FNDC5 Expression Research Articles

Effect of Different Exercise Mode and Ursolic Acid Supplementation on FNDC5 and UCP1 Gene Expression and Plasma Irisin in Rats

Effect of Different Exercise Mode and Ursolic Acid Supplementation on FNDC5 and UCP1 Gene Expression and Plasma Irisin in Rats

Hepatic FNDC5 is a potential local protective factor against Non-Alcoholic Fatty Liver

The proteolytic cleavage of Fibronectin type III domain-containing 5 (FNDC5) generates soluble irisin. Initially described as being mainly produced in muscle during physical exercise, irisin mediates adipose tissue thermogenesis and also regulates carbohydrate and lipid metabolism. The aim of this study was to evaluate the hepatic expression of FNDC5 and its role in hepatocytes in Non-Alcoholic Fatty Liver (NAFL). Here we report that hepatic expression of FNDC5 increased with hepatic steatosis and liver injury without impacting the systemic level of irisin in mouse models of NAFLD (HFD and MCDD) and in obese patients. The increased Fndc5 expression in fatty liver resulted from its upregulation in hepatocytes and non-parenchymal cells in mice. The local production of Fndc5 in hepatocytes was influenced by genotoxic stress and p53-dependent pathways. The down-regulation of FNDC5 in human HepG2 cells and in primary mouse hepatocytes increased the expression of PEPCK, a key enzyme involved in gluconeogenesis associated with a decrease in the expression of master genes involved in the VLDL synthesis (CIDEB and APOB). These alterations in FNDC5-silenced cells resulted to increased steatosis and insulin resistance in response to oleic acid and N-acetyl glucosamine, respectively. The downregulation of Fndc5 also sensitized primary hepatocytes to apoptosis in response to TNFα, which has been associated with decreased hepatoprotective autophagic flux. In conclusion, our human and experimental data strongly suggest that the hepatic expression of FNDC5 increased with hepatic steatosis and its upregulation in hepatocytes could dampen the development of NAFLD by negatively regulating steatogenesis and hepatocyte death.

Positive effects of conjugated linoleic acid (CLA) on the PGC1-α expression under the inflammatory conditions induced by TNF-α in the C2C12 cell line

The aim of the current study was to evaluate the effects of conjugated linoleic acid (CLA) on the expression of the genes involved in the reduction of inflammatory conditions induced by tumor necrosis factor alpha (TNF-α). To fulfill this, the C2C12 murine myoblast cell line was used. The experimental treatments consisted of 50 and 100 µM of CLA with 10, 15 and 20 ng/mL of TNF-α. Our results indicated that the concentrations of 50, 100 and 150 µM of CLA at 24 and 48 h increased the cell survival rate (p < 0.05), as compared with the control group. The effect of pre-treating CLA before the inflammation induced by TNF-α showed that the amount of cell death caused by TNF-α was inhibited in both 50 and 100 µM concentrations of CLA (p < 0.05). Modulatory effects of CLA on PGC1-α and Fndc5 transcript levels showed that the PGC1-α and Fndc5 expression levels were significantly increased 48 h after treating with 50 and 100 µM of CLA (p < 0.05). Overall, these findings indicate that using CLA could considerably improve the inflammatory condition induced by TNF-α.

Jingui Shenqi Pills Regulate Bone‐Fat Balance in Murine Ovariectomy‐Induced Osteoporosis with Kidney Yang Deficiency

