeletal muscle and adipose tissue via mitogen-activated protein kinases (MAPK) signaling pathway. Ruderman et al. showed that IL6 is mainly found in adipose tissue and the center of the hypothalamus and regulates the body composition. Deletion of IL6 gene in mice leads to obesity and insulin resistance. AMPK is the main signal regulating lipid metabolism. Activation of AMPK signaling inhibits fat synthesis and promotes fatty acid oxidation.

    TNF-α activates the Wnt/β-catenin signaling pathway by inducing the expression of the homeobox gene Msx2, thereby inhibiting adipocyte differentiation. The study also indicated that TNF-α inhibits the differentiation of pre-adipocytes into mature cells by down-regulating the expression of C/EBPα and PPARγ in pre-adipocytes. Studies have shown that overexpression of resistin in 3T3-L1 precursor adipocytes promotes differentiation of precursor adipocytes, and inhibits adipocyte differentiation of preadipocytes by up-regulating genes associated with adipocyte differentiation, such as C/EBPα and LPL. Factor (Pref1).

    Resistin has a role in promoting fat breakdown. Bai Cuiling and other studies have shown that resistin inhibits glucose uptake in porcine tissue cells and enhances LPL activity by increasing LPL activity and plays an important role in regulating lipid metabolism balance. Kim found that resistin stimulates LPL activity via a glucose-dependent insulinotropic polypeptide (GIP) in 3T3-L1 cells and is involved in the activation of protein kinase B (PKB) and reduces phosphorylation of LKB1 and AMPK, thereby enhancing the adipocytokines signaling pathway.

  2. Pathway regulation

    Li et al. reported that phosphorylation of AMPK reduces the activity of sterol regulatory element binding protein 1c (SREBP1-c), an important adipogenic transcription factor that directly regulates fatty acid synthesis-related genes ACC and adipocytokines signaling pathway, therefore, activation of AMPK phosphorylation can inhibit the synthesis of liver TG and promote the oxidation of fatty acids. In addition, PPARγ coactivator (PGC1α) is one of the major transcription factors regulating fatty acid oxidation in skeletal muscle. Studies have shown that AMPK activates PGC1α, thereby promoting the adipocytokine signaling pathway. Studies have shown that inhibitors of JAK2 inhibit the downstream transcription factor STAT3, and STAT3 regulates ATGL expression. Treatment of bovine adipocytes with STAT3 inhibitor Stattic attenuates the breakdown of fat and reduces the protein abundance of ATGL. These results indicate that leptin increases the protein abundance of ATGL and promotes lipolysis through the JAK2-STAT3 signaling pathway. In addition, leptin can also promote fatty acid oxidation in skeletal muscle through the AMPK pathway. Insulin binds to the insulin receptor (IR) on the cell surface to activate phosphatidylinositol 3-kinase (PI3K), which enhances the phosphorylation of serine/threonine protein kinase (Akt) in the plasma membrane. However, studies by Roman et al. showed that central leptin promotes fatty acid oxidation and reduces fat synthesis in rat skeletal muscle by activating AMPK, which promotes phosphorylation of ACC; in addition, leptin enhances insulin-induced signaling pathway IR/PI3K/Akt that improves insulin resistance in rats. Therefore, the absence of the leptin-PI3K signaling pathway in the hypothalamus leads to peripheral tissue insulin resistance, which is associated with the interaction of leptin signaling with insulin signaling. Studies have found that damaging the hypothalamic leptin signaling pathway enhances the delivery of fatty acid substrates and PPARα ligands in the heart to enhance myocardial fatty acid oxidation. These studies further demonstrate that leptin regulates lipid metabolism through the JAK2-STAT3, AMPK, and IR/PI3K/Akt signaling pathways. The Wnt/β-chain protein (β-catenin) signaling pathway regulates the adipocytokine signaling pathway. Activation of the Wnt/β-catenin signaling pathway inhibits the activity of the target gene CCAAT enhancer binding protein (CPAAT/enhancer binding protein α, C/EBPα) and PPARγ, leaving the preadipocytes in an undifferentiated state and inhibiting adipocytes.

  3. Role in disease

    Atherosclerosis

    The study of the relationship between adipose factors secreted by EAT (epithelial adipose tissue) and atherosclerosis has become a research hotspot. Regarding the relationship between atherosclerosis and adipokines, it has been confirmed that adiponectin, leptin, chemokine, and resistin have a certain effect on the development of coronary atherosclerosis.

    Diabetes

    Palmitic acid and oleic acid are the main constituents of free fatty acids (FFAs). Palmitic acid is a high-grade saturated fatty acid widely found in nature, and almost all fat and oil contain different amounts of palmitic acid components. Later, it was found that obstruction of the fat cell signaling pathway causes an increase in the content of FFAs, which in turn leads to IR and insulin secretion in liver, fat, and muscle tissue, further affecting islet β cells and leading to diabetes.

References:

1. Kazama K, Okada M, Yamawaki H. Is novel adipocytokine, omentin, a therapeutic target for obesity-related hypertension? Nihon Yakurigaku Zasshi Folia Pharmacologica Japonica. 2015, 145(2):65-9.
2. Guclu M, Gul O O, Cander S, et al. Effect of Rosiglitazone and Insulin Combination Therapy on Inflammation Parameters and Adipocytokine Levels in Patients with Type 1 DM. Journal of Diabetes Research. 2015(69):807891.
3. Mcmanus R, Summers K, Vrijer B D, et al. Maternal, umbilical arterial and umbilical venous 25-hydroxyvitamin D and adipocytokine concentrations in pregnancies with and without gestational diabetes. Clinical Endocrinology. 2014, 80(5):635-641.
4. Gupta A. Serum adipokine levels in metabolic syndrome women of north india: relationship of Adipokine levels with anthropometric status, lipid profile and metabolic risk factors. Journal of Diabetes. 2011, 3(Suppl. 1):S43.

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