OR-010 The potential role of MG53 in exercise-mediated modulation of diabetic cardiomyopathy in db/db mice

Objective Diabetic cardiomyopathy is a major complication of Type 2 diabetes. Recent studies have shown that as an E3 ligase targeting insulin receptor (IR) and insulin receptor substrate 1 (IRS1), MG53 could result in insulin resistance and metabolic disorders. However, it is still to be investigated whether MG53 plays a role in the pathogenesis of diabetic cardiomyopathy, as well as whether the effect of exercise intervention on diabetic cardiomyopathy is mediated by MG53. Methods 20 db/db mice and 20 m/m mice were randomly assigned to Groups DC (db/db control, N=10), DE (db/db exercise, N=10), MC (m/m control, N=10) and ME (m/m exercise, N=10). The mice of Groups ME and DE were trained to run on the treadmill for 12 weeks in total. For Week 1, the mice ran for 20min at 7-13m/min, four times a week. Since the second week, the mice were trained to run at 13.3m/min, 6d/wk, and the running duration was increased from 30-45min/d for Week 2 to 1h/d since the third week. At the end of the intervention period, IPGTT and IPITT were performed to determine the effect of exercise training. The mice were then euthanized and the heart was removed. Real-time PCR and Western blotting were performed to determine the expression levels of mRNA and proteins. Results According to the result of IPGTT and IPITT, glucose concentration was significantly higher in DC compared to MC, and exercise intervention significantly decreased the glucose level of diabetic mice. Heart weight to tibia length ratio was not significantly different between MC and DC, but was higher in DE than in DC. As expected, the mRNA expression of MG53 was significantly higher in the diabetic mice, and was significantly decreased by exercise training. However, the protein level of MG53 was not significantly different between MC and DC, even though exercise intervention caused lower MG53 protein level in DE. The protein level of p-IR-β (Tyr1146) was significantly higher in DC than MC. Exercise intervention significantly decreased the protein level of p-IRS1 (Ser1101) in both the lean and diabetic mice. Diabetes caused a significant decrease in p-AKT (Ser473), while exercise training increased the protein level of p-AKT (Ser473) of the diabetic mice. The mRNA expressions of Ppargc1a, Cpt1b, Acadm, Acadvl, Acacb and Acaa2 were significantly increased in DC compared to MC, suggesting that fat metabolism was enhanced in the hearts of diabetic mice. To the contrary, the enhanced fat metabolism was compromised by exercise intervention, as revealed by the mRNA expression level of Cpt1b, Acadm, Acacb and Acaa2. Besides, the mRNA expression of Pdk1 and Pdk2 were significantly increased in db/db mice, suggesting that glucose metabolism was reduced by diabetes. PPAR-α is an important regulator of fat metabolism. The protein level of PPAR-α was significantly increased in DC compared to MC, and was decreased in DE compared to DC. Besides, the mRNA expression of key components of PPAR-α pathway, including Cd36, Ppargc1b and Fabp3 were all significantly increased in db/db mice, while exercise intervention significantly decreased the mRNA expression of Cd36 and Ppargc1b. Conclusions MG53 is involved in the pathogenesis of diabetic cardiomyopathy of db/db mice by inhibiting insulin signaling, downregulating glucose metabolism and promoting fat metabolism. The state of insulin resistance and alteration of substrate utilization brought by diabetes could be improved by 12 week treadmill training, partly through the regulation of PPAR-α pathway

PO-063 Exercise alleviates insulin resistance by regulating MG53 and IR/IRS/AKT/mTOR signaling in db/db mice skeletal muscle