Jingui Shenqi Pills (JGSQP) have been a staple of traditional Chinese medicine for thousands of years, used primarily as a treatment for kidney yang deficiency (KYD). In vitro analyses of JGSQP revealed strong induction of osteogenic differentiation and inhibition of adipogenic differentiation in bone-marrow-derived mesenchymal stem/stromal cells. However, the mechanisms by which JGSQP regulate the bone-fat balance in murine ovariectomy-induced osteoporosis with KYD have not been reported. Materials and Methods. Two-month-old female C57BL/6 mice were divided randomly into three groups: those receiving a sham operation (Sham); those undergoing bilateral ovariectomy and selection of KYD syndrome (Model); and those subjected to both bilateral ovariectomy and KYD syndrome selection for 8 weeks, followed by JGSQP treatment for 4 weeks (JGSQP). In the Sham and Model groups, mice were given the same dose of distilled water orally for 4 weeks. Animals from all three groups were euthanised at the 12th week. Vertebral microarchitecture and histomorphology were examined by micro-CT and H&E staining, respectively. In addition, we examined the mRNA expression of Akt, Wnt10b, Osterix (Osx), Fndc5, PPARγ, and Fabp4, as well as the protein of AKT, phosphorylation-AKT (p-AKT), BMP2, COL1A1, and FNDC5. Results. JGSQP treatment improved bone microarchitecture and mitigated histomorphological damage relative to the Model group. The osteoblast number (Ob.N/BS) and area (Ob.S/BS) were increased, whereas adipocyte number (adipocyte/tissue area) and area (adipocyte area/tissue area) were decreased in the JGSQP group. JGSQP treatment reduced the mRNA expression of Akt and adipogenesis-related genes (Fndc5, PPARγ, and Fabp4) while promoting osteogenesis-related genes (Wnt10b and Osx) mRNA expression. Additionally, the expression of p-AKT, BMP2, and COL1A1 proteins was increased and FNDC5 protein expression was decreased after JGSQP treatment. Conclusions. JGSQP treatment reversed murine ovariectomy-induced osteoporosis with KYD by controlling bone-fat balance via AKT pathway.

Genetic Variants in the Activation of the Brown-Like Adipocyte Pathway and the Risk for Severe Obesity

Background: Regular physical activity has an important role in energy expenditure and combats the development of obesity. During exercise, PPARGC1A is overexpressed, stimulating an increase of the expression of FNDC5. This protein is cleaved to release the hormone irisin, which activates a browning process in white adipose tissue through an increase in UCP1 expression. As a result, irisin leads to mitochondrial heat production and energy expenditure. Objectives:The aim of this study was to investigate whether genetic variants in genes related to browning are associated with severe obesity and obesity-related features. This case-control study comprised 210 individuals with severe obesity (median body mass index [BMI] 45.6 [range 40.5–52.2]) and 191 normal-weight subjects (BMI 22.8 [21.1–23.9]). Methods: Genomic DNA was extracted from peripheral blood and the genotypes of the PPARGC1A(rs8192678, rs3736265, rs2970847, and rs3755863) and UCP1 (rs6536991 and rs12502572) genes were obtained using Taqman® assay. For the FNDC5 gene, screening of exons 3–5 as well as their intron-exon boundaries was performed using automatic sequencing. Results: Our results demonstrated that PPARGC1Ars2970847 and UCP1rs12502572 are associated with severe obesity. Furthermore, these polymorphisms influence anthropometric traits, such as BMI, body weight, and body adiposity index. Our findings also showed a dose-effect relationship between PPARGC1A rs8192678 and fasting plasma glucose. Finally, 5 rare mutations were identified in FNDC5, and 1 of these is a novel missense mutation. Conclusion: This study shows that genetic variants in the activation of brown-like adipocyte pathway play an important role in the susceptibility to severe obesity.

고지방식이 섭취와 수영운동 수행시 오렉신 호르몬과 백색지방 갈변화에 미치는 영향

The objective of the present study was to investigate the effects of a high-fat diet and swimming exercise on neuropeptide hormone orexin and browning of white adipose tissue. Accordingly, a high-fat diet was administered and a swimming exercise regimen was applied for 6 weeks to 32 male Sprague-Dawley rats. In the comparison between the groups, body fat mass was significantly lower. The amount of dietary intake was significantly higher in the highfat diet group. Although there were no significant changes in orexin hormone levels in blood. With respect to heat generating factors, the high-fat diet + exercise and high-fat diet group showed significantly higher expression of PGC-1α and UCP-1 in muscles. The high-fat diet and high-fat diet + exercise groups showed a significantly higher expression of FNDC5 in fat tissues, whereas the high-fat diet group showed significantly higher expression of UCP-1 in fat tissues. The findings of the present study revealed that regular exercise stimulates the hypothalamus of the brain to regulate the function of orexin, a neuropeptide hormone, which promotes the expression of heat generating factors PGC-1α, FNDC5, and UCP-1, However, the future studies might have a positive impact on obesity treatment and improvement.

