PLA2G12A protects against diet-induced obesity and insulin resistance by enhancing energy expenditure and clearance of circulating triglycerides.

Secreted phospholipase A2s are involved in the development of obesity, type 2 diabetes mellitus (T2DM) and cardiovascular disease, which have become serious and growing health concerns worldwide. Integration of genome-wide association study and gene co-expression networks analysis showed that the secreted phospholipase A2 group XIIA (PLA2G12A) may participate in hepatic lipids metabolism. Nevertheless, the role of PLA2G12A in lipid metabolism and its potential mechanism remain elusive. Here, we used AAV9 vector carrying human PLA2G12A gene to exogenously express hPLA2G12A in the liver of mice. We demonstrated that the overexpression of hPLA2G12A resulted in a significant decrease in serum lipid levels in wild-type mice fed with chow diet or high-fat diet (HFD). Moreover, hPLA2G12A treatment protected against diet-induced obesity and insulin resistance in mice fed a HFD. Notably, we found that hPLA2G12A treatment confers protection against obesity and hyperlipidemia independent of its enzymatic activity, but rather by increasing physical activity and energy expenditure. Furthermore, we demonstrated that hPLA2G12A treatment induced upregulation of ApoC2 and Cd36 and downregulation of Angptl8, which contributed to the increase in clearance of circulating triglycerides and hepatic uptake of fatty acids without affecting hepatic de novo lipogenesis, very low-density lipoprotein secretion, or intestinal lipid absorption. Our study highlights the potential of PLA2G12A gene therapy as a promising approach for treating obesity, insulin resistance and T2DM.

Isotope Labeling and Biochemical Assessment of Liver-Triacylglycerol in Patients with Different Levels of Histologically-Graded Liver Disease.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) prevalence is rapidly growing, and fatty liver has been found in a quarter of the US population. Increased liver lipids, particularly those derived from the pathway of de novo lipogenesis (DNL), have been identified as a hallmark feature in individuals with high liver fat. This has led to much activity in basic science and drug development in this area. No studies to date have investigated the contribution of DNL across a spectrum of disease, although it is clear that inhibition of DNL has been shown to reduce liver fat. OBJECTIVES: The purpose of this study was to determine whether liver lipid synthesis increases across the continuum of liver injury. METHODS: Individuals (n = 49) consumed deuterated water for 10 d before their scheduled bariatric surgeries to label DNL; blood and liver tissue samples were obtained on the day of the surgery. Liver lipid concentrations were quantitated, and levels of protein and gene expression assessed. RESULTS: Increased liver DNL, measured isotopically, was significantly associated with liver fatty acid synthase protein content (R = 0.470, P = 0.003), total steatosis assessed by histology (R = 0.526, P = 0.0008), and the fraction of DNL fatty acids in plasma very low-density lipoprotein-triacylglycerol (R = 0.747, P < 0.001). Regression analysis revealed a parabolic relationship between fractional liver DNL (percent) and NAFLD activity score (R = 0.538, P = 0.0004). CONCLUSION: These data demonstrate that higher DNL is associated with early to mid stages of liver disease, and this pathway may be an effective target for the treatment of NAFLD and nonalcoholic steatohepatitis. This study was registered at clinicaltrials.gov as NCT03683589.

Acute effects of a single moderate-intensity exercise bout performed in fast or fed states on cell metabolism and signaling: Comparison between lean and obese rats.

AIMS: Although the benefits of exercise can be potentiated by fasting in healthy subjects, few studies evaluated the effects of this intervention on the metabolism of obese subjects. This study investigated the immediate effects of a single moderate-intensity exercise bout performed in fast or fed states on the metabolism of gastrocnemius and soleus of lean and obese rats. MAIN METHODS: Male rats received a high-fat diet (HFD) for twelve weeks to induce obesity or were fed standard diet (SD). After this period, the animals were subdivided in groups: fed and rest (FER), fed and exercise (30 min treadmill, FEE), 8 h fasted and rest (FAR) and fasted and exercise (FAE). Muscle samples were used to investigate the oxidative capacity and gene expression of AMPK, PGC1α, SIRT1, HSF1 and HSP70. KEY FINDINGS: In relation to lean animals, obese animals' gastrocnemius glycogen decreased 60 %, triglycerides increased 31 %; glucose and alanine oxidation decreased 26 % and 38 %, respectively; in soleus, triglycerides reduced 46 % and glucose oxidation decreased 37 %. Exercise and fasting induced different effects in glycolytic and oxidative muscles of obese rats. In soleus, fasting exercise spared glycogen and increased palmitate oxidation, while in gastrocnemius, glucose oxidation increased. In obese animals' gastrocnemius, AMPK expression decreased 29 % and SIRT1 increased 28 % in relation to lean. The AMPK response was more sensitive to exercise and fasting in lean than obese rats. SIGNIFICANCE: Exercise and fasting induced different effects on the metabolism of glycolytic and oxidative muscles of obese rats that can promote health benefits in these animals.

