Echo time optimization for in-vivo measurement of unsaturated lipid resonances using J-difference-edited MRS.

PURPOSE: Measuring lipid composition provides more information than just total lipid content. Hence, the non-invasive measurement of unsaturated lipid protons with both high efficiency and precision is of pressing need. This study was to optimize echo time (TE) for the best resolving of J-difference editing of unsaturated lipid resonances. METHODS: The TE dependence of J-difference-edited (JDE) MRS was verified in the density-matrix simulation, soybean oil phantom, in-vivo experiments of white adipose tissue (WAT), and skeletal muscles using single-voxel MEGA-PRESS sequence at 3T. The peak SNRs and Cramér-Rao lower bounds (CRLBs) acquired at the proposed TE of 45 ms and previously published TE of 70 ms were compared (eight pairs) in WAT, extramyocelluar lipids (EMCLs), and intramyocellular lipids (IMCLs). The lipid composition in skeletal muscles was compared between healthy males (n = 7) and females (n = 7). RESULTS: The optimal TE was suggested as 45 ms. Compared to 70 ms, the mean signal gains at TE of 45 ms were 151% in WAT, 168% in EMCL, 204% in IMCL for allylic resonance, and 52% in EMCL for diallylic resonance. CRLBs were significantly reduced at TE of 45 ms in WAT, EMCL, IMCL for allylic resonance and in EMCL for diallylic resonance. With TE of 45 ms, significant gender differences were found in the lipid composition in EMCL pools, while no difference in IMCL pools. CONCLUSION: The JDE-MRS protocol with TE of 45 ms allows improved quantification of unsaturated lipid resonances in vivo and future lipid metabolism investigations.

Transthyretin knockdown recapitulates the insulin-sensitizing effects of exercise and promotes skeletal muscle adaptation to exercise endurance.

Liver transthyretin (TTR) synthesis and release are exacerbated in insulin-resistant states but are decreased by exercise training, in relation to the insulin-sensitizing effects of exercise. We hypothesized that TTR knockdown (TTR-KD) may mimic this exercise-induced metabolic improvement and skeletal muscle remodeling. Adeno-associated virus-mediated TTR-KD and control mice were trained for 8 weeks on treadmills. Their metabolism status and exercise capacity were investigated and then compared with sedentary controls. After treadmill training, the mice showed improved glucose and insulin tolerance, hepatic steatosis, and exercise endurance. Sedentary TTR-KD mice displayed metabolic improvements comparable to the improvements in trained mice. Both exercise training and TTR-KD promoted the oxidative myofiber compositions of MyHC I and MyHC IIa in the quadriceps and gastrocnemius skeletal muscles. Furthermore, training and TTR-KD had an additive effect on running performance, accompanied by substantial increases in oxidative myofiber composition, Ca2+-dependent Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity, and the downstream expression of PGC1α as well as the unfolded protein response (UPR) segment of PERK-p-eIF2a pathway activity. Consistent with these findings, electrical pulse stimulation of an in vitro model of chronic exercise (with differentiated C2C12 myoblasts) showed that exogenous TTR protein was internalized and localized in the endoplasmic reticulum, where it disrupted Ca2+ dynamics; this led to decreases in intracellular Ca2+ concentration and downstream pathway activity. TTR-KD may function as an exercise/Ca2+-dependent CaMKII-PGC1α-UPR regulator that upregulates the oxidative myofiber composition of fast-type muscles; it appears to mimic the effect of exercise training on insulin sensitivity-related metabolic improvement and endurance capacity.

Canagliflozin ameliorates the development of NAFLD by preventing NLRP3-mediated pyroptosis through FGF21-ERK1/2 pathway.