Objective In the current study, we aim to investigate whether 12-week treadmill exercise alleviates insulin resistance and muscle atrophy, and to explore whether MG53 along with IR/IRS/AKT/mTOR cascade play a role in the physiopathological changes of db/db mice. Methods 20 db/db mice and 20 age-matched non-diabetic m/m mice were assigned to 4 groups as MC (m/m control) group, ME (m/m exercise) group, DC (db/db control) group and DE (db/db exercise) group. After an intervention of treadmill exercise of moderate intensity for 12 weeks, glucose and insulin tolerance tests, insulin resistance index (HOMA-IR, homeostasis model assessment of insulin resistance) and lipid metabolic profile were determined using blood samples. Skeletal muscles were utilized for determination of cross-sectional area (CSA), protein level detection of MG53 and insulin signaling pathway. Results Compared with MC mice, the AUC (areas under curve) of IPGTT (intraperitoneal glucose tolerance test) and IPITT (intraperitoneal insulin tolerance test) as well as HOMA-IR were significantly increased, and lipid parameters (serum triglyceride and total cholesterol) increased significantly in DC group. The upregulation of MG53 protein in different skeletal muscles (quadriceps, gastrocnemius and soleus muscle) could be observed in DC mice. Phosphorylated proteins of IR-β (β subunit of insulin receptor), IRS1, AKT (protein kinase B), mTOR (mammalian target of rapamycin), p70S6k and S6 ribosomal protein after acute insulin stimulation were downregulated with significance, whereas no significant difference was found in total protein levels of IR-β and AKT except IRS1 in DC group. The results of AUC of IPGTT and IPITT, HOMA-IR and serum lipid parameters in DE group were significantly decreased compared with DC group. 12-week moderate exercise was sufficient to downregulate the expression of MG53 in skeletal muscles of diabetic db/db mice. In addition, treadmill exercise-induced improvement of insulin signal transduction and insulin-dependent protein synthesis may partially account for the heavier muscle mass and larger muscle size. Conclusions In summary, insulin resistance and muscle atrophy of diabetic db/db mice could be effectively attenuated by 12-week moderate treadmill exercise by regulating MG53, MG53-mediated ubiquitin-dependent degradation of IRS1 and insulin signaling transduction

Acute Exercise Induced Mitochondrial H 2

Exercise induced skeletal muscle phenotype change involves a complex interplay between signaling pathways and downstream regulators. This study aims to investigate the effect of acute exercise on mitochondrial H2O2 production and its association with p66Shc, FOXO3a, and antioxidant enzymes. Male ICR/CD-1 mice were subjected to an acute exercise. Muscle tissues (gastrocnemius and quadriceps femoris) were taken after exercise to measure mitochondrial H2O2 content, expression of p66Shc and FOXO3a, and the activity of antioxidant enzymes. The results showed that acute exercise significantly increased mitochondrial H2O2 content and expressions of p66Shc and FOXO3a in a time-dependent manner, with a linear correlation between the increase in H2O2 content and p66Shc or FOXO3a expression. The activity of mitochondrial catalase was slightly reduced in the 90 min exercise group, but it was significantly higher in groups with 120 and 150 min exercise compared to that of 90 min exercise group. The activity of SOD was not significantly affected. The results indicate that acute exercise increases mitochondrial H2O2 production in the skeletal muscle, which is associated with the upregulation of p66Shc and FOXO3a. The association of p66Shc and FOXO3a signaling with exercise induced H2O2 generation may play a role in regulating cellular oxidative stress during acute exercise

Antioxidant Supplement Inhibits Skeletal Muscle Constitutive Autophagy rather than Fasting-Induced Autophagy in Mice

In this study, we tested the hypothesis that NAC administration leads to reduced oxidative stress and thus to decreased expression of autophagy markers in young mice. Our results reveal that NAC administration results in reduced muscle mRNA levels of several autophagy markers, including Beclin-1, Atg7, LC3, Atg9, and LAMP2. However, NAC supplement fails to block the activation of skeletal muscle autophagy in response to fasting, because fasting significantly increases the mRNA level of several autophagy markers and LC3 lipidation. We further examined the effects of NAC administration on mitochondrial antioxidant capacity in fed and 24-hour fasted mice. Our results clearly show that NAC administration depresses the expression of manganese superoxide dismutase (MnSOD) and TP53-induced glycolysis and apoptosis regulator (TIGAR), both of which play a predominant antioxidant role in mitochondria by reducing ROS level. In addition, we found no beneficial effect of NAC supplement on muscle mass but it can protect from muscle loss in response to fasting. Collectively, our findings indicate that ROS is required for skeletal muscle constitutive autophagy, rather than starvation-induced autophagy, and that antioxidant NAC inhibits constitutive autophagy by the regulation of mitochondrial ROS production and antioxidant capacity

PO-125 Fis1 governs normal mitophagy in slow muscle during the low-intensity and long-period exercise