Expression of Irisin/FNDC5 in Cancer Cells and Stromal Fibroblasts of Non-small Cell Lung Cancer.

Background: Recent in vitro studies have indicated that irisin inhibits proliferation, migration and epithelial-mesenchymal transition. Irisin expression has not been studied in tumour tissues of non-small cell lung cancer (NSCLC) patients yet. The aim of the study was to determine the irisin expression in NSCLCs in comparison to the clinicopathological factors and expression of TTF-1, p63 and Ki-67. Material and methods: Tissue microarrays with 729 NSCLC and 140 non-malignant lung tissue (NMLT) were used to perform immunohistochemical reactions. Laser Capture Microdissection (LCM) was used to collect cancer and stromal cells from NSCLCs. FNDC5 expression was tested for LCM samples, 75 NSCLCs and 25 NMLTs with the RT-PCR technique. Western-blot, immunofluorescence reaction and RT-PCR assays were performed on lung cancer cell lines. Results: Irisin expression was observed in NSCLC cancer cells and stromal fibroblasts. In cancer cells, irisin expression was decreased in higher grades (G) of malignancy, tumour size (T) and according to lymph node metastasis. In stromal cells, irisin expression was increased in higher G and advanced T. A shorter overall survival was observed in patients with higher irisin expression in NSCLC stromal cells. Conclusions: Irisin expression in stromal fibroblasts may influence cancer cell proliferation and may be a prognostic factor for survival in NSCLC.

Irisin - evidence for benefits resulting from physical activity

Irisin is a myokine with wide metabolic action, which makes it very similar to a hormone. Its serum level depends on the expression of the genes FNDC5 and PGC-1α which, in turn, are induced, among others, by physical activity, especially aerobic exercises. According to many studies, aerobic training lasting for 45-60 minutes significantly increased the level of irisin in blood or muscles, and was considerably more effective than endurance training. Irisin shows protective properties against type 2 diabetes by decreasing insulin-resistance and against atherosclerosis by the improvement of lipid profile and anti-inflammatory action. It helps patients with overweight and obesity struggle with an excess of adipose tissue, and induces the conversion of white adipose tissue to brown. It also improves metabolic profile by the acceleration of metabolism and increase in thermogenesis. This myokine reduces the risk of occurrence of metabolic syndrome. Also, the neuroprotective effect of irisin has been confirmed, which would indicate a tremendous role of physical effort in slowing down the course of neurodegenerative diseases in seniors. In addition, irisin acts through many signal pathways exerting an anti-inflammatory, anti-oxidative, anti-apoptotic and anti-cancer effects, which is a potential therapeutic goal. Unfortunately, further studies concerning irisin are still needed before it can be clinically used. However, already now it may be the tool for psychologists working with persons suffering from overweight, obesity, diabetes, atherosclerosis, metabolic syndrome, neurodegenerative diseases, and many other disorders to motivate them for regular physical effort. DOI: http://dx.doi.org/10.5281/zenodo.3385065

Irisin Exerts Inhibitory Effect on Adipogenesis Through Regulation of Wnt Signaling.

