Cancer causes dysfunctional insulin signaling and glucose transport in a muscle-type-specific manner.

Metabolic dysfunction and insulin resistance are emerging as hallmarks of cancer and cachexia, and impair cancer prognosis. Yet, the molecular mechanisms underlying impaired metabolic regulation are not fully understood. To elucidate the mechanisms behind cancer-induced insulin resistance in muscle, we isolated extensor digitorum longus (EDL) and soleus muscles from Lewis Lung Carcinoma tumor-bearing mice. Three weeks after tumor inoculation, muscles were isolated and stimulated with or without a submaximal dose of insulin (1.5 nM). Glucose transport was measured using 2-[3 H]Deoxy-Glucose and intramyocellular signaling was investigated using immunoblotting. In soleus muscles from tumor-bearing mice, insulin-stimulated glucose transport was abrogated concomitantly with abolished insulin-induced TBC1D4 and GSK3 phosphorylation. In EDL, glucose transport and TBC1D4 phosphorylation were not impaired in muscles from tumor-bearing mice, while AMPK signaling was elevated. Anabolic insulin signaling via phosphorylation of the mTORC1 targets, p70S6K thr389, and ribosomal-S6 ser235, were decreased by cancer in soleus muscle while increased or unaffected in EDL. In contrast, the mTOR substrate, pULK1 ser757, was reduced in both soleus and EDL by cancer. Hence, cancer causes considerable changes in skeletal muscle insulin signaling that is dependent on muscle-type, which could contribute to metabolic dysregulation in cancer. Thus, the skeletal muscle could be a target for managing metabolic dysfunction in cancer.

Effect and potential mechanism of action of sea cucumber saponins on postprandial blood glucose in mice.

Postprandial blood glucose control is the major goal in the treatment of diabetes. Here, we investigated the effect of sea cucumber saponins (SCSs) on postprandial blood glucose levels. SCS inhibited yeast as well as rat intestinal α-glucosidase activity in a dose-dependent manner and showed better inhibition of yeast α-glucosidases compared to the positive control. Further studies were performed using ICR mice treated with SCS and starch or SCS alone by oral gavage. Unexpectedly, SCS increased postprandial blood glucose levels a short time (1 h) after oral gavage. The serum corticosterone (CORT) level showed a consistent correlation with glucose levels. In vitro experiments confirmed that SCS treatment increased the secretion of CORT in the Y1 adrenal cell line. Overall, these studies demonstrated that SCS gavage could inhibit α-glucosidase activity but cannot attenuate postprandial blood glucose level within short time periods. The underlying mechanisms are probably related to increased serum CORT levels.

Long-term fatty liver-induced insulin resistance in orotic acid-induced nonalcoholic fatty liver rats.

We investigated whether fatty liver preceded insulin resistance or vice versa using a long-term orotic acid (OA)-induced nonalcoholic fatty liver disease (NAFLD) model without the confounding effects of obesity and hyperlipidemia and explored the role of the liver in insulin resistance. Male Wistar rats were fed with or without OA supplementation for 30, 60, and 90 days. The NAFLD group showed increased liver lipid at 30, 60, and 90 days; glucose intolerance was noted at 60 and 90 days. Furthermore, partial liver proteins and gene expressions related to upstream signaling of insulin were decreased. However, the liver glycogen content was elevated, and gluconeogenesis genes expressions were obviously decreased at 90 days. The occurrence of fatty liver preceded insulin resistance in OA-induced NAFLD without the interference of obesity and hyperlipidemia, and hepatic insulin resistance may not play a conclusive role in insulin resistance in this model.

Adenosine monophosphate-activated protein kinase is elevated in human cachectic muscle and prevents cancer-induced metabolic dysfunction in mice.