Objective Mitochondrial dynamics include mitochondrial fusion and mitochondrial fission. It has long been widely recognized that Fis1 plays a role in mitochondrial fission in mammals. However, the finding of Dr. Youle’s team suggests that Fis1 may play an important role in mediating normal mitophagy. Both of mitochondrial dynamics and mitophagy are closely related to skeletal muscle homeostasis. Therefore, in this study, Fis1 was specifically knocked out in skeletal muscle in vivo, looking forward to: 1) investigating the relationship between Fis1 and mitochondrial morphology, mitophagy in mouse skeletal muscle. 2) The mechanism of Fis1 in mitochondrial quality in skeletal muscle under exercise stress. So as to we can clarify the molecular mechanism of Fis1 in mediating mitochondrial quality in skeletal muscle, but also expect to provide more theoretical basis for skeletal muscle health and exercise adaptation. Methods We constructed conditional skeletal muscle Fis1 knockout mice (C57BL/6) and littermate control mice through Cre / Loxp technique. The mice were free feeding, drinking and activity during the teat, we only selected male mice for all of the tests. And the genotypes were Fis1FL / FL MCK-Cre + (Fis1KO) and Fis1FL / FL MCK-Cre – (WT). First, we performed endurance test on 10 WT and 10 Fis1KO mice (32-40 weeks, n = 10), then dissected quadriceps, gastrocnemius and soleus (n=4-5) quickly and rapidly frozen in liquid nitrogen, then stored at -80 ° C freezer for testing Fis1 and OXPHOS expression (Western-blot). On the other hand, we selected WT and Fis1KO mice (n=3) to prepare EM samples, so as to observe mitochondrial morphology and muscle ultrastructure. Skeletal muscle (n=3-4) was snap-frozen in isopentane cooled with liquid nitrogen for HE, NADH staining, and observing GFP-LC3 (mitophagy).  Base on the exploration of loss of Fis1 without stress, we adopted endurance exhaustive exercise on WT (WT EEE) and Fis1KO mice (Fis1KO EEE) (n=3-4). Mice were acclimated to and trained on a 10o uphill treadmill. Mice were acclimated to and trained on a 10o uphill treadmill (Columbus Instruments) for 2 days. On day 3, mice were subjected to a single bout of running starting at the speed of 10m/min. Forty minutes later, the treadmill speed was increased at a rate of 1m/min every 10 min for a total of 30 min, and then increased at the rate of 1m/min every 5 min until mice were exhausted. Exhaustion was defined as the point at which mice spent more than 5 s on the electric shocker without attempting to resume running even if we used short air puffs and tail tickles with bristle brush. We dissected soleus and gastrocnemius to observe muscle ultrastructure and mitophagy through EM and confocal microscope respectively (same methods as before). At the same time, we used immune-EM to observe autophagosome morphology and LC3 distribution. Results Behavior test on specific knock out skeletal muscle Fis1 mice model We found that loss of Fis1 induced significantly lower performance in treadmill endurance tests than controls (P <0.001). The effect of loss of Fis1 on mitochondrial morphology and function In soleus, knocking out Fis1 caused mitochondrial hyperfusion (mitochondrial size was significantly increased, P = 0.01). In addition, we found more swollen mitochondria in Fis1 knock-out gastrocnemius. On the other hand, compared with the control mice, lack of Fis1 significantly reduced the protein expression of Complex I, Complex II and Complex IV in soleus (P <0.01). As same as before, we also found a significant increase GFP-LC3 (P <0.01) in Fis1KO soleus. 3) Changes of muscle ultrastructure and mitophagy after endurance exhaustive exercise (EEE) First, comparing with the control group, swollen sarcoplasmic reticulum (skeletal muscle endoplasmic reticulum (ER)) and extremely swollen terminal cisternae (TC) were found in Fis1KO soleus and gastrocnemius respectively after endurance exhaustive exercise. We found a significant accumulation of GFP-LC3 (P <0.0001) in Fis1KO soleus compared to the control. However, GFP-LC3 signal still increased (P <0.001) in Fis1KO soleus after exercise compared with that in soleus before exercise. Moreover, we observed a lot of large and irregular autophagosomes appeared in Fis1KO soleus after EEE through immune electron microscope. Conclusions 1) Loss of Fis1 causes a certain degree of mitochondrial hyperfusion, increases mitophagy and significantly decreases mitochondrial function in slow muscle. However, losing Fis1 does not cause obvious alteration on quick muscle and synthetic muscle. Therefore, the absence of Fis1 has a significant effect on mitochondria-rich muscle. 2) Mitochondrial-ER interactions may be involved in the connection of endoplasmic reticulum swelling after endurance exhaustive exercise. 3) Endurance exercise with oxidative phosphorylation aggravate the increase and abnormality of mitophagy caused by the loss of Fis1 in slow muscle, suggesting that Fis1 governs normal mitophagy in slow muscle during the low-intensity and long-period exercise. This phenomenon may be related to the worse performance in treadmill endurance test of Fis1 KO mice