Irisin is an exercise-induced myokine known to induce adipocyte browning through induction of uncoupling protein 1. Recent studies have reported that irisin is also an adipokine. However, there is limiting evidence on the role of endogenous irisin from adipocytes. In this study we aim to elucidate the expression and secretion pattern of irisin during adipocyte differentiation and the role of endogenous and exogenous irisin on the adipogenic process. As such, recombinant irisin, plasmid expressing FNDC5 and small interfering RNA were utilized. Our results show that the gene expression of irisin precursor FNDC5 and irisin secretion increases at the early stage of adipogenesis. Both recombinant irisin treated cells and FNDC5-overexpressed cells resulted in inhibition of adipogenesis evidenced by downregulated C/EBPα, PPARγ, and FABP4 expression and reduced lipid accumulation. Further data showed that the inhibitory effect of irisin on adipogenesis is mediated though potentiation of Wnt expression, which is known to determine the fate of mesenchymal stem cells and regulate adipogenesis. Conversely, FNDC5 knockdown cells showed downregulated Wnt expression, but failed to further induce adipogenesis. This study suggests that both exogenous and endogenous irisin is able to inhibit adipogenesis and that activation of Wnt and subsequent repression of transcription factors is partly involved in this process. This provides a novel insight on the local effect of irisin on adipocytes and additional benefit to protect against obesity-related metabolic disorders.

MON-289 Urokinase-type Plasminogen Activator May be Linked to FNDC5 Expression during Exercise

Irisin secretes from myocytes and cleavage by FNDC5 during muscle mechanic contraction in exercise. Evidence has shown myokines are mediated to crosslink between muscle and kidney. However, the relationship between Irisin and urokinase-type plasminogen activator (uPA) is unclear. In the present study, using mice model, we explored the role of uPA in irisin/FNDC5 during exercise.

수영운동이 비만이 유도된 쥐의 심장근 내 염증반응 및 FNDC5 발현에 미치는 영향

수영운동이 비만이 유도된 쥐의 심장근 내 염증반응 및 FNDC5 발현에 미치는 영향

Irisin in the primate hypothalamus and its effect on GnRH in vitro.

Irisin, encoded by the FNDC5 gene, is a recently discovered endocrine factor mainly secreted as a myokine and adipokine. However, irisin/FNDC5 expression has also been reported in different other organs including components of the reproductive axis. Yet, there is the scarcity of data on FNDC5/irisin expression, regulation and its reproductive effects, particularly in primates. Here, we report the expression of FNDC5/irisin, along with PGC1A (peroxisome proliferator-activated receptor gamma coactivator 1-alpha) and ERRA (estrogen-related receptor alpha), in components of the reproductive axis of marmoset monkeys. Hypothalamic FNDC5 and ERRA transcript levels are developmentally regulated in both male and female. We further uncovered sex-specific differences in FNDC5, ERRA and PGC1A expression in muscle and the reproductive axis. Moreover, irisin and ERRα co-localize in the marmoset hypothalamus. Additionally, in the arcuate nucleus of rhesus monkeys, the number of irisin+ cells was significantly increased in short-term fasted monkeys as compared to ad libitum-fed monkeys. More importantly, we observed putative interaction of irisin-immunoreactive fibers and few GnRH-immunoreactive cell bodies in the mediobasal hypothalamus of the rhesus monkeys. Functionally, we noted a stimulatory effect of irisin on GnRH synthesis and release in mouse hypothalamic neuronal GT1-7 cells. In summary, our findings show that FNDC5 and irisin are developmentally, metabolic-status dependently and sex-specifically expressed in the primate hypothalamic-pituitary-gonadal axis and exert a stimulatory effect on GnRH expression and release in mouse hypothalamic cells. Further studies are required to confirm the reproductive effects of irisin in vivo and to illuminate the mechanisms of its regulation.

Irisin Is Controlled by Farnesoid X Receptor and Regulates Cholesterol Homeostasis.