Recent Updates in Hypertriglyceridemia Management for Cardiovascular Disease Prevention.

PURPOSE OF REVIEW: Mounting evidence continues to support the causal role of triglyceride-rich lipoproteins (TRL) in the development of atherosclerotic cardiovascular disease (ASCVD). Substantial residual ASCVD risk remains among high-risk patients who have elevated triglycerides despite reduction in low-density lipoprotein cholesterol (LDL-C) with statin therapy. Ongoing research efforts have focused on evaluating triglyceride-lowering therapies among patients with hypertriglyceridemia. RECENT FINDINGS: The REDUCE-IT trial showed that the addition of icosapent ethyl, a highly purified form of eicosapentaenoic acid (EPA), can reduce vascular events among statin-treated individuals with elevated triglycerides who have either clinical ASCVD or diabetes plus another risk factor. Although additional evidence for EPA has emerged from other trials, conflicting results have been reported by subsequent trials that tested different omega-3 fatty acid formulations. Randomized clinical trials have not demonstrated incremental ASCVD benefit of fibrates on background of statin therapy, but fibrates are used to help prevent pancreatitis in patients with severe hypertriglyceridemia. Selective inhibitors of apolipoprotein C-III (apoC3) and angiopoietin-like protein 3 (ANGPTL3), proteins that are involved in metabolism of TRLs by regulating lipoprotein lipase, have been tested in selected patient populations and showed significant reduction in triglyceride and LDL-C levels. Statin therapy continues to be the cornerstone of pharmacologic reduction of cardiovascular risk. High-dose EPA in the form of icosapent ethyl has been demonstrated to have cardiovascular benefit on top of statins in persons with elevated triglycerides at high ASCVD risk. Ongoing clinical trials are evaluating novel selective therapies such as apoC3 and ANGPTL3 inhibitors.

Ferulic Acid Prevents Nonalcoholic Fatty Liver Disease by Promoting Fatty Acid Oxidation and Energy Expenditure in C57BL/6 Mice Fed a High-Fat Diet.

There is a consensus that ferulic acid (FA), the most prominent phenolic acid in whole grains, displays a protective effect in non-alcoholic fatty liver disease (NAFLD), though its underlying mechanism not fully elucidated. This study aimed to investigate the protective effect of FA on high-fat diet (HFD)-induced NAFLD in mice and its potential mechanism. C57BL/6 mice were divided into the control diet (CON) group, the HFD group, and the treatment (HFD+FA) group, fed with an HFD and FA (100 mg/kg/day) by oral gavage for 12 weeks. Hematoxylin and eosin (H&E) staining and Oil Red O staining were used to evaluate liver tissue pathological changes and lipid accumulation respectively. It was demonstrated that FA supplementation prevented HFD-induced NAFLD, which was evidenced by the decreased accumulation of lipid and hepatic steatosis in the HFD+FA group. Specifically, FA supplementation decreased hepatic triacylglycerol (TG) content by 33.5% (p < 0.01). Metabolic cage studies reveal that FA-treated mice have elevated energy expenditure by 11.5% during dark phases. Mechanistically, FA treatment increases the expression of rate-limiting enzymes of fatty acid oxidation and ketone body biosynthesis CPT1A, ACOX1 and HMGCS2, which are the peroxisome proliferator-activated receptors α (PPARα) targets in liver. In conclusion, FA could effectively prevent HFD-induced NAFLD possibly by activating PPARα to increase energy expenditure and decrease the accumulation of triacylglycerol in the liver.

Assessment on the oil accumulation by knockdown of triacylglycerol lipase in the oleaginous diatom Fistulifera solaris.