BACKGROUND: Metabolic dysfunction and cachexia are associated with poor cancer prognosis. With no pharmacological treatments, it is crucial to define the molecular mechanisms causing cancer-induced metabolic dysfunction and cachexia. Adenosine monophosphate-activated protein kinase (AMPK) connects metabolic and muscle mass regulation. As AMPK could be a potential treatment target, it is important to determine the function for AMPK in cancer-associated metabolic dysfunction and cachexia. We therefore established AMPK's roles in cancer-associated metabolic dysfunction, insulin resistance and cachexia. METHODS: In vastus lateralis muscle biopsies from n = 26 patients with non-small cell lung cancer (NSCLC), AMPK signalling and protein content were examined by immunoblotting. To determine the role of muscle AMPK, male mice overexpressing a dominant-negative AMPKα2 (kinase-dead [KiDe]) specifically in striated muscle were inoculated with Lewis lung carcinoma (LLC) cells (wild type [WT]: n = 27, WT + LLC: n = 34, mAMPK-KiDe: n = 23, mAMPK-KiDe + LLC: n = 38). Moreover, male LLC-tumour-bearing mice were treated with (n = 10)/without (n = 9) 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) to activate AMPK for 13 days. Littermate mice were used as controls. Metabolic phenotyping of mice was performed via indirect calorimetry, body composition analyses, glucose and insulin tolerance tests, tissue-specific 2-[3H]deoxy-d-glucose (2-DG) uptake and immunoblotting. RESULTS: Patients with NSCLC presented increased muscle protein content of AMPK subunits α1, α2, ß2, γ1 and γ3 ranging from +27% to +79% compared with control subjects. In patients with NSCLC, AMPK subunit protein content correlated with weight loss (α1, α2, ß2 and γ1), fat-free mass (α1, ß2 and γ1) and fat mass (α1 and γ1). Tumour-bearing mAMPK-KiDe mice presented increased fat loss and glucose and insulin intolerance. LLC in mAMPK-KiDe mice displayed lower insulin-stimulated 2-DG uptake in skeletal muscle (quadriceps: -35%, soleus: -49%, extensor digitorum longus: -48%) and the heart (-29%) than that in non-tumour-bearing mice. In skeletal muscle, mAMPK-KiDe abrogated the tumour-induced increase in insulin-stimulated TBC1D4thr642 phosphorylation. The protein content of TBC1D4 (+26%), pyruvate dehydrogenase (PDH; +94%), PDH kinases (+45% to +100%) and glycogen synthase (+48%) was increased in skeletal muscle of tumour-bearing mice in an AMPK-dependent manner. Lastly, chronic AICAR treatment elevated hexokinase II protein content and normalized phosphorylation of p70S6Kthr389 (mTORC1 substrate) and ACCser212 (AMPK substrate) and rescued cancer-induced insulin intolerance. CONCLUSIONS: Protein contents of AMPK subunits were upregulated in skeletal muscle of patients with NSCLC. AMPK activation seemed protectively inferred by AMPK-deficient mice developing metabolic dysfunction in response to cancer, including AMPK-dependent regulation of multiple proteins crucial for glucose metabolism. These observations highlight the potential for targeting AMPK to counter cancer-associated metabolic dysfunction and possibly cachexia.

Ultrasonographic assessment of cardiac function and disease severity in coronary heart disease.