ObjectiveThe aim of this study was to investigate whether the nuclear receptor farnesoid X receptor (FXR) could regulate FNDC5/Irisin expression and the role of Irisin in hyperlipidemia and atherosclerosis in ApoE-/- mice.Methods and ResultsWe treated primary human hepatocytes, HepG2 cells, and Rhesus macaques with FXR agonist (CDCA, GW4064, and ivermectin). FNDC5 expression was highly induced by CDCA and GW4064 in hepatocytes, HepG2 cells, and the circulating level of Irisin increased in Rhesus macaques. Luciferase reporter and CHIP assays were used to determine whether FXR could regulate FNDC5 promoter activity. Irisin-ApoE-/- and ApoE-/- mice were used to study the metabolic function of Irisin in dyslipidemia and atherosclerosis. Irisin-ApoE-/- mice showed improved hyperlipidemia and alleviated atherosclerosis as compared with ApoE-/- mice. Irisin upregulated the expression of Abcg5/Abcg8 in liver and intestine, which increased the transport of biliary cholesterol and fecal cholesterol output.ConclusionActivation of FXR induces FNDC5 mRNA expression in human and increased the circulating level of Irisin in Rhesus macaques. FNDC5/Irisin is a direct transcriptional target of FXR. Irisin may be a novel therapeutic strategy for dyslipidemia and atherosclerosis.

Effect of skeletal muscle phenotype and gender on fasting-induced myokine expression in mice

Skeletal muscle secretes myokines, which are involved in metabolism and muscle function regulation. The role of fasting on myokine expression in skeletal muscle is largely unknown. In this study, we used gastrocnemius skeletal muscle RNA sequencing data from fasting male mice in the Gene Expression Omnibus (GEO) database. Adopted male and female C57BL/6J mice that fasted for 24 h were included to examine the effect of fasting on myokine expression in slow-twitch soleus and fast-twitch tiabialis anterior (TA) skeletal muscle. We found that fasting significantly affected many myokines in muscle. Fasting reduced Fndc5 and Igf1 gene expression in soleus and TA muscles in both male and female mice without muscle phenotype or gender differences, but Il6, Mstn and Erfe expression was influenced by fasting with fibre type- and gender-dependent effects. Fasting also induced muscle atrophy marker genes Murf1 and Fbxo32 and reduced myogenesis factor Mef2 expression without muscle fibre or gender differences. We further found that the expression of transcription factors Pgc1α, Pparα, Pparγ and Pparδ had muscle fibre type-dependent effects, and the expression of Pgc1α and Pparα had gender-dependent effects. The sophisticated expression pattern of myokines would partially explain the complicated cross-talk between skeletal muscle and other organs in different genders and muscles phenotypes, and it is worth further investigation.

Expression Analysis of Fibronectin Type III Domain-Containing (FNDC) Genes in Inflammatory Bowel Disease and Colorectal Cancer.

Background Fibronectin type III domain-containing (FNDC) proteins fulfill manifold functions in tissue development and regulation of cellular metabolism. FNDC4 was described as anti-inflammatory factor, upregulated in inflammatory bowel disease (IBD). FNDC signaling includes direct cell-cell interaction as well as release of bioactive peptides, like shown for FNDC4 or FNDC5. The G-protein-coupled receptor 116 (GPR116) was found as a putative FNDC4 receptor. We here aim to comprehensively analyze the mRNA expression of FNDC1, FNDC3A, FNDC3B, FNDC4, FNDC5, and GPR116 in nonaffected and affected mucosal samples of patients with IBD or colorectal cancer (CRC). Methods Mucosa samples were obtained from 30 patients undergoing diagnostic colonoscopy or from surgical resection of IBD or CRC. Gene expression was determined by quantitative real-time PCR. In addition, FNDC expression data from publicly available Gene Expression Omnibus (GEO) data sets (GDS4296, GDS4515, and GDS5232) were analyzed. Results Basal mucosal expression revealed higher expression of FNDC3A and FNDC5 in the ileum compared to colonic segments. FNDC1 and FNDC4 were significantly upregulated in IBD. None of the investigated FNDCs was differentially expressed in CRC, just FNDC3A trended to be upregulated. The GEO data set analysis revealed significantly downregulated FNDC4 and upregulated GPR116 in microsatellite unstable (MSI) CRCs. The expression of FNDCs and GPR116 was independent of age and sex. Conclusions FNDC1 and FNDC4 may play a relevant role in the pathobiology of IBD, but none of the investigated FNDCs is regulated in CRC. GPR116 may be upregulated in advanced or MSI CRC. Further studies should validate the altered FNDC expression results on protein levels and examine the corresponding functional consequences.