Microalgae are promising producers of biofuel due to higher accumulation of triacylglycerol (TAG). However, further improvement of the lipid metabolism is critical for feasible application of microalgae in industrial production of biofuel. Suppression of lipid degradation pathways is a promising way to remarkably increase the lipid production in model diatoms. In this study, we established an antisense-based knockdown (KD) technique in the marine oleaginous diatom, Fistulifera solaris. This species has a capability to accumulate high content of lipids. Tgl1 KD showed positive impact on cell growth and lipid accumulation in conventional culture in f/2 medium, resulting in higher oil contents compared to wild type strain. However, these impacts of Tgl1 KD were slight when the cells were subjected to the two-stage growth system. The Tgl1 KD resulted in slight change of fatty acid composition; increasing in C14:0, C16:0 and C16:1, and decreasing in C20:5. This study indicates that, although Tgl1 played a certain role in lipid degradation in F. solaris, suppression of only a single type of TAG lipase was not significantly effective to improve the lipid production. Comprehensive understanding of the lipid catabolism in this microalga is essential to further improve the lipid production.

Associations between ultrasound measurements and hematochemical parameters for the assessment of liver metabolic status in Holstein-Friesian cows.

Metabolic disorders, including hepatic lipidosis and ketosis, severely affect animal health status and welfare with a large economic burden in dairy herds. The gold standard for diagnosing hepatic lipidosis is the liver biopsy, which is impractical and invasive for the screening at farm level. Ultrasound (US) imaging is a promising technique for identifying liver dysfunction, but standardized specifications in physiological conditions are needed. Herein, we described the features of four US measurements, namely the liver predicted triacylglycerol (pTAG) content, liver depth (LD), and portal vein area (PVA) and depth (PVD) and we investigated their associations with a set of hematochemical (HC) indicators in 342 clinically healthy Holstein Friesian dairy cows. Liver pTAG content was negatively associated with hematocrit and positively with globulin, whereas PVA was negatively associated with thiol group levels, and LD positively with ceruloplasmin. We found significant interactions between some HC parameters and parity: in particular, creatinine, thiol groups and globulin for PVA, and aspartate aminotransferase, paraoxonase and ceruloplasmin for PVD. This study offers new insights on variations in liver function occurring after calving and pave the way for the potential use of minimally invasive techniques for prompt detection of metabolic disorders in dairy herds.

Performance of early risk assessment tools to predict the later development of gestational diabetes.

BACKGROUND: Several prognostic models for gestational diabetes mellitus (GDM) are provided in the literature; however, their clinical significance has not been thoroughly evaluated, especially with regard to application at early gestation and in accordance with the most recent diagnostic criteria. This external validation study aimed to assess the predictive accuracy of published risk estimation models for the later development of GDM at early pregnancy. METHODS: In this cohort study, we prospectively included 1132 pregnant women. Risk evaluation was performed before 16 + 0 weeks of gestation including a routine laboratory examination. Study participants were followed-up until delivery to assess GDM status according to the IADPSG 2010 diagnostic criteria. Fifteen clinical prediction models were calculated according to the published literature. RESULTS: Gestational diabetes mellitus was diagnosed in 239 women, that is 21.1% of the study participants. Discrimination was assessed by the area under the ROC curve and ranged between 60.7% and 76.9%, corresponding to an acceptable accuracy. With some exceptions, calibration performance was poor as most models were developed based on older diagnostic criteria with lower prevalence and therefore tended to underestimate the risk of GDM. The highest variable importance scores were observed for history of GDM and routine laboratory parameters. CONCLUSIONS: Most prediction models showed acceptable accuracy in terms of discrimination but lacked in calibration, which was strongly dependent on study settings. Simple biochemical variables such as fasting glucose, HbA1c and triglycerides can improve risk prediction. One model consisting of clinical and laboratory parameters showed satisfactory accuracy and could be used for further investigations.

Whole-body insulin resistance and energy expenditure indices, serum lipids, and skeletal muscle metabolome in a state of lipoprotein lipase overexpression.