Optimization of training for professional rugby union players: investigating the impact of different small-sided games models on GPS-derived performance metrics

Introduction: Professional rugby union players can improve their performance by engaging in small-sided games (SSGs), which simulate the movement patterns of the game. This study collected metrics related to running performance and mechanical workload and their relative values from both forward and back positions, aiming to explore the impact of different SSGs factors on athlete workload, as well as the workload difference between official games (OGs) and SSGs.Methods: The monitored GPS data were collected from SSGs with different player numbers and pitch sizes (five sessions), SSG rules (5 weeks, four sessions per week), and OGs conducted throughout the year. Additionally, the study compared changes in players’ sprinting performance before and after two SSG sessions.Results: Backs had greater workload than forwards. Less space and number of players SSG (4 vs. 4, 660 m2) was conducive to facilitating training for players in acceleration and deceleration. Conversely, larger spaces were associated with improved running performance. However, the introduction of a floater had no significant impact on performance improvement. Additionally, the 7 vs. 4 model (seven players engaged with four opponents) resulted in the greatest workload during medium-hard accelerations (F = 52.76–88.23, p < 0.001, ηp2 = 0.19–0.28). Japan touch model allowed for more high-speed running training (F = 47.93–243.55, p < 0.001, ηp2 = 1.52). The workload performed by SSGs can almost cover that of OGs (F = 23.36–454.21, p < 0.05, ηp2 = 0.03–0.57). In the context of ηp2, values around 0.01, 0.06 and 0.14 indicate small, medium and large effects respectively.Discussion: However, given the significantly higher workload of SSGs and the slight decrease in sprinting performance, further research is required to examine the training patterns of SSGs. This study provided insight into the impact of player numbers, pitch size, and rules on rugby-specific SSGs. Coaches should optimize SSG setups for enhanced training outcomes, ensuring the long-term development of physical capacity, technical and tactical skills

PO-062 Acute exercise intervention combined with metformin’s influences on glucose homeostasis in T2D mice

