Associations of Circulating Irisin with FNDC5 Expression in Fat and Muscle in Type 1 and Type 2 Diabetic Mice

Jiang, Songling; Piao, Lingjuan; Bi, Eun; Ha, Hunjoo; Huh, Joo Young

doi:10.3390/biom11020322

Cited by 15 publications

(7 citation statements)

References 47 publications

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“…Although skeletal muscle is the predominant organ for irisin secretion [ 28 ], the local expression of irisin in other tissues has also been described [ 33 , 55 ]. In our study, hepatic irisin was increased in the HFD group, indicating a compensatory secretion under pathological conditions.…”

Section: Discussionmentioning

confidence: 99%

Exercise-Induced Irisin Decreases Inflammation and Improves NAFLD by Competitive Binding with MD2

Zhu

Sahar

Javaid

et al. 2021

Cells

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Non-alcoholic fatty liver disease (NAFLD) is a global clinical problem. The MD2-TLR4 pathway exacerbates NAFLD progression by promoting inflammation. Long-term exercise is considered to improve NAFLD but the underlying mechanism is still unclear. In this study, we examined the protective effect and molecular mechanism of exercise on high-fat diet (HFD)-induced liver injury. In an HFD-induced NAFLD mouse model, exercise training significantly decreased hepatic steatosis and fibrosis. Interestingly, exercise training blocked the binding of MD2-TLR4 and decreased the downstream inflammatory response. Irisin is a myokine that is highly expressed in response to exercise and exerts anti-inflammatory effects. We found that circulating irisin levels and muscle irisin expression were significantly increased in exercised mice, suggesting that irisin could mediate the effect of exercise on NAFLD. In vitro studies showed that irisin improved lipid metabolism, fibrosis, and inflammation in palmitic acid (PA)-stimulated AML12 cells. Moreover, binding assay results showed that irisin disturbed MD2-TLR4 complex formation by directly binding with MD2 but not TLR4, and interfered with the recognition of stimuli such as PA and lipopolysaccharide with MD2. Our study provides novel evidence that exercise-induced irisin inhibits inflammation via competitive binding with MD2 to improve NAFLD. Thus, irisin could be considered a potential therapy for NAFLD.

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Section: Discussionmentioning

confidence: 99%

Exercise-Induced Irisin Decreases Inflammation and Improves NAFLD by Competitive Binding with MD2

Zhu

Sahar

Javaid

et al. 2021

Cells

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“…Chloroform/methanol (2:1) extraction was used to extract triglycerides from cell homogenates, and the intracellular triglyceride content was then quantitatively evaluated with an EnzyChrom™ Triglyceride Assay Kit (Bioassay Systems, Hayward, CA) following the instructions of the kit [ 34 – 36 ].…”

Section: Methodsmentioning

confidence: 99%

Pyruvate carboxylase promotes thyroid cancer aggressiveness through fatty acid synthesis

et al. 2021

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Background Pyruvate carboxylase (PC) is an important anaplerotic enzyme in the tricarboxylic acid cycle (TCA) in cancer cells. Although PC overexpression has been observed in thyroid cancer (TC), the mechanisms involved in the carcinogenic effects of PC are still unclear. Methods Bioinformatics analysis and clinical specimens were used to analyze the relationship of PC expression with clinicopathological variables in TC. Fatty acid synthesis was monitored by LC/MS, Nile red staining, and triglyceride analysis. Mitochondrial oxygen consumption was evaluated by the Seahorse XF Mito Cell Stress Test. The correlation of PC with FASN and SREBP1c was assessed by qRT-PCR and IHC in 38 human TC tissues. Western blotting was used to evaluate the protein expression of PC, FASN, and SREBP1c and members of the AKT/mTOR and EMT pathways in TC cell lines. Wound-healing, CCK-8, and Transwell assays and a nude mouse xenograft model were used to verify the regulatory effects of PC and SREBP1c on thyroid tumor cell proliferation, migration and invasion. Results We demonstrated that PC increased fatty acid synthesis, which then promoted TC progression and metastasis. Analysis of GEO data showed that the overexpression of PC in papillary thyroid cancer (PTC) was associated with PTC invasion and the fatty acid synthesis pathway. Analysis of clinical tissue specimens from PTC patients revealed that PC was more highly expressed in specimens from PTC patients with lymph node metastasis than in those from patients without metastasis. Multiple genes in the fatty acid synthesis signaling pathway, including FASN and SREBP1c, were downregulated in PC-knockdown TC cells compared to control cells. Lipid levels were also decreased in the PC-knockdown TC cells. Moreover, the ability of cells to grow, invade, and metastasize was also suppressed upon PC knockdown, suggesting that PC-mediated lipogenesis activation increases the aggressiveness of TC cells. In addition, PC was found to activate the AKT/mTOR pathway, thus improving FASN-mediated de novo lipogenesis in TC cells by upregulating SREBP1c expression. Studies in a nude mouse xenograft model showed that PC knockdown decreased tumor weight, but this effect was attenuated by forced expression of SREBP1c. Conclusions Our results demonstrate that PC is strongly involved in the tumor aggressiveness of TC via its stimulation of fatty acid synthesis.