Recent studies have suggested that sodium-glucose co-transporter2 inhibitors go beyond their glycemic advantages to ameliorate the development of NAFLD. However, little research has been done on the underlying mechanisms. Here, we took deep insight into the effect of canagliflozin (CANA), one of the sodium-glucose co-transporter2 inhibitor, on the progression of NAFLD, and explored the molecular mechanisms. Our findings showed that CANA-treated ob/ob and diabetic mice developed improved glucose and insulin tolerance, although their body weights were comparable or even increased compared with the controls. The CANA treatment ameliorated hepatic steatosis and lipid accumulation of free fatty acid-treated AML12 cells, accompanied by decreased lipogenic gene expression and increased fatty acid ß oxidation-related gene expression. Furthermore, inflammation and fibrosis genes decreased in the livers of CANA-treated ob/ob and diabetic mice mice. FGF21 and its downstream ERK1/2/AMPK signaling decreased, whereas NLRP3-mediated pyroptosis increased in the livers of the ob/ob and diabetic mice mice, which was reversed by the CANA treatment. In addition, blocking FGF21 or ERK1/2 activity antagonized the effects of CANA on NLRP3-mediated pyroptosis in lipopolysaccharide plus nigericin-treated J774A.1 cells. We conclude that CANA treatment alleviated insulin resistance and the progression of NAFLD in ob/ob and diabetic mice mice independent of the body weight change. CANA protected against the progression of NAFLD by inhibiting NLRP3-mediated pyroptosis and enhancing FGF21-ERK1/2 pathway activity in the liver. These findings suggest the therapeutic potential of sodium-glucose co-transporter2 inhibitors in the treatment of NAFLD.

Mice harboring a R133L heterozygous mutation in LMNA exhibited ectopic lipid accumulation, aging, and mitochondrial dysfunction in adipose tissue.

The LMNA gene encodes for the nuclear envelope proteins lamin A and C (lamin A/C). A novel R133L heterozygous mutation in the LMNA gene causes atypical progeria syndrome (APS). However, the underlying mechanism remains unclear. Here, we used transgenic mice (LmnaR133L/+ mice) that expressed a heterozygous LMNA R133L mutation and 3T3-L1 cell lines with stable overexpression of LMNA R133L (by lentiviral transduction) as in vivo and in vitro models to investigate the mechanisms of LMNA R133L mutations that mediate the APS phenotype. We found that a heterozygous R133L mutation in LMNA induced most of the metabolic disturbances seen in patients with this mutation, including ectopic lipid accumulation, limited subcutaneous adipose tissue (SAT) expansion, and insulin resistance. Mitochondrial dysfunction and senescence promote ectopic lipid accumulation and insulin resistance. In addition, the FLAG-mediated pull-down capture followed by mass spectrometry assay showed that p160 Myb-binding protein (P160 MBP; Mybbp1 a $$ a $$ ), the critical transcriptional repressor of PGC-1α, was bound to lamin A/C. Increased Mybbp1 a $$ a $$ levels in tissues and greater Mybbp1 a $$ a $$ -lamin A/C binding in nuclear inhibit PGC-1α activity and promotes mitochondrial dysfunction. Our findings confirm that the novel R133L heterozygous mutation in the LMNA gene caused APS are associated with marked mitochondrial respiratory chain impairment, which were induced by decreased PGC-1α levels correlating with increased Mybbp1a levels in nuclear, and a senescence phenotype of the subcutaneous fat.

Automated Measurement of Pancreatic Fat Deposition on Dixon MRI Using nnU-Net.

BACKGROUND: Pancreatic fat accumulation may cause or aggravate the process of acute pancreatitis, ß-cell dysfunction, T2DM disease, and even be associated with pancreatic tumors. The pathophysiology of fatty pancreas remains overlooked and lacks effective imaging diagnostics. PURPOSE: To automatically measure the distribution of pancreatic fat deposition on Dixon MRI in multicenter/population datasets using nnU-Net models. STUDY TYPE: Retrospective. POPULATION: A total of 176 obese/nonobese subjects (90 males, 86 females; mean age, 27.2 ± 19.7) were enrolled, including a training set (N = 132) and a testing set (N = 44). FIELD STRENGTH/SEQUENCE: A 3 T and 1.5 T/gradient echo T1 dual-echo Dixon. ASSESSMENT: The segmentation results of four types of nnU-Net models were compared using dice similarity coefficient (DSC), positive predicted value (PPV), and sensitivity. The ground truth was the manual delineation by two radiologists according to in-phase (IP) and opposed-phase (OP) images. STATISTICAL TESTS: The group difference of segmentation results of four models were assessed by the Kruskal-Wallis H test with Dunn-Bonferroni comparisons. The interobserver agreement of pancreatic fat fraction measurements across three observers and test-retest reliability of human and machine were assessed by intragroup correlation coefficient (ICC). P < 0.05 was considered statistically significant. RESULTS: The three-dimensional (3D) dual-contrast model had significantly improved performance than 2D dual-contrast (DSC/sensitivity) and 3D one-contrast (IP) models (DSC/PPV/sensitivity) and had less errors than 3D one-contrast (OP) model according to higher DSC and PPV (not significant), with a mean DSC of 0.9158, PPV of 0.9105 and sensitivity of 0.9232 in the testing set. The test-retest ICC of this model was above 0.900 in all pancreatic regions, exceeded human. DATA CONCLUSION: 3D Dual-contrast nnU-Net aided segmentation of pancreas on Dixon images appears to be adaptable to multicenter/population datasets. It fully automates the assessment of pancreatic fat distribution and has high reliability. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 3.