BACKGROUND: Coronary heart disease (CHD) causes many adverse cardiovascular events and poses a threat to the patient's health and quality of life. AIM: To evaluate ultrasonography for evaluation of cardiac function and lesion degree in patients with CHD. METHODS: A total of 106 patients with CHD (study group) and 106 healthy individuals (control group) in our hospital from March 2019 to September 2020 were selected for this study. All subjects were examined by ultrasound, and the mitral orifice's early-to-late diastolic blood flow velocity ratio (E/A), left ventricular end-diastolic volume (LVDd), and left atrial diameter (LAD) were measured. Values were compared between the study group and healthy group, and the correlation between the ultrasonic parameters of patients with different cardiac function grades and the degree of CHD were assessed. In addition, the ultrasonic parameters of patients with different prognoses were compared after a follow-up for 6 mo. RESULTS: E/A (1.46 ± 0.34) of the study group was smaller than that of the control group (1.88 ± 0.44), while LVDd (58.24 ± 5.05 mm) and LAD (43.31 ± 4.38 mm) were larger (48.15 ± 3.93 and 34.94 ± 2.81, respectively; P < 0.05). E/A for patients with grade III disease (1.41 ± 0.43) was smaller and their LVDd (60.04 ± 4.21 mm) and LA (44.16 ± 2.79 mm) were larger than those in patients with grade II disease (1.71 ± 0.48, 52.18 ± 3.67 mm, and 39.68 ± 2.37, respectively; P < 0.05). Patients with grade IV disease had smaller E/A (1.08 ± 0.39) and larger LVDd (66.81 ± 5.39 mm) and LAD (48.81 ± 3.95 mm) than patients with grade II and III disease (P < 0.05). In patients with moderate disease, E/A (1.44 ± 0.41) was smaller and LVDd (59.95 ± 4.14 mm) and LAD (45.15 ± 2.97 mm) were larger than in patients with mild disease (1.69 ± 0.50, 51.97 ± 3.88 and 38.81 ± 2.56 mm, respectively; P < 0.05). In patients with severe disease, E/A (1.13 ± 0.36) was smaller and LVDd (67.70 ± 6.11 mm) and LAD (49.09 ± 4.05 mm) were larger than in patients with moderate disease (P < 0.05). E/A was negatively correlated with cardiac function classification and disease severity, while LVDd and LAD were positively correlated with cardiac function classification and disease severity (P < 0.05). E/A (1.83 ± 0.51) for patients with good prognosis was higher than that for those with poor prognosis (1.39 ± 0.32), while LVDd (49.60 ± 4.39 mm) and LAD (36.13 ± 3.05 mm) were lower (P < 0.05). CONCLUSION: The ultrasonic parameters of patients with CHD are abnormal, and differ significantly in patients with different cardiac function grades, lesion degree, and prognosis.

The effect of scalp electroacupuncture combined with Memantine in patients with vascular dementia: A retrospective study.

Currently there is no effective treatment for vascular dementia (VaD). Pharmacological treatment often lead to severe complications and require drug dosage adjustment. This study investigated the effect of scalp electroacupuncture combined with Memantine in VaD. The safety and antioxidative effect of scalp electroacupuncture were also explored.A retrospective study was conducted and data of inpatients of Linyi Central Hospital with VaD between June 2017 and May 2018 were collected and sorted. The patients were divided into scalp electroacupuncture-medication (A), scalp electroacupuncture (B) and medication (control) (C) groups, in which Memantine was prescribed as medication. Cognitive function, activities of daily living and quality of life assessed by Montreal Cognitive Assessment (MoCA), Barthel index and dementia quality of life questionnaire; the contents of superoxide dismutase, lipid peroxide and nitric oxide in blood samples; and adverse reaction were compared.Data from a total of 150 patients were collected (Group A, n = 55; Group B, n = 50; Group C, n = 45). The post-treatment/follow-up Montreal Cognitive Assessment, Barthel index and dementia quality of life questionnaire scores were significantly improved in all groups compared to pre-treatment (groups A and B, P<.01; group C, P<.05). The improvements were significant for groups A vs C, B vs C (P<0.01, both), and group A vs B (P<.05). The post-treatment/follow-up levels of lipid peroxide and nitric oxide decreased significantly while superoxide dismutase increased significantly in groups A and B compared to pre-treatment (P<.01, both). The differences were significant for groups A vs C, and B vs C (P < .01, both), but not significant between groups A and B (P > .05). There were no significant adverse events occurred during the study and follow-up.In combined treatment, scalp electroacupuncture works in parallel with Memantine and significantly increase the therapeutic effect in VaD with no significant adverse events. Scalp electroacupuncture may have the potential to serve as an option or alternative treatment for VaD. Scalp electroacupuncture may alleviate VaD symptoms through its antioxidative mechanism.

Beneficial effects of walnut (Juglans regia L.) oil-derived polyunsaturated fatty acid prevents a prooxidant status and hyperlipidemia in pregnant rats with diabetes.