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“…A correlation between SIRT1 expression and irisin serum levels has been reported in type 2 diabetic patients and mice (Safarpour et al, 2020;Jiang et al, 2021), suggesting the involvement of SIRT1 in PGC-1α-mediated irisin release. The treatment of obese type 2 diabetes patients with vitamin D also induces higher serum levels of SIRT1 and irisin, further pointing to the SIRT1-mediated release of irisin (Safarpour et al, 2020).…”

Section: Histone Deacetylases Affect Myokine Synthesismentioning

confidence: 83%

Histone Deacetylases as Modulators of the Crosstalk Between Skeletal Muscle and Other Organs

et al. 2022

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Skeletal muscle plays a major role in controlling body mass and metabolism: it is the most abundant tissue of the body and a major source of humoral factors; in addition, it is primarily responsible for glucose uptake and storage, as well as for protein metabolism. Muscle acts as a metabolic hub, in a crosstalk with other organs and tissues, such as the liver, the brain, and fat tissue. Cytokines, adipokines, and myokines are pivotal mediators of such crosstalk. Many of these circulating factors modulate histone deacetylase (HDAC) expression and/or activity. HDACs form a numerous family of enzymes, divided into four classes based on their homology to their orthologs in yeast. Eleven family members are considered classic HDACs, with a highly conserved deacetylase domain, and fall into Classes I, II, and IV, while class III members are named Sirtuins and are structurally and mechanistically distinct from the members of the other classes. HDACs are key regulators of skeletal muscle metabolism, both in physiological conditions and following metabolic stress, participating in the highly dynamic adaptative responses of the muscle to external stimuli. In turn, HDAC expression and activity are closely regulated by the metabolic demands of the skeletal muscle. For instance, NAD+ levels link Class III (Sirtuin) enzymatic activity to the energy status of the cell, and starvation or exercise affect Class II HDAC stability and intracellular localization. SUMOylation or phosphorylation of Class II HDACs are modulated by circulating factors, thus establishing a bidirectional link between HDAC activity and endocrine, paracrine, and autocrine factors. Indeed, besides being targets of adipo-myokines, HDACs affect the synthesis of myokines by skeletal muscle, altering the composition of the humoral milieu and ultimately contributing to the muscle functioning as an endocrine organ. In this review, we discuss recent findings on the interplay between HDACs and circulating factors, in relation to skeletal muscle metabolism and its adaptative response to energy demand. We believe that enhancing knowledge on the specific functions of HDACs may have clinical implications leading to the use of improved HDAC inhibitors for the treatment of metabolic syndromes or aging.

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Associations of Circulating Irisin with FNDC5 Expression in Fat and Muscle in Type 1 and Type 2 Diabetic Mice

Cited by 15 publications

References 47 publications

Exercise-Induced Irisin Decreases Inflammation and Improves NAFLD by Competitive Binding with MD2

Exercise-Induced Irisin Decreases Inflammation and Improves NAFLD by Competitive Binding with MD2

Pyruvate carboxylase promotes thyroid cancer aggressiveness through fatty acid synthesis

Histone Deacetylases as Modulators of the Crosstalk Between Skeletal Muscle and Other Organs

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