Case Report: Recurrent Autoimmune Hypoglycemia Induced by Non-Hypoglycemic Medications.

We present a case of recurrent autoimmune hypoglycemia induced by non-hypoglycemic agents. We review reported cases of autoimmune hypoglycemia related to non-hypoglycemic agents, and discuss the effects of different detection methods for insulin autoantibodies on the results obtained. We aim to provide information for clinicians and a warning for medication usage. Considering the increasing number of clopidogrel-induced AIH cases and the hypoglycemia-induced increase in the risk of cardiovascular events, we recommend that cardiovascular disease patients being treated with clopidogrel be informed of this rare side effect and that clinicians be vigilant for the possibility of autoimmune hypoglycemia in this patient population.

Clinical and genetic analysis of pseudohypoparathyroidism complicated by hypokalemia: a case report and review of the literature.

BACKGROUND: Pseudohypoparathyroidism (PHP) encompasses a highly heterogenous group of disorders, characterized by parathyroid hormone (PTH) resistance caused by mutations in the GNAS gene or other upstream targets. Here, we investigate the characteristics of a female patient diagnosed with PHP complicated with hypokalemia, and her family members. CASE PRESENTATION AND GENE ANALYSIS: A 27-year-old female patient occasionally exhibited asymptomatic hypocalcemia and hypokalemia during her pregnancy 1 year ago. Seven months after delivery, she experienced tetany and dysphonia with diarrhea. Tetany symptoms were relieved after intravenous calcium gluconate supplementation and she was then transferred to our Hospital. Laboratory assessments of the patient revealed hypokalemia, hypocalcemia and hyperphosphatemia despite elevated PTH levels. CT scanning of the brain revealed globus pallidus calcification. Possible mutations in GNAS and hypokalemia related genes were identified using WES, exon copies of STX16 were analized by MLPA and the methylation status of GNAS in three differential methylated regions (DMRs) was analyzed by methylation-specific polymerase chain reaction, followed by confirmation with gene sequencing. The patient was clinically diagnosed with PHP-1b. Loss of methylation in the A/B region and hypermethylation in the NESP55 region were detected. No other mutations in GNAS or hypokalemia related genes and no deletions of STX16 exons were detected. A negative family history and abnormal DMRs in GNAS led to a diagnosis of sporadic PHP-1b of the patient. CONCLUSIONS: Hypokalemia is a rare disorder associated with PHP-1b. Analysis of genetic and epigenetic mutations can aid in the diagnosis and accurate subtyping of PHP.

CircRNF111 Protects Against Insulin Resistance and Lipid Deposition via Regulating miR-143-3p/IGF2R Axis in Metabolic Syndrome.

Abnormal expression of circRNAs (circular RNAs), a subclass of non-coding RNAs, has been documented in numerous human diseases. Herein, we explored whether circRNAs act as ceRNAs (competing endogenous RNAs) to modulate the pathological process-insulin resistance, as well as dyslipidemia of MetS (Metabolic Syndrome). The profile of circRNAs in serume of MetS and control samples was characterized by circRNA deep sequencing. We identified circRNF111 as a key downregulated circRNA involved in MetS. The decreased expression of circRNF111 in the serum samples of MetS was directly linked to excessive insulin resistance and dyslipidemia. Loss-of-function experiments showed that circRNF111 knockdown inhibited the glucose uptake and the Akt signaling pathway, meanwhile increased the deposition of triglycerides in adipogenic differentiated hADSCs (human adipose-derived stem cells). Mechanistically, circRNF111 sponged miR-143-3p and functioned via targeting miR-143-3p along with its downstream target gene IGF2R. The role along with the mechanism of circRNF111 sponging miR-143-3p in MetS was also explored in obese mice triggered by high-fat die. Therefore, our data suggest a protective role of the novel circRNA-circRNF111 in MetS progression. CircRNF111 inhibition enhances insulin resistance and lipid deposition in MetS through regulating miR-143-3p-IGF2R cascade. This provides a promising therapeutic approach for MetS.