BACKGROUND: Gestational diabetes mellitus has a long-term effect on pregnant women. Walnut (Juglans regia L.) oil-derived polyunsaturated fatty acid (PUFA) possesses multifarious pharmacological activities. This study investigated the beneficial effects of walnut oil-derived PUFA on glucose metabolism, pregnancy outcomes, oxidative stress, and lipid metabolism in gestational diabetes mellitus. METHODS: The GDM rat model was generated by intraperitoneal injection of streptozotocin (40 mg/kg) on gestational day (GD) 6, GD7 and GD8. The differences between groups were estimated using one-way ANOVA followed by the Tukey's multiple comparison test for post-hoc analysis. RESULTS: The results indicated that PUFA could mitigate GDM in pregnant diabetic rats, as embodied by the decrease of fasting blood glucose and the increase of plasma insulin and hepatic glycogen levels. Also, PUFA could suppress oxidative stress in pregnant diabetic rats, as reflected by the decrease of malondialdehyde content, an increase of superoxide dismutase, catalase and gutathione peroxidase activities. PUFA could also mitigate the abnormal changes of lipid profiles in plasma and hepatic tissue. Moreover, the relative mRNA expression of sterol regulatory element-binding transcription factor-1, stearoyl-CoA desaturase-1, fatty acid synthase, and acetyl-coenzyme A carboxylase, was suppressed by PUFA in pregnant diabetic rats. CONCLUSIONS: These results suggested that PUFA supplementation during pregnancy is beneficial in preventing diabetic complications in pregnant rats.

Relationship between structure and efficacy of sea cucumber saponins echinoside A and its derivatives on hemolytic activity and prevention of nonalcoholic fatty liver disease.

The hemolytic property discourages the development of sea cucumber saponins on alleviating lipids metabolism disturbance. The hemolytic activity of saponins has been reported to be highly correlative to their chemical structures. The aim of this study was to reduce the hemolytic activity of sea cucumber-derived saponins echinoside A (EA) and simultaneously remain its effect on alleviating non-alcoholic fatty liver disease (NAFLD) by structural modifications. Administration with EA and its derivatives for 8 weeks remarkably mitigated orotic acid-induced NAFLD via inhibiting the activities and mRNA expressions of enzymes involved in lipogenesis, enhancing the activities and expressions of enzymes related to hepatic lipolysis in a rat model. Importantly, aglycone exhibited a distinct advantage in stimulating hepatic lipolysis compared with EA and dsEA, meanwhile possessed lowest hemolytic activity. This study may provide the theoretical basis to strengthen the application of sea cucumber saponins as food supplements and/or functional ingredients.

Cancer causes metabolic perturbations associated with reduced insulin-stimulated glucose uptake in peripheral tissues and impaired muscle microvascular perfusion.

BACKGROUND: Redirecting glucose from skeletal muscle and adipose tissue, likely benefits the tumor's energy demand to support tumor growth, as cancer patients with type 2 diabetes have 30% increased mortality rates. The aim of this study was to elucidate tissue-specific contributions and molecular mechanisms underlying cancer-induced metabolic perturbations. METHODS: Glucose uptake in skeletal muscle and white adipose tissue (WAT), as well as hepatic glucose production, were determined in control and Lewis lung carcinoma (LLC) tumor-bearing C57BL/6 mice using isotopic tracers. Skeletal muscle microvascular perfusion was analyzed via a real-time contrast-enhanced ultrasound technique. Finally, the role of fatty acid turnover on glycemic control was determined by treating tumor-bearing insulin-resistant mice with nicotinic acid or etomoxir. RESULTS: LLC tumor-bearing mice displayed reduced insulin-induced blood-glucose-lowering and glucose intolerance, which was restored by etomoxir or nicotinic acid. Insulin-stimulated glucose uptake was 30-40% reduced in skeletal muscle and WAT of mice carrying large tumors. Despite compromised glucose uptake, tumor-bearing mice displayed upregulated insulin-stimulated phosphorylation of TBC1D4Thr642 (+18%), AKTSer474 (+65%), and AKTThr309 (+86%) in muscle. Insulin caused a 70% increase in muscle microvascular perfusion in control mice, which was abolished in tumor-bearing mice. Additionally, tumor-bearing mice displayed increased (+45%) basal (not insulin-stimulated) hepatic glucose production. CONCLUSIONS: Cancer can result in marked perturbations on at least six metabolically essential functions; i) insulin's blood-glucose-lowering effect, ii) glucose tolerance, iii) skeletal muscle and WAT insulin-stimulated glucose uptake, iv) intramyocellular insulin signaling, v) muscle microvascular perfusion, and vi) basal hepatic glucose production in mice. The mechanism causing cancer-induced insulin resistance may relate to fatty acid metabolism.