Association between Irisin, hs-CRP, and Metabolic Status in Children and Adolescents with Type 2 Diabetes Mellitus.

Proinflammatory cytokines and the novel myokine irisin, a cleavage product of FNDC5, have been found to play a role in obesity and type 2 diabetes mellitus (T2DM). Irisin has been shown to increase browning of adipose tissue, thermogenesis, energy expenditure, and insulin sensitivity, yet its association with inflammatory markers is still limited. Circulating irisin has been found to be increased in obesity, while in adult subjects with T2DM decreased levels have been found. However, data establishing the association of circulating irisin in children and adolescents with T2DM has not been described in the literature. The objective of this study was to determine irisin plasma concentration and its association with metabolic and adiposity markers and with hs-CRP, a surrogate marker of inflammation used in clinical practice, in a pediatric population with T2DM. A cross-sample of 40 Mexican children and adolescents aged 7-17 were recruited, 20 diagnosed with T2DM and 20 healthy controls. Plasma irisin levels were found to be lower in the T2DM group compared with controls, which could be attributed to a reduced PGC-1α activity in muscle tissue with a consequent decrease in FNDC5 and irisin expression. Irisin concentration was found to be positively correlated with HDL-c, LDL-c, and total cholesterol, while negatively correlated with BMI, waist circumference, and triglycerides. However, after multiple regression analysis, only HDL-c correlation remained significant. hs-CRP was higher in the T2DM group and positively associated with adiposity markers, unfavorable lipid profile, insulin levels, and HOMA-IR, but no association with irisin was found. Given the favorable metabolic effects attributed to irisin, the low plasma levels found in children and adolescents with T2DM could exacerbate the inflammatory and metabolic imbalances and the intrinsic cardiovascular risk of this disease. We propose an “irisin-proinflammatory/anti-inflammatory axis” to explain the role of irisin as a metabolic regulator in obesity and T2DM.

The effect of 14 weeks of endurance training with two different Intensity on serum irisin level, gene expression of skeletal muscle PGC1-α and FNDC5 and subcutaneous adipose tissue UCP1 in obese rats

The effect of 14 weeks of endurance training with two different Intensity on serum irisin level, gene expression of skeletal muscle PGC1-α and FNDC5 and subcutaneous adipose tissue UCP1 in obese rats

Physical activity and muscle-brain crosstalk.

Neurological and mental illnesses account for a considerable proportion of the global burden of disease. Exercise has many beneficial effects on brain health, contributing to decreased risks of dementia, depression and stress, and it has a role in restoring and maintaining cognitive function and metabolic control. The fact that exercise is sensed by the brain suggests that muscle-induced peripheral factors enable direct crosstalk between muscle and brain function. Muscle secretes myokines that contribute to the regulation of hippocampal function. Evidence is accumulating that the myokine cathepsin B passes through the blood-brain barrier to enhance brain-derived neurotrophic factor production and hence neurogenesis, memory and learning. Exercise increases neuronal gene expression of FNDC5 (which encodes the PGC1α-dependent myokine FNDC5), which can likewise contribute to increased brain-derived neurotrophic factor levels. Serum levels of the prototype myokine, IL-6, increase with exercise and might contribute to the suppression of central mechanisms of feeding. Exercise also increases the PGC1α-dependent muscular expression of kynurenine aminotransferase enzymes, which induces a beneficial shift in the balance between the neurotoxic kynurenine and the neuroprotective kynurenic acid, thereby reducing depression-like symptoms. Myokine signalling, other muscular factors and exercise-induced hepatokines and adipokines are implicated in mediating the exercise-induced beneficial impact on neurogenesis, cognitive function, appetite and metabolism, thus supporting the existence of a muscle-brain endocrine loop.