Knockdown of insulin-like growth factor 2 gene disrupts mitochondrial functions in the liver.

Even though insulin-like growth factor 2 (IGF2) has been reported to be overexpressed in nonalcoholic fatty liver disease (NAFLD), its role in the progression of NAFLD and the potential mechanism remain largely unclear. Using in vitro models, we found that IGF2 was the key overexpressed gene in steatosis, suggesting a possible association between IGF2 and NAFLD. Interestingly, loss-of-function experiments revealed that inhibition of IGF2 protein impaired mitochondrial biogenesis and respiration. It additionally disrupted the expression changes of mitochondrial fusion and fission-related proteins necessary in maintaining mitochondrial homeostasis. Consistently, IGF2 knockdown reduced the mitochondrial membrane potential and increased the production of reactive oxygen species. Mechanistically, IGF2 regulates mitochondrial functions by modulating the expression of SIRT1 and its downstream gene PGC1α. This research opens a new frontier on the role of IGF2 in energy metabolism, which potentially participates in the development of NAFLD. As such, IGF2 is a potential therapeutic target against NAFLD.

Transthyretin contributes to insulin resistance and diminishes exercise-induced insulin sensitivity in obese mice by inhibiting AMPK activity in skeletal muscle.

Exercise improves obesity-induced insulin resistance and metabolic disorders via mechanisms that remain unclear. Here, we show that the levels of the hepatokine transthyretin (TTR) in circulation are elevated in insulin-resistant individuals including high-fat diet (HFD)-induced obese mice, db/db mice, and patients with metabolic syndrome. Liver Ttr mRNA and circulating TTR levels were reduced in mice by treadmill training, as was the TTR levels in quadriceps femoris muscle; however, AMP-activated protein kinase (AMPK) signaling activity was enhanced. Transgenic overexpression of TTR or injection of purified TTR triggered insulin resistance in mice fed on regular chow (RC). Furthermore, TTR overexpression reduced the beneficial effects of exercise on insulin sensitivity in HFD-fed mice. TTR was internalized by muscle cells via the membrane receptor Grp78 and the internalization into the quadriceps femoris was reduced by treadmill training. The TTR/Grp78 combination in C2C12 cells was increased, whereas the AMPK activity of C2C12 cells was decreased as the TTR concentration rose. In addition, Grp78 silencing prevented the TTR internalization and reversed its inhibitory effect on AMPK activity in C2C12 cells. Our study suggests that elevated circulating TTR may contribute to insulin resistance and counteract the exercise-induced insulin sensitivity improvement; the TTR suppression might be an adaptive response to exercise through enhancing AMPK activity in skeletal muscles.NEW & NOTEWORTHY Exercise improves obesity-induced insulin resistance via mechanisms that remain unclear. The novel findings of the study are that circulating TTR (a hepatokine) level is decreased by exercise, and the elevated circulating TTR, as was the elevated transthyretin internalization mediated by Grp78, counteracts the exercise-induced insulin sensitivity by downregulating AMPK activity in skeletal muscle of obese mice. These data suggest that TTR suppression might be an adaptive response to exercise through the crosstalk between liver and muscle.

Metabolic Syndrome and Its Components Are Associated With Altered Amino Acid Profile in Chinese Han Population.