Objective Type 2 diabetes mellitus is a common chronic diseases prevailing in the world and the amount of diabetic and pre-diabetic patients is increasing gradually. Exercise combined with hypoglycemic drug is the first recommended therapy to treat type 2 diabetes. Metformin was found from galegine in 1957 and has been used now as the first cheap and effective hypoglycemic guanidines. Our study aims to explore the effects of different ways of acute exercise intervention combined with high dose of metformin on glucose homeostasis and its relative molecular mechanisms in type 2 diabetic mice. Methods Adopt 4-week high fat diet (HFD, 45% fat content) and one-time STZ (Streptozocin, 100mg/kg) intraperitoneal injection to build type 2 diabetic mice. There are 84 mice in total, 24 mice were divided into three groups: normal control (NC) group, normal acute resistance training (NCR) group and normal acute endurance training (NCE) group, N=8 each group, they were fed normal chow. The rest 60 mice were fed HFD as T2D modeling group. 48 mice were developing type 2 diabetes and they were divided into 6 groups: diabetic control (DC) group, diabetic acute resistance training (DCR) group, diabetic acute endurance training (DCE) group, high dose of metformin control (HMC) group, high dose of metformin combined with acute resistance training (HMR) group and high dose of metformin combined with acute endurance training (HME) group, N=8 each group. Acute resistance training is climbing 1 meter ladder from down to up, 5 times a group, 3 groups in total, monitoring the glucose change with extracting mouse tail vein blood during each group, using ACCU-CHEK monitor. Acute endurance training is running at the speed of 18 m/min on the platform for 50 minutes and blood glucose change was monitored every 10 minutes by extracting mouse tail vein blood. HMC, HMR and HME group mice were intraperitoneally injected high dose of metformin (200mg/kg) one hour before the acute exercise intervention. Comparatively, NC, NCR, NCE, DC, DCR, DCE group mice were intraperitoneally injected 0.9% saline one hour before the acute exercise intervention. ELISA, RT-PCR and Western Blot were used to evaluate relative serum indicators, mRNA and protein expression of regulating blood glucose homeostasis. Results 1) 4-week high fat diet and one time 100mg/kg Streptozocin intraperitoneal injection induces mice to develop type 2 diabetes. The fasting blood glucose, IPGTT, ITT, glucose AUC and insulin AUC of T2D group mice are significantly higher than NC group. 2) Compared with DCR group, the blood glucose value and fluctuation of HMR group mice are both significantly decreased, but the blood glucose value of DCR and HMR group mice are significantly higher than NCR group. In the same way, the blood glucose value and fluctuation of HME group mice is lower than DCE group and the whole blood glucose level of both group are higher than NCE group. Acute resistance training and acute endurance training combined with high dose of metformin have not affected the weight of type 2 diabetic mice. Hence compared with HMC group, the eWAT (epididymal white adipose tissue) of HMR and HME group mice is significantly declined. 3) Compared with NC group, the indicators of serum glucose, GSP (glycosylated serum protein), serum TG and serum T-CHO of DC group are notably increased, further reflect that the success model of type 2 diabetic mice. Compared with HMC group, the indicators of serum glucose, GSP, serum TG and serum T-CHO of HMR group mice are notably decreased, in the mean time, the indicators of serum glucose and serum TG of HME group mice are significantly declined. Interestingly, the serum insulin of HME group mice is notably lower than HMR group. 4) Compared with DC group, the indicators of mRNA expression about hepatic gluconeogenesis key rate-limiting enzymes PEPCK and G6pase of HMC group are significantly declined, but mRNA expression of regulating hepatic glucose homeostasis GLUT2 of HMC group is notably raised. Compared with HMC group, G6Pase mRNA expression of HMR and HME group is significantly escalated and Fbp mRNA expression of both groups are significantly declined. Compared with HMC, the indicators of mRNA expression about regulating hepatic glucose homeostasis GLUT2 and Gck of HMR and HME group mice show opposite trend, the former is down and the latter is up. Compared with HMC group, PEPCK mRNA expression of HMR group mice is notably escalated. Compared with HMR group, PEPCK and G6Pase mRNA expression of HME group mice are notably raised. 5) In the liver, there is a signaling pathway of AMPKα-PGC-1α-CREB to regulate glucose homeostasis and hepatic gluconeogenesis. Our study find that compared with HMC group, AMPKα2, PGC-1α and CREB mRNA expression of HMR and HME group mice are notably increased and only AMPKα1 mRNA expression of HMR group mice is significantly increased. Conclusions 1) Acute resistance training and acute endurance training combined with high dose of metformin can effectively reduce glucose fluctuation during exercise in type 2 diabetic mice, therefore these two way can both improve glucose homeostasis during acute exercise intervention in type 2 diabetic mice. 2) Acute resistance training and acute endurance training combined with high dose of metformin can improve serum glucose and lipid metabolism in type 2 diabetic mice, but acute resistance training combined with high dose of metformin are better to improve serum lipid metabolism. 3) Acute exercise intervention combined with high dose of metformin can comparatively increase hepatic gluconeogenesis key rate-limiting enzymes PEPCK and G6Pase and regulating hepatic glucose transport Gck mRNA expression. In the opposite, these two ways inhibit the other hepatic gluconeogenesis key rate-limiting enzyme Fbp and regulating hepatic glucose transport GLUT2 mRNA expression. 4) Compared with acute endurance training combined with high dose of metformin, acute resistance training combined with high dose of metformin can better improve glucose homeostasis and hepatic gluconeogenesis in type 2 diabetic mice via the signaling pathway of AMPKα-PGC-1α-CREB

Physical Exercise Regulates p53 Activity Targeting SCO2 and Increases Mitochondrial COX Biogenesis in Cardiac Muscle with Age