Hepatoprotective Effects of Silymarin on Liver Injury via Irisin Upregulation and Oxidative Stress Reduction in Rats with Type 2 Diabetes.

Diabetes is one of the most prevalent metabolic diseases. Irisin (FNDC5 protein) is involved in the new strategy of combating type 2 diabetes. In the liver, the antidiabetic mechanism of silymarin at the molecular level is unknown. This study investigated the effects of silymarin on irisin and the related gene expression and oxidative stress status in the liver of type 2 diabetic rats. Thirty-six rats were divided into 6 groups (n=6 each) by simple randomization: control, control+silymarin (60 mg/kg daily in normal saline orally for 60 days), control+silymarin (120 mg/kg daily in normal saline orally for 60 days), diabetic, diabetic+silymarin (60 mg/kg daily for 60 days), and diabetic+silymarin (120 mg/kg daily for 60 days). Biochemical parameters were measured by spectrophotometric and immunoassay methods, and quantitative polymerase chain reaction was used to evaluate gene expression. The data were analyzed by one-way ANOVA, followed by the Tukey test, using SPSS software, version 16.0. The results were considered statistically significant at a P value less than 0.05. In the diabetic rats treated with silymarin (60 and 120 mg/kg), by comparison with the diabetic group, body weight (P=0.04 and P=0.02), insulin (P<0.001), expression of PGC-1α (P=0.04 and P=0.02), expression of FNDC5 (P=0.03 and P=0.01), and concentration of irisin in the liver (P=0.02 and P=0.01) and serum (P<0.001) were significantly increased, whereas the levels of glucose (P<0.001), HOMA-IR (P=0.03 and P=0.01), and liver injury markers (P<0.001) were significantly reduced. Oxidative stress status and histopathological changes were improved in the treated groups. These results suggest that silymarin because of its ability to upregulate irisin and antioxidant effects can be considered an antidiabetic agent.

Obesity caused by a high-fat diet regulates the Sirt1/PGC-1α/FNDC5/BDNF pathway to exacerbate isoflurane-induced postoperative cognitive dysfunction in older mice

ABSTRACT Objectives: To investigate the effects of obesity caused by high-fat diet (HFD) on postoperative cognitive dysfunction (POCD) and expression of the Sirt1/PGC-1α/FNDC5/BDNF pathway in the hippocampus of older mice. Methods: Fifty-six 15-month-old male C57BL/6 mice were randomly divided into eight groups – ad libitum control (ALC), ad libitum surgery (ALS), ad libitum surgery with PBS (ALS + PBS), ad libitum surgery with resveratrol (ALS + Res), HFD control (HFC), HFD surgery (HFS), HFD surgery with PBS (HFS + PBS), HFD surgery with resveratrol (HFS + Res). Surgery group mice were exposed to isoflurane before tibial fracture internal fixation. Open field tests and fear conditioning were performed to test motor ability and memory. The levels of expression of Sirt1, PGC-1α, FNDC5, and BDNF were detected using western blot and immunofluorescence. Results: The results of the open field tests indicated there were no between-group differences in motor ability and anxiety. The results of the fear conditioning indicated that the memory of the HFC group and HFS group mice were significantly worse compared with the ALC group and ALS group mice, respectively. There were parallel decreases in expression of the Sirt1/PGC-1α/FNDC5/BDNF pathway in the hippocampi of the HFC and HFS group mice. Resveratrol treatment attenuated the memory loss by increasing hippocampal Sirt1 expression. Expression of the PGC-1α/FNDC5/ BDNF pathway in the CA1 area of the hippocampus was upregulated after resveratrol treatment. Conclusion: An HFD exacerbates POCD in older mice. This change was related to HFD inhibition of expression of the Sirt1/PGC-1α/FNDC5/BDNF pathway in the hippocampus. Resveratrol pretreatment reversed the memory loss via upregulation of this pathway.