Objective: Recent studies have found that the levels of plasma amino acids, such as branched-chain amino acids and aromatic amino acids, were associated with visceral obesity, insulin resistance, future development of diabetes and cardiovascular diseases. However, few studies have involved a Chinese Han population. This study aimed to examine the association between amino acid profile and metabolic syndrome (MetS) and its components in the Chinese Han population. Methods: This is a cross-sectional study, which enrolled a cohort of 473 participants from a community. We employed the isotope internal standard method to determine the plasma concentrations of 28 amino acids using high-performance liquid chromatography-tandem mass spectrometry (LC/MS). Participants were divided into MetS (n = 72) and non-MetS groups (n = 401) to analyze the association between amino acids and MetS and its components. Results: The prevalence of MetS was 15.2% according to the criteria. Plasma concentrations of isoleucine (Ile), leucine (Leu), valine (Val), tyrosine (Tyr), tryptophan (Trp), phenylalanine (Phe), glutamic acid (Glu), aspartic acid (Asp), alanine (Ala), histidine (His), methionine (Met), asparagine (Asn), and proline (Pro) were significantly higher in the MetS group than those in the non-MetS group (P < 0.05), but taurine (Tau) was significantly lower (P < 0.05). When MetS components were increased, the concentrations of these 13 amino acids significantly increased (P < 0.05), but Tau concentration was significantly decreased (P < 0.05). We extracted the amino acid profile by principal component analysis (PCA), PC1 and PC2, which extracted from the 14 amino acids, were significantly associated with MetS (odds ratio, 95% confidence interval: 1.723, 1.325-2.085 and 1.325, 1.043-1.684, respectively). A total of 260 non-MetS participants were followed up effectively, and 42 participants developed new-onset MetS within 5 years. We found that the amino acid profile of PC1 was linked to the occurrence of future MetS. Decreased Tau was correlated with the future development of MetS. Conclusion: Participants with MetS exhibit an abnormal amino acid profile, and its components gradually increase when these amino acids are altered. Amino acid PCA profile can be employed for assessing and monitoring MetS risk. Finally, decreased Tau may be linked to the future development of MetS.

LncRNAH19 improves insulin resistance in skeletal muscle by regulating heterogeneous nuclear ribonucleoprotein A1.

BACKGROUND: Skeletal muscle is essential for glucose and lipid metabolism. Growing evidence reveals the importance of long non-coding RNAs (LncRNAs) in metabolism. This study aimed to investigate the function of LncRNA H19 (H19) in lipid metabolism of skeletal muscle and its potential mechanisms. METHODS: Glucose tolerance, serum insulin and lipid content in serum and skeletal muscle were determined in control and H19-overexpressed db/db mice. Lipid metabolism was evaluated in H19-overexpressed or H19-silencing muscle cells by detecting lipid contents and mitochondria related functions. The underlying mechanisms were explored by RNA pull-down, mass spectrometry and RNA immunoprecipitation (RIP). RESULTS: H19 was downregulated in skeletal muscle of db/db mice. H19 overexpression in db/db mice inhibited lipid ectopic deposition in skeletal muscle, meanwhile improved glucose intolerance and insulin resistance as compared with control db/db mice treated with ad-GFP. Furthermore, overexpression of H19 reversed FFA-induced lipid accumulation and increased cellular respiration in muscle cells, while H19 knockdown exhibited opposite effects in muscle cells. Mechanistically, H19 interacted with heterogeneous nuclear ribonucleoprotein (hnRNPA1) which was validated by RNA pulldown and RIP analysis, which increased translation of fatty acid oxidation closely related genes PGC1a and CPT1b. CONCLUSION: Our data suggest that overexpression of H19 ameliorates insulin resistance by reducing ectopic lipid accumulation in skeletal muscle. The possible underlying mechanisms are that overexpression of lncRNAH19 promotes fatty acids oxidation via targeting of hnRNPA1. Video abstract.

Development and validation of a prognostic nomogram to predict overall survival and cancer-specific survival for patients with anaplastic thyroid carcinoma.