Synergistic effect of sea cucumber saponins and EPA-enriched phospholipids on insulin resistance in high-fat diet-induced obese mice.

Sea cucumber saponins (SCS) exhibit a significant effect on ameliorating glucose and lipid disorders by inhibiting fatty acid biosynthesis; however, high cytotoxicity and hemolytic activity limit their application. Eicosapentaenoic acid-enriched phospholipids (EPA-PL) significantly ameliorate insulin resistance and elevate the level of hepatic lipolysis, which may have a synergistic effect with SCS in alleviating obesity-related insulin resistance via multiple mechanisms. In the present study, high-fat diet-induced male C57BL/6J mice with obesity-related insulin resistance were used to evaluate the synergistic effect of SCS and EPA-PL on alleviating the insulin resistance. Results show that the combination of SCS and EPA-PL at a half dose exhibited a significant improvement on glucose intolerance and systematic insulin sensitivity than SCS or EPA-PL alone. Moreover, the half dose-combination remarkably inhibited the macrophage infiltration (F4/80) to white adipose tissue (WAT) and significantly down-regulated the level of MCP1, TNF-α and IL-6 compared with SCS and EPA-PL alone. Consequently, the combined administration not only decreased hepatic gluconeogenesis and increased hepatic glycogen synthesis (P < 0.05), but also stimulated the glucose uptake in WAT and muscle (P < 0.05). Nevertheless, neither SCS or EPA-PL alone exhibited any effect on the glucose uptake. The combination of SCS and EPA-PL contributed to a synergistic effect on alleviating the obesity-related insulin resistance due to the amelioration of an inflammation-centric peripheral insulin response.

Mechanisms involved in follistatin-induced hypertrophy and increased insulin action in skeletal muscle.

BACKGROUND: Skeletal muscle wasting is often associated with insulin resistance. A major regulator of muscle mass is the transforming growth factor ß (TGF-ß) superfamily, including activin A, which causes atrophy. TGF-ß superfamily ligands also negatively regulate insulin-sensitive proteins, but whether this pathway contributes to insulin action remains to be determined. METHODS: To elucidate if TGF-ß superfamily ligands regulate insulin action, we used an adeno-associated virus gene editing approach to overexpress an activin A inhibitor, follistatin (Fst288), in mouse muscle of lean and diet-induced obese mice. We determined basal and insulin-stimulated 2-deoxy-glucose uptake using isotopic tracers in vivo. Furthermore, to evaluate whether circulating Fst and activin A concentrations are associated with obesity, insulin resistance, and weight loss in humans, we analysed serum from morbidly obese subjects before, 1 week, and 1 year after Roux-en-Y gastric bypass (RYGB). RESULTS: Fst288 muscle overexpression markedly increased in vivo insulin-stimulated (but not basal) glucose uptake (+75%, P < 0.05) and increased protein expression and intracellular insulin signalling of AKT, TBC1D4, PAK1, pyruvate dehydrogenase-E1α, and p70S6K, while decreasing TBC1D1 signaling (P < 0.05). Fst288 increased both basal and insulin-stimulated protein synthesis, but no correlation was observed between the Fst288-driven hypertrophy and the increase in insulin-stimulated glucose uptake. Importantly, Fst288 completely normalized muscle glucose uptake in insulin-resistant diet-induced obese mice. RYGB surgery doubled circulating Fst and reduced activin A (-24%, P < 0.05) concentration 1 week after surgery before any significant weight loss in morbidly obese normoglycemic patients, while major weight loss after 1 year did not further change the concentrations. CONCLUSIONS: We here present evidence that Fst is a potent regulator of insulin action in muscle, and in addition to AKT and p70S6K, we identify TBC1D1, TBC1D4, pyruvate dehydrogenase-E1α, and PAK1 as Fst targets. Circulating Fst more than doubled post-RYGB surgery, a treatment that markedly improved insulin sensitivity, suggesting a role for Fst in regulating glycaemic control. These findings demonstrate the therapeutic potential of inhibiting TGF-ß superfamily ligands to improve insulin action and Fst's relevance to muscle wasting-associated insulin-resistant conditions in mice and humans.