The purpose of this study was to outline the timelines of mitochondrial function, oxidative stress and cytochrome c oxidase complex (COX) biogenesis in cardiac muscle with age, and to evaluate whether and how these age-related changes were attenuated by exercise. ICR/CD-1 mice were treated with pifithrin-μ (PFTμ), sacrificed and studied at different ages; ICR/CD-1 mice at younger or older ages were randomized to endurance treadmill running and sedentary conditions. The results showed that mRNA expression of p53 and its protein levels in mitochondria increased with age in cardiac muscle, accompanied by increased mitochondrial oxidative stress, reduced expression of COX subunits and assembly proteins, and decreased expression of most markers in mitochondrial biogenesis. Most of these age-related changes including p53 activity targeting cytochrome oxidase deficient homolog 2 (SCO2), p53 translocation to mitochondria and COX biogenesis were attenuated by exercise in older mice. PFTμ, an inhibitor blocking p53 translocation to mitochondria, increased COX biogenesis in older mice, but not in young mice. Our data suggest that physical exercise attenuates age-related changes in mitochondrial COX biogenesis and p53 activity targeting SCO2 and mitochondria, and thereby induces antisenescent and protective effects in cardiac muscle

PL-010 Chronic mild stress improves glucose homeostasis via myonectin-mediated suppression of sympathetic activity in high-fat diet-fed mice

Objective Recent studies suggest that chronic stress exposure can ameliorate the progression of diet-induced prediabetic disease, by inhibiting an increase in weight gain, caloric intake and efficiency and insulin resistance. To determine the underlying mechanism by which chronic stress improves the progression of type 2 diabetes, we developed a model of chronic mild stress in high-fat diet(HFD)-fed mice which are resistant to obesity and exhibit a healthy-like metabolic phenotype. Methods High-fat diet (HFD): 45% kcal derived from fat (Research Diets, Inc.).Mice experienced one stressor during the day and a different stressor during the night. Stressors were randomly chosen from the following list : cage tilt on a 45° angle for 1 to 16 h; food deprivation for 12 to 16 h; white noise for 1 to 16 h; strobe light illumination for 1 to 16 h; crowded housing; light cycle (continuous illumination) for 24 to 36 h; dark cycle (continuous darkness) for 24 to 36 h; water deprivation for 12 to 16 h; damp bedding (200 ml water poured into sawdust bedding) for 12 to 16 h.Recombinant adeno-associated virus (AAV): AAV9 vectors encoding myonectin under the control of the ubiquitous CMV promoter (AAV9-CMV-Vip) or an equal dose of the AAV9-CMV-null vector were delivered to C57BL/6 mice by the tail vein. Mice were deprived of food for 16 h and then subjected to test 7 days after AAV injection. Results Chronic stress improved glucose intolerance and sympathetic overactivity in HFD-fed mice. Chronic stress attenuated epinephrine(EPI)-stimulated glycerol release into blood in vivo and accelerated glycerol release from white adipose tissue followed by in vitro incubation with EPI. Chronic stress reduced plasma triglyceride but increased the levels of plasma insulin and myonectin. We further found that adeno-associated virus 9 (AAV9)-mediated myonectin overexpression improved glucose homeostasis and reduced epinephrine sensitivity. Myonectin overexpression reduced plasma norepinephrine, EPI and leptin levels, and increased insulin sensitivity in brown and white adipose tissue. Intense sympathetic activity with high-intensity running inhibited myonectin expression in skeletal muscle, whereas medium and low-intensity exercise running increased myonectin expression. Conclusions These findings suggest that chronic mild stress can improve glucose homeostasis via myonectin-mediated suppression of sympathetic activity in high-fat diet-fed mice

Transcriptional Regulation by Nuclear Corepressors and PGC-1α: Implications for Mitochondrial Quality Control and Insulin Sensitivity

The peroxisome proliferator-activated receptors (PPARs) and estrogen-related receptor (ERRα) are ligand-activated nuclear receptors that coordinately regulate gene expression. Recent evidence suggests that nuclear corepressors, NCoR, RIP140, and SMRT, repress nuclear receptors-mediated transcriptional activity on specific promoters, and thus regulate insulin sensitivity, adipogenesis, mitochondrial number, and activity in vivo. Moreover, the coactivator PGC-1α that increases mitochondrial biogenesis during exercise and calorie restriction directly regulates autophagy in skeletal muscle and mitophagy in the pathogenesis of Parkinson's disease. In this paper, we discuss the PGC-1α’s novel role in mitochondrial quality control and the role of nuclear corepressors in regulating insulin sensitivity and interacting with PGC-1α