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is a rare malignant tumor with a poor prognosis. However, there is no useful clinical prognostic predictive tool for ATC so far. Our study identified risk factors for survival of ATC and created a reliable nomogram to predict overall survival (OS) and cancer-specific survival (CSS) of patients with ATC. METHODS: A total of 1,404 cases of ATC diagnosed between 1983 and 2013 were extracted from on the Surveillance, Epidemiology and End Results database based on our inclusion criteria. OS and CSS were compared among patients between each variable by Kaplan-Meier methods. The Cox proportional hazards model was used to evaluate multiple prognostic factors and obtain independent predictors. All independent risk factors were included to build nomograms, whose accuracy and practicability were tested by concordance index (C-index), calibration curves, ROC curves, DCA, net reclassification improvement (NRI) and integrated discrimination improvement (IDI). RESULTS: Historic stage, tumor size, surgery and radiotherapy were independent risk factors associated with ATC according to multivariate Cox regression analysis of OS. However, gender was also an important prognostic predictor in CSS besides the factors mentioned above. These characteristics were included in the nomograms predicting OS and CSS of patients with ATC. The nomograms predicting OS and CSS performed well with a C-index of 0.765 and 0.773. ROC curves, DCA, NRI and IDI suggested that the nomogram was superior to TNM staging and age. CONCLUSION: The proposed nomogram is a reliable tool based on the prediction of OS and CSS for patients with ATC. Such a predictive tool can help to predict the survival of the patients.

Identification of a novel mutation in pseudohypoparathyroidism type Ia in a Chinese family: A case report.

INTRODUCTION: Pseudohypoparathyroidism (PHP) indicates a group of rare disorders characterized by end-organ resistance to various hormones, primarily parathyroid hormone (PTH). One of its most common type is PHP-Ia, which is caused by maternally inherited inactivating mutations in GNAS. In this report, we present a Chinese girl with typical features of PHP-Ia and a novel mutation of the GNAS gene. PATIENT CONCERNS: A 9-year-old Chinese girl presented with recurrent epileptic seizure. DIAGNOSIS: Biochemical and imaging findings were consistent with PHP-Ia, including typical Albright hereditary osteodystrophy phenotype (short stature, round face, brachydactyly, and mild mental retardation), PTH resistance (hypocalcemia, hyperphosphatemia, elevated serum PTH, and multiple intracranial calcification) and thyroid stimulating hormone resistance (elevated serum thyroid stimulating hormone). INTERVENTIONS: The patient was given 1α-hydroxylated vitamin D (calcitriol, 0.5 ug/d), calcium carbonate and vitamin D3 tablets (1.5 g/d, including 600 mg calcium and 125 IU vitamin D3). DNA analysis of the GNAS gene was performed for the whole family. OUTCOMES: Investigation of the GNAS gene revealed a novel mutation c.313delG (p.Glu105Lysfs*7) in the patient, as well as her mother. So the diagnosis of PHP-Ia was confirmed. CONCLUSION: The study further expands the spectrum of known GNAS mutations associated with PHP and lay emphasis on the genetic analysis of GNAS gene for identifying genetic abnormalities as well as making diagnosis and differentiation of various subtypes of PHP.

The Long Noncoding RNA Blnc1 Protects Against Diet-Induced Obesity by Promoting Mitochondrial Function in White Fat.

INTRODUCTION: Long noncoding RNAs (lncRNAs) play critical regulatory roles in metabolic disorder. Whereas, the regulatory role of lncRNAs in mitochondrial function of white adipose tissue (WAT) is unknown. MATERIALS AND METHODS: We investigated the role of Blnc1 in metabolic homeostasis and mitochondrial function of C57BL/6 mice fed a high-fat diet (HFD) for 12 weeks, followed by multi-point injection of adenovirus carrying Blnc1 into epididymal fat (eWAT). In vitro, mitochondrial biogenesis and function were analyzed in 3T3-L1 pre-adipocytes with Blnc1 overexpression or knockdown. Mechanically, RNA immunoprecipitation (RIP) and chromatin immunoprecipitation (ChIP) were used to highlight the molecular mechanism of Blnc1 in pre-adipocytes. RESULTS: Gross eWAT weight was significantly decreased and insulin resistance was improved in HFD-Ad-Blnc1 mice. Mitochondrial biosynthesis was induced by Blnc1 in eWAT, as evidenced by an increased mitochondrial DNA and enhanced Mito-tracker staining. The expression of mitochondria-related genes was increased in eWAT, hepatic fatty acid oxidation was upregulated, and lipid deposition was reduced in HFD-Ad-Blnc1 mice. Knockdown of Blnc1 in 3T3-L1 pre-adipocytes resulted in mitochondrial dysfunction. The mechanistic investigation indicated that Blnc1 stimulated the transcription of Pgc1ß via decoying hnRNPA1. CONCLUSION: Therefore, eWAT-specific overexpression of Blnc1 improves hepatic steatosis and systemic insulin sensitivity, likely by enhancing mitochondrial biogenesis and function.

The Effects of New Selective PPARα Agonist CP775146 on Systematic Lipid Metabolism in Obese Mice and Its Potential Mechanism.

PURPOSE: Peroxisome proliferator-activated receptor α (PPARα) plays a crucial role in the control of lipid homeostasis. Here, we investigated the effects of CP775146, a new selective PPARα agonist, on lipid metabolism in diet-induced obese mice and its possible mechanism. METHODS: C57BL/6 mice were fed a high-fat diet (HFD) for 12 weeks to induce obesity and then received CP775146 via intraperitoneal injection for 3 days. The content/morphology of the liver, serum lipid, and liver function was measured. The expression of genes related to lipolysis and synthesis in liver was detected by quantitative real-time PCR (qRT-PCR). RESULTS: The safe dose of CP775146 was <0.3 mg/kg. CP775146 reduced the serum levels of liver enzymes, such as alanine aminotransferase (ALT) and glutamic-oxaloacetic transaminase (AST) and lipid metabolism-related biomarkers, including triglycerides (TGs) and low-density lipoprotein cholesterol (LDL-c), non-high-density lipoprotein cholesterol (non-HDL-c), and hepatic TG content, at a dosage of 0.1 mg/kg. HFD-induced pathological liver changes improved after CP775146 treatment. The expression of genes involved in liver fatty acid oxidation (acyl-coenzyme A dehydrogenase, long chain (Acadl), acyl-CoA oxidase 1 (Acox-1), carnitine palmitoyltransferase-1 (CPT-1), and enoyl-CoA, hydratase/3-hydroxyacyl CoA dehydrogenase (Ehhadh)) was upregulated in CP775146-treated mice. Furthermore, CP775146 induced the expression of thermogenesis genes (cell death-inducing DFFA-like effector a (Cidea), uncoupling protein 1 (Ucp1)) and lipolysis genes (hormone-sensitive lipase (Hsl), adipose tissue triglyceride lipase (Atgl)) in epididymal white adipose tissue (eWAT), activating browning and thermogenesis. CONCLUSION: CP775146 efficiently alleviates obesity-induced liver damage, prevents lipid accumulation by activating the liver fatty acid ß-oxidation pathway, and regulates the expression of genes that control brown fat-like pathway in eWAT.

Liver X receptor activation induces podocyte injury via inhibiting autophagic activity.

Podocyte injury plays a key role in the occurrence and development of kidney diseases. Decreased autophagic activity in podocyte is closely related to its injury and the occurrence of proteinuria. Liver X receptors (LXRs), as metabolic nuclear receptors, participate in multiple pathophysiological processes and express in several tissues, including podocytes. Although the functional roles of LXRs in the liver, adipose tissue and intestine are well established; however, the effect of LXRs on podocytes function remains unclear. In this study, we used mouse podocytes cell line to investigate the effects of LXR activation on podocytes autophagy level and related signaling pathway by performing Western blotting, RT-PCR, GFP-mRFP-LC3 transfection, and immunofluorescence staining. Then, we tested this effect in STZ-induced diabetic mice. Transmission electron microscopy and immunohistochemistry were employed to explore the effects of LXR activation on podocytes function and autophagic activity. We found that LXR activation could inhibit autophagic flux through blocking the formation of autophagosome in podocytes in vitro which was possibly achieved by affecting AMPK, mTOR, and SIRT1 signaling pathways. Furthermore, LXR activation in vivo induced autophagy suppression in glomeruli, leading to aggravated podocyte injury. In summary, our findings indicated that activation of LXRs induced autophagy suppression, which in turn contributed to the podocyte injury.

A new laminopathy caused by an Arg133/Leu mutation in lamin A/C and the effects thereof on adipocyte differentiation and the transcriptome.

We report a new laminopathy that includes generalized lipoatrophy, insulin-resistant diabetes, micrognathia and biopsy-proven, focal segmental glomerulosclerosis in a female, caused by a de novo heterozygous mutation R133L in the lamin A/C gene (LMNA). We analysed the nuclear morphology and laminar distribution in 3T3-L1 pre-adipocytes overexpressing human wild-type lamin A/C (LMNA WT) or lamin A/C with the R133L mutation (LMNA R133L). We found the nuclear size was varied, nuclear membrane invagination or blebbing, and an irregular A-type lamin meshwork in cells overexpressing LMNA R133L.3T3-L1 pre-adipocyte differentiation into adipocytes was impaired in cells expressing LMNA R133L; contemporaneously, the expression levels of genes associated with adipose tissue self-renewal, including adipogenesis, angiogenesis, and extracellular matrix maintenance, were downregulated. Furthermore, the insulin-signalling pathway was inhibited in LMNA R133L adipocytes. Microarray gene expression profiling showed that the most prominent differences between 3T3-L1 cells expressing wild-type LMNA and LMNA R133L were in genes implicated in metabolic pathways, the cellular response to DNA damage and repair. We thus expand the clinical spectrum of laminopathy and conclude that the LMNA R133L mutation associated with lipodystrophic features and multisystem disorders likely impairs adipocyte renewal and disrupts the expression of genes implicated in the induction and repair of DNA damage.

Small cell lung cancer with panhypopituitarism due to ectopic adrenocorticotropic hormone syndrome: A case report.

BACKGROUND: Small cell lung cancer (SCLC) accounts for 15% of lung cancers, and it commonly expresses peptide and protein factors that are active as hormones. These secreting factors manifest as paraneoplastic disorders, such as ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS). The clinical features are abnormalities in carbohydrate metabolism, hypokalemia, peripheral edema, proximal myopathy, hypertension, hyperpigmentation, and severe systemic infection. However, it is uncommon that EAS has an influence on hypothalamus-pituitary function. CASE SUMMARY: A 62-year-old man presented with complaints of haemoptysis, polyuria, polydipsia, increased appetite, weight loss, and pigmentation. Following a series of laboratory and imaging examinations, he was diagnosed with SCLC, EAS, hypogonadism, hypothyroidism, and central diabetes insipidus. After three rounds of chemotherapy, levels of ACTH, cortisol, thyroid hormone, gonadal hormone, and urine volume had returned to normal levels. In addition, the pulmonary tumor was reduced in size. CONCLUSION: We report a rare case of SCLC complicated with panhypopituitarism due to EAS. We hypothesize that EAS induced high levels of serum glucocorticoid and negative feedback for the synthesis and secretion of antidiuretic hormone from the paraventricular nucleus, and trophic hormones from the anterior pituitary. Therefore, patients who present with symptoms of hypopituitarism, or even panhypopituitarism, with SCLC should be evaluated for EAS.

Protective effects of honokiol against oxidative stress-induced apoptotic signaling in mouse podocytes treated with H2O2.

Honokiol (HNK), an important bioactive compound purified from Magnolia officinalis Cortex, has been demonstrated to have manifold beneficial anti-oxidative, anti-inflammatory, anti-bacterial and antitumor pharmacological effects. In the present study, the association of HNK in the signaling mechanism associated with hydrogen peroxide (H2O2)-induced apoptosis of cultured mouse podocytes was investigated. HNK did not cause significant changes in podocyte viability when its concentration remained below 20 µM. MTS assay and flow cytometry confirmed that H2O2 significantly enhanced the rates of apoptosis while produce significant reduction in viability of podocytes. Following 24 h of pre-treatment with different concentrations of HNK, the viability of adherent podocytes increased and apoptosis significantly decreased in a dose-dependent manner below 20 µM. Reverse transcription-polymerase chain reaction and western blot results indicated that HNK significantly decreased the expression of mRNA and cleaved protein of caspase-3 and caspase-9 in podocytes pre-treated with H2O2. Furthermore, phosphorylation of the signaling molecules protein kinase B (Akt) and extracellular signal-regulated kinase (Erk) 1/2 appeared to increase following HNK treatment. In conclusion, HNK largely eliminated the role of promoting podocyte apoptosis in an oxidative stress environment, which was a protective factor on podocytes cultured with H2O2. The anti-oxidative stress mechanisms of HNK are partly due to suppressing the expression of caspase-3 and caspase-9 and upregulating phosphorylated-Akt and -Erk 1/2.