Synergistic effect of eicosapentaenoic acid-enriched phospholipids and sea cucumber saponin on orotic acid-induced non-alcoholic fatty liver disease in rats.

Non-alcoholic fatty liver disease (NAFLD) is becoming an increasingly prevalent chronic liver disease all over the world. The present study was undertaken to explore the synergistic effects of sea cucumber saponins (SCS) and eicosapentaenoic acid-enriched phospholipids (EPA-PL) at ratios of 0.5 : 0.5 and 1 : 1 on NAFLD and demonstrate possible protective mechanisms. It was found that the combination of EPA-PL and SCS at half dose exhibited better effects than EPA-PL or SCS alone and the combination of EPA-PL and SCS at full dose in alleviating orotic acid (OA)-induced symptoms including growth parameters, serum parameters and liver function. Further evaluation of the mechanism illustrated that EPA-PL and SCS combination at the ratio of 0.5 : 0.5 could markedly reduce the mRNA expressions of fatty acid synthase, acetyl-CoA carboxylase, glucose-6-phosphate dehydrogenase and malic enzyme genes and significantly increase expression of genes relevant to fatty acid ß-oxidation including peroxisome proliferator-activated receptor and its target genes (CPT1, CPT2 and ACOX1), suggesting that the protection of the EPA-PL and SCS combination at the ratio of 0.5 : 0.5 against OA-induced NAFLD might be mainly via lipogenesis inhibition and ß-oxidation enhancement in the liver. The synergistic effects of EPA-PL and SCS make it possible to reduce the doses of EPA-PL or SCS to avoid side effects, which is of value for the development of dietary supplements or functional foods for preventing or treating NAFLD.

Comparative Analysis of EPA/DHA-PL Forage and Liposomes in Orotic Acid-Induced Nonalcoholic Fatty Liver Rats and Their Related Mechanisms.

Nonalcoholic fatty liver disease (NAFLD) has become one predictive factor of death from various illnesses. The present study was to comparatively investigate the effects of eicosapentaenoic acid-enriched and docosahexaenoic acid-enriched phospholipids forage (EPA-PL and DHA-PL) and liposomes (lipo-EPA and lipo-DHA) on NAFLD and demonstrate the possible protective mechanisms involved. The additive doses of EPA-PL and DHA-PL in all treatment groups were 1% of total diets, respectively. The results showed that Lipo-EPA could significantly improve hepatic function by down-regulating orotic acid-induced serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels by 55.6% and 34.2%, respectively (p < 0.01). Moreover, lipo-EPA exhibited excellent inhibition on the mRNA expression of SREBP-1c and FAS at the values of 0.454 ± 0.09 (p < 0.01) and 0.523 ± 0.08 (p < 0.01), respectively, thus ameliorating OA-induced NAFLD. Meanwhile, lipo-EPA could significantly suppress the SREBP-2 and HMGR levels (31.4% and 66.7%, p < 0.05, respectively). In addition, EPA-PL and lipo-DHA could also significantly suppress hepatic lipid accumulation mainly by enhancement of hepatic lipolysis and cholesterol efflux. Furthermore, DHA-PL played a certain role in inhibiting hepatic lipogenesis and accelerating cholesterol efflux. The results obtained in this work might contribute to the understanding of the biological activities of EPA/DHA-PL and liposomes and further investigation on its potential application values for food supplements.

Sea cucumber saponin liposomes ameliorate obesity-induced inflammation and insulin resistance in high-fat-diet-fed mice.