INTRODUCTION: Overexpression of lipoprotein lipase (LPL) protects against high-fat-diet (HFD)-induced obesity and insulin resistance in transgenic rabbits; however, the molecular mechanisms remain unclear. Skeletal muscle is a major organ responsible for insulin-stimulated glucose uptake and energy expenditure. OBJECTIVES: The main purpose of the current study was to examine the effects of the overexpression of LPL on the skeletal muscle metabolomic profiles to test our hypothesis that the mitochondrial oxidative metabolism would be activated in the skeletal muscle of LPL transgenic rabbits and that the higher mitochondrial oxidative metabolism activity would confer better phenotypic metabolic outcomes. METHODS: Under a HFD, insulin resistance index was measured using the intravenous glucose tolerance test, and total energy expenditure (TEE) was measured by doubly-labeled water in control and LPL transgenic rabbits (n = 12, each group). Serum lipids, such as triglycerides and free fatty acid, were also measured. The skeletal muscle metabolite profile was analyzed using capillary electrophoresis time-of flight mass spectrometry in the two groups (n = 9, each group). A metabolite set enrichment analysis (MSEA) with muscle metabolites and a false discovery rate q < 0.2 was performed to identify significantly different metabolic pathways between the 2 groups. RESULTS: The triglycerides and free fatty acid levels and insulin resistance index were lower, whereas the TEE was higher in the LPL transgenic rabbits than in the control rabbits. Among 165 metabolites detected, the levels of 37 muscle metabolites were significantly different between the 2 groups after false discovery rate correction (q < 0.2). The MSEA revealed that the TCA cycle and proteinogenic amino acid metabolism pathways were significantly different between the 2 groups (P < 0.05). In the MSEA, all four selected metabolites for the TCA cycle (2-oxoglutaric acid, citric acid, malic acid, fumaric acid), as well as eight selected metabolites for proteinogenic amino acid metabolism (asparagine, proline, methionine, phenylalanine, histidine, arginine, leucine, isoleucine) were consistently increased in the transgenic rabbits compared with control rabbits, suggesting that these two metabolic pathways were activated in the transgenic rabbits. Some of the selected metabolites, such as citric acid and methionine, were significantly associated with serum lipids and insulin resistance (P < 0.05). CONCLUSION: The current results suggest that the overexpression of LPL may lead to increased activities of TCA cycle and proteinogenic amino acid metabolism pathways in the skeletal muscle, and these enhancements may play an important role in the biological mechanisms underlying the anti-obesity/anti-diabetes features of LPL overexpression.

In-vivo anti-inflammatory activity and safety assessment of the aqueous extract of Algerian Erica arborea L. (Ericaceae) aerial parts.

ETHNOPHARMACOLOGICAL RELEVANCE: Erica arborea known as Khlenj in Algeria is a small shrub belonging to Ericaceae family. E. arborea Aqueous extract (EAAE) is used in traditional medicine for anti-inflammatory, diuretic, antimicrobial, and antiulcer purposes. AIM OF THE STUDY: To our knowledge, no data reveal the combination between in-vivo anti-inflammatory and toxicological studies of EAAE. For this purpose, the aim of this study is to evaluate the biological activity cited above and assess its safety. MATERIAL AND METHODS: Anti-inflammatory activity was undergone using carrageenan-induced paw edema and croton oil-induced ear edema. The acute and sub-acute toxicity were conducted following the OECD guidelines 423 and 407, respectively. Phytochemical identification was carried out using HPLC-DAD-MS. Quantitative evaluation of polyphenols; flavonoids and antioxidant activity of EAAE were also determined. RESULTS: Oral administration of EAAE (250 and 500 mg/kg) significantly (p < 0.05) reduced the edema induced by carrageenan. Administration of EAAE dosed at 250 and 500 mg/kg exhibited efficacy in reducing edema induced by croton oil. The acute administration of EAAE at doses of 2000 and 5000 mg/kg did not cause any mortality or adverse effects indicating that the LD50 is above 5000 mg/kg. The prolonged administration of EAAE (500 and 1000 mg/kg) showed a significant reduction in triglycerides levels in male and female rats whereas no significant changes in other biochemical and hematological parameters were observed. Histopathological damages were recorded in both liver and kidney animal's tissues of both sexes treated with medium and maximum doses of EAAE. Phytochemical characterization of EAAE revealed a high amount of phenolic compounds, HPLC-DAD-MS analysis led to the identification of chlorogenic acid and five flavonol glycosides: myricetin pentoside, quercetin-3-O-glucoside, myricetin-3-O-rhamnoside, quercetin-3-O-pentoside, and quercetin-3-O-rhamnoside. CONCLUSION: In the light of the results obtained in this study, EAAE corroborates the popular use to treat the anti-inflammatory impairments. EAAE can be considered as non-toxic in acute administration and exhibited a moderate toxicity in sub-acute administration. High phenolic content and in-vitro antioxidant activity observed indicate that EAAE may reduce oxidative stress markers in-vivo.

Non-invasive Assessment of Liver Fat in ob/ob Mice Using Ultrasound-Induced Thermal Strain Imaging and Its Correlation with Hepatic Triglyceride Content.

Non-alcoholic fatty liver disease is the accumulation of triglycerides in liver. In its malignant form, it can proceed to steatohepatitis, fibrosis, cirrhosis, cancer and ultimately liver impairment, leading to liver transplantation. In a previous study, ultrasound-induced thermal strain imaging (US-TSI) was used to distinguish between excised fatty livers from obese mice and non-fatty livers from control mice. In this study, US-TSI was used to quantify lipid composition of fatty livers in ob/ob mice (n = 28) at various steatosis stages. A strong correlation coefficient was observed (R2 = 0.85) between lipid composition measured with US-TSI and hepatic triglyceride content. Hepatic triglyceride content is used to quantify adipose tissue in liver. The ob/ob mice were divided into three groups based on the degree of steatosis that is used in clinics: none, mild and moderate. A non-parametric Kruskal-Wallis test was conducted to determine if US-TSI can potentially differentiate among the steatosis grades in non-alcoholic fatty liver disease.

Assessment of exopolysaccharides, bacteriocins and in vitro and in vivo hypocholesterolemic potential of some Egyptian Lactobacillus spp.

Lactobacilli probiotics have been suggested to reduce cholesterol with low side effects to host. Bacteriocins and exopolysaccharides (EPSs) production are two meaningful examples of functional applications of lactobacilli in the food industry. Eight Lactobacillus strains were isolated from some Egyptian fermented food and tested for their probiotic properties. Analysis of the monosaccharide composition by thin layer chromatography showed the presence of glucose, galactose and unknown sugar. The main functional groups of EPSs were elucidated by Fourier-Transform Infrared Spectroscopy. Their fermentation cultures displayed powerful antioxidant activities extending from 97.5 to 99%, 40-75% for their EPSs and free cells, respectively, and exhibited in vitro cholesterol downgrading from 48 to 82% and 72 to 91% after 48 and 120 h, respectively. Their EPSs showed good anticancer activities against carcinoma cells with low IC50 values for HCT-116, PC-3 and HepG-2 cells. To the best of our knowledge, there have been no previous reports on the potential of Lactobacillus EPSs activity against PC-3. The selected strains, L. plantarum KU985433 and L. rhamnosus KU985436 produced two different bacteriocins as detected by gel permeation chromatography with good antimicrobial activities. In vivo study demonstrated that feeding Westar rats with fermented milk exhibited greater cholesterol, LDL and blood triglyceride reduction for both strains. Whereas, HDL was increased by about 43 and 38%, respectively, and the atherogenic indices decreased.

Dysfunction of estrogen-related receptor alpha-dependent hepatic VLDL secretion contributes to sex disparity in NAFLD/NASH development.

Rationale: Men and postmenopausal women are more prone to developing non-alcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) than premenopausal women. However, the pathological links and underlying mechanisms of this disparity are still elusive. The sex-difference in hepatic very low-density lipoprotein (VLDL) assembly and secretion may contribute to NAFLD development. Estrogen-related receptor alpha (ERRα) is a key regulator of several metabolic processes. We hypothesized that ERRα plays a role contributing to the sex-difference in hepatic VLDL assembly and secretion. Methods: VLDL secretion and essential genes governing said process were assessed in male and female mice. Liver-specific ERRα-deficient (ERRαLKO) mice were generated to assess the rate of hepatic VLDL secretion and alteration in target gene expression. Overexpression of either microsomal triglyceride transfer protein (Mttp) or phospholipase A2 G12B (Pla2g12b) by adenovirus was performed to test if the fatty liver phenotype in male ERRαLKO mice was due to defects in hepatic VLDL secretion. Female ERRαLKO mice were put on a diet high in saturated fat, fructose and cholesterol (HFHC) to promote NASH development. Wild type female mice were either ovariectomized or treated with tamoxifen to induce a state of estrogen deficiency or disruption in estrogen signaling. Adenovirus was used to overexpress ERRα in these mice to test if ERRα was sufficient to rescue the suppressed VLDL secretion due to estrogen dysfunction. Finally, wild type male mice on a high-fat diet (HFD) were treated with an ERRα inverse agonist to assess if suppressing ERRα activity pharmacologically would lead to fatty liver development. Results: ERRα is an indispensable mediator modulating hepatic triglyceride-rich very low-density lipoprotein (VLDL-TG) assembly and secretion through coordinately controlling target genes apolipoprotein B (Apob), Mttp and Pla2g12b in a sex-different manner. Hepatic VLDL-TG secretion is blunted in ERRαLKO mice, leading to hepatosteatosis which exacerbates endoplasmic reticulum stress and inflammation paving ways for NASH development. Importantly, ERRα acts downstream of estrogen/ERα signaling in contributing to the sex-difference in hepatic VLDL secretion effecting hepatic lipid homeostasis. Conclusions: Our results highlight ERRα as a key mediator which contributes to the sex disparity in NAFLD development, suggesting that selectively restoring ERRα activity in the liver may be a novel strategy for treating NAFLD/NASH.

CTRP12 ablation differentially affects energy expenditure, body weight, and insulin sensitivity in male and female mice.

Secreted hormones facilitate tissue cross talk to maintain energy balance. We previously described C1q/TNF-related protein 12 (CTRP12) as a novel metabolic hormone. Gain-of-function and partial-deficiency mouse models have highlighted important roles for this fat-derived adipokine in modulating systemic metabolism. Whether CTRP12 is essential and required for metabolic homeostasis is unknown. We show here that homozygous deletion of Ctrp12 gene results in sexually dimorphic phenotypes. Under basal conditions, complete loss of CTRP12 had little impact on male mice, whereas it decreased body weight (driven by reduced lean mass and liver weight) and improved insulin sensitivity in female mice. When challenged with a high-fat diet, Ctrp12 knockout (KO) male mice had decreased energy expenditure, increased weight gain and adiposity, elevated serum TNFα level, and reduced insulin sensitivity. In contrast, female KO mice had reduced weight gain and liver weight. The expression of lipid synthesis and catabolism genes, as well as profibrotic, endoplasmic reticulum stress, and oxidative stress genes were largely unaffected in the adipose tissue of Ctrp12 KO male mice. Despite greater adiposity and insulin resistance, Ctrp12 KO male mice fed an obesogenic diet had lower circulating triglyceride and free fatty acid levels. In contrast, lipid profiles of the leaner female KO mice were not different from those of WT controls. These data suggest that CTRP12 contributes to whole body energy metabolism in genotype-, diet-, and sex-dependent manners, underscoring complex gene-environment interactions influencing metabolic outcomes.

Genome-Wide Assessment for Resting Heart Rate and Shared Genetics With Cardiometabolic Traits and Type 2 Diabetes.

BACKGROUND: High resting heart rate (RHR) occurs in parallel with type 2 diabetes (T2D) and metabolic disorders, implying shared etiology between them. However, it is unknown if they are causally related, and no study has been conducted to investigate the shared mechanisms underlying these associations. OBJECTIVES: The objective of this study was to understand the genetic basis of the association between resting heart rate and cardiometabolic disorders/T2D. METHODS: This study examined the genetic correlation, causality, and shared genetics between RHR and T2D using LD Score regression, generalized summary data-based Mendelian randomization, and transcriptome wide association scan (TWAS) in UK Biobank data (n = 428,250) and summary-level data for T2D (74,124 cases and 824,006 control subjects) and 8 cardiometabolic traits (sample size ranges from 51,750 to 236,231). RESULTS: Significant genetic correlation between RHR and T2D (rg = 0.22; 95% confidence interval: 0.18 to 0.26; p = 1.99 × 10-22), and 6 cardiometabolic traits (fasting insulin, fasting glucose, waist-hip ratio, triglycerides, high-density lipoprotein, and body mass index; rg range -0.12 to 0.24; all p < 0.05) were observed. RHR has significant estimated causal effect on T2D (odds ratio: 1.12 per 10-beats/min increment; p = 7.79 × 10-11) and weaker causal estimates from T2D to RHR (0.32 beats/min per doubling increment in T2D prevalence; p = 6.14 × 10-54). Sensitivity analysis by controlling for the included cardiometabolic traits did not modify the relationship between RHR and T2D. TWAS found locus chr2q23.3 (rs1260326) was highly pleiotropic among RHR, cardiometabolic traits, and T2D, and identified 7 genes (SMARCAD1, RP11-53O19.3, CTC-498M16.4, PDE8B, AKTIP, KDM4B, and TSHZ3) that were statistically independent and shared between RHR and T2D in tissues from the nervous and cardiovascular systems. These shared genes suggested the involvement of epigenetic regulation of energy and glucose metabolism, and AKT activation-related telomere dysfunction and vascular endothelial aging in the shared etiologies between RHR and T2D. Finally, FADS1 was found to be shared among RHR, fasting glucose, high-density lipoprotein, and triglycerides. CONCLUSIONS: These findings provide evidence of significant genetic correlations and causation between RHR and T2D/cardiometabolic traits, advance our understanding of RHR, and provide insight into shared etiology for high RHR and T2D.

Systematic Analysis of Metabolic Pathway Distributions of Bacterial Energy Reserves.

Previous bioinformatics studies have linked gain or loss of energy reserves with host-pathogen interactions and bacterial virulence based on a comparatively small number of bacterial genomes or proteomes. Thus, understanding the theoretical distribution patterns of energy reserves across bacterial species could provide a shortcut route to look into bacterial lifestyle and physiology. So far, five major energy reserves have been identified in bacteria due to their capacity to support bacterial persistence under nutrient deprivation conditions. These include polyphosphate (polyP), glycogen, wax ester (WE), triacylglycerol (TAG), and polyhydroxyalkanoates (PHAs). Although the enzymes related with metabolism of energy reserves are well understood, there is a lack of systematic investigations into the distribution of bacterial energy reserves from an evolutionary point of view. In this study, we sourced 8282 manually reviewed bacterial reference proteomes and combined a set of hidden Markov sequence models (HMMs) to search homologs of key enzymes related with the metabolism of energy reserves. Our results revealed that specific pathways like trehalose-related glycogen metabolism and enzymes such as wax ester synthase/acyl-CoA:diacylglycerol acyltransferase (WS/DGAT) are mainly restricted within specific types of bacterial groups, which provides evolutionary insights into the understanding of their origins and functions. In addition, the study also confirms that loss of energy reserves like polyP metabolism absence in Mollicutes is correlated with bacterial genome reduction. Through this analysis, a clearer picture about the metabolism of energy reserves in bacteria is presented, which could serve as a guide for further theoretical and experimental analyses of bacterial energy metabolism.

Assessment of the Main Compounds of the Lipolytic System in Treadmill Running Rats: Different Response Patterns between the Right and Left Ventricle.

The aim of the present study was to investigate the time and intensity dependent effects of exercise on the heart components of the lipolytic complex. Wistar rats ran on a treadmill with the speed of 18 m/min for 30 min (M30) or 120 min (M120) or with the speed of 28 m/min for 30 min (F30). The mRNA and protein expressions of the compounds adipose triglyceride lipase (ATGL), comparative gene identification-58 (CGI-58), G0/G1 switch gene 2 (G0S2), hormone sensitive lipase (HSL) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) were examined by real-time PCR and Western blot, respectively. Lipid content of free fatty acids (FFA), diacylglycerols (DG) and triacylglycerols (TG) were estimated by gas liquid chromatography. We observed virtually no changes in the left ventricle lipid contents and only minor fluctuations in its ATGL mRNA levels. This was in contrast with its right counterpart i.e., the content of TG and DG decreased in response to both increased duration and intensity of a run. This occurred in tandem with increased mRNA expression for ATGL, CGI-58 and decreased expression of G0S2. It is concluded that exercise affects behavior of the components of the lipolytic system and the lipid content in the heart ventricles. However, changes observed in the left ventricle did not mirror those in the right one.

Body Composition, Resting Energy Expenditure, and Metabolic Changes in Women Diagnosed with Differentiated Thyroid Carcinoma.

Background: Thyroid hormones heavily impact energy expenditure, body mass, and body composition. Their role in the state of exogenous subclinical hyperthyroidism in differentiated thyroid carcinoma (DTC) patients, however, is less well defined. The first aim of this study was to assess changes in body weight, body composition, resting energy expenditure (REE), respiratory quotient (RQ), and metabolic parameters in female DTC patients, starting from the phase of a euthyroid state before total thyroidectomy through the subsequent year after thyrotropin (TSH) suppression. The second aim was to assess the relationship between these variables and thyroid function parameters. Methods: This observational case series analyzed changes in body composition, calorimetric, and metabolic parameters of 15 DTC female patients at 5 time points: (1) at initial DTC diagnosis (euthyroid state), (2) at 2-3 weeks after thyroidectomy (hypothyroid state), (3) at 2-3 months of levothyroxine (LT4) treatment (exogenous euthyroid state), (4) after 6-9 months, and (5) after 1 year of TSH suppressive LT4 therapy (exogenous subclinical hyperthyroid state). A generalized estimating equation (GEE) analysis was performed to estimate the longitudinal correlations of the total triiodothyronine (TT3)/free thyroxine (fT4) ratio (as an independent variable) with body composition, metabolic, and calorimetric parameter changes (as dependent variables). Results: REE, REE per kilogram of lean body mass (REE/LBM), pulse, and systolic and diastolic blood pressure were significantly higher after TSH suppressive LT4 therapy. The GEE analysis revealed longitudinal negative correlations between the TT3/fT4 ratio and systolic blood pressure, fasting blood glucose, body mass index, android (abdominal wall and visceral mesentery) fat distribution, trunk, and arm fat distribution, REE, and REE/LBM. There was a positive correlation with RQ. Conclusions: REE, REE/LBM, pulse, and systolic and diastolic blood pressure were significantly higher after thyroidectomy, radioiodine and TSH suppressive therapy in female DTC patients, while no changes were observed in body weight or body composition. A lower TT3/fT4 ratio longitudinally correlated with increases in REE, REE/LBM, abdominal fat distribution, systolic blood pressure, and fasting blood glucose, as well as with decreased RQ. These findings highlight the importance of judicial balancing of the benefits and detriments of TSH suppression with subsequent decreased TT3/fT4 ratios for female DTC patients.

Effects of Estrogen Therapies on Outcomes in Turner Syndrome: Assessment of Induction of Puberty and Adult Estrogen Use.

CONTEXT: Turner syndrome (TS) is often associated with delayed puberty. To induce puberty, estrogen is administered in incremental doses at an age determined by age of presentation. After puberty, various types of maintenance estrogen replacement therapy (ERT) are used. OBJECTIVE: We sought associations between age of induction of puberty and type of ERT on adult health outcomes. DESIGN: Health surveillance data included blood profiles, bone density, and blood pressure. We assessed interactions between these data and age at first estrogen exposure in women with primary amenorrhea. We also assessed these data according to ERT subgroups [combined oral contraceptive pill (OCP), oral estrogen (OE), and transdermal estradiol (TE)] using data from each of 6679 clinic visits, controlling for age, body mass index, and height. SETTING: Adult TS clinic at University College London Hospital. PATIENTS: Of 799 women with TS, 624 had primary amenorrhea and 599 had accurate maintenance ERT data. MAIN OUTCOME MEASURES: Parameters of health surveillance derived from clinical guidelines. RESULTS: Estrogen start age was negatively correlated with adult bone density (spine: r = -0.20 and hip: r = -0.022; P ≤ 0.001). OCP users had higher blood pressure and an adverse lipid profile compared with other ERT subgroups. TE was associated with elevated liver enzymes and hemoglobin A1c compared with OE (P ≤ 0.01). CONCLUSIONS: An earlier age of induction of puberty may be beneficial for adult bone density. Given the high prevalence of hypertension in TS, the use of OCP for ERT should be limited. OE may be a benefit for steatohepatitis.

Postpartum assessment of the beta cell function and insulin resistance for Chinese women with previous gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) imparts a high risk of developing postpartum diabetes and is considered to be an early stage of type 2 diabetes mellitus (T2DM). In this study, a 75-g oral glucose tolerance test was performed on 472 women with GDM at 6-8 weeks after delivery. The clinical and metabolic characteristics were compared between the patients with normal glucose tolerance (NGT) and abnormal glucose metabolism (AGM). These data were then compared between pre-diabetic and diabetic patients. A total of 37.7% of the women with GDM continued to have abnormal glucose levels after delivery. Compared with the women who reverted to normal, HOMA-IR was significantly higher in AGM. A multiple stepwise regression analysis revealed that age, the postpartum body mass index (BMI), low density lipoprotein-cholesterol (LDL-C), 2 h glucose load plasma glucose (2 h PG), triglycerides (TG), hemoglobin A1c