Obesity has become a worldwide concern in recent years, which may cause many diseases. Much attention has been paid to food components that are considered to be beneficial in preventing chronic metabolic diseases. The present study was conducted to investigate the effects of sea cucumber saponin liposomes on certain metabolic markers associated with obesity. C57/BL6 mice fed with high-fat diet were treated with different forms of sea cucumber saponins for eight weeks. The results showed that liposomes exhibited better effects on anti-obesity and anti-hyperlipidemia activities than the common form of sea cucumber saponins. Sea cucumber saponin liposomes could also effectively alleviate adipose tissue inflammation by reducing pro-inflammatory cytokine releases and macrophage infiltration. Moreover, sea cucumber saponin liposomes improved insulin resistance by altering the uptake and utilization of glucose. Taken together, our results indicated that the intake of sea cucumber saponin liposomes might be able to ameliorate obesity-induced inflammation and insulin resistance.

Quantitative proteomic characterization of cellular pathways associated with altered insulin sensitivity in skeletal muscle following high-fat diet feeding and exercise training.

Regular exercise elicits advantageous metabolic adaptations in skeletal muscle, such as improved insulin sensitivity. However, the underpinning molecular mechanisms and the effect of diet on muscle exercise training benefits are unclear. We therefore characterized the skeletal muscle proteome following exercise training (ET) in mice fed chow or high-fat diet (HFD). ET increased exercise performance, lowered body-weight, decreased fat mass and improved muscle insulin action in chow- and HFD-fed mice. At the molecular level, ET regulated 170 muscle proteins in chow-fed mice, but only 29 proteins in HFD-fed mice. HFD per se altered 56 proteins, most of which were regulated in a similar direction by ET. To identify proteins that might have particular health-related bearing on skeletal muscle metabolism, we filtered for differentially regulated proteins in response to ET and HFD. This yielded 15 proteins, including the major urinary protein 1 (MUP1), which was the protein most decreased after HFD, but increased with ET. The ET-induced Mup1 expression was absent in mouse muscle lacking functional AMPK. MUP1 also potentiated insulin-stimulated GLUT4 translocation in cultured muscle cells. Collectively, we provide a resource of ET-regulated proteins in insulin-sensitive and insulin-resistant skeletal muscle. The identification of MUP1 as a diet-, ET- and AMPK-regulated skeletal muscle protein that improves insulin sensitivity in muscle cells demonstrates the usefulness of these data.

Hypoperfusion retinopathy and elevated intraocular pressure in a 17-year-old.

We describe a case of bilateral hypoperfusion retinopathy (HR) in a 17-year-old man with intraocular pressure (IOP) of >40 mm Hg. After 6 months of antiglaucoma drug therapy, the patient's bilateral IOP remained over 35 mm Hg, and features of HR were found bilaterally in the absence of carotid artery obstruction. On restoration of IOP to normal by means of trabeculectomy, the bilateral signs of HR regressed. We speculate that the elevated IOP contributed to HR in this patient.

Sea Cucumber Saponin Echinoside A (EA) Stimulates Hepatic Fatty Acid ß-Oxidation and Suppresses Fatty Acid Biosynthesis Coupling in a Diurnal Pattern.

Circadian rhythms control aspects of physiological events, including lipid metabolism, showing rhythmic fluctuation over 24 h. Therefore, it is not sufficient to evaluate thoroughly how dietary components regulate lipid metabolism with a single time-point assay. In the present study, a time-course study was performed to analyze the effect of sea cucumber saponin echinoside A (EA) on lipid metabolism over 24 h. Results showed that EA lowered the levels of TC and TG in both serum and liver at most time-points during the 24 h. Activities of hepatic lipogenic enzymes and lipolytic enzymes were inhibited and elevated respectively by EA to varied degrees at different time-points. Meanwhile, parallel variation trends of gene expression involved in fatty acid synthesis and ß-oxidation were observed accordingly. The interaction between EA and lipid metabolism showed a time-dependent effect. Overall, EA impaired fatty acid synthesis and enhanced mitochondrial fatty acid ß-oxidation in ad libitum feeding over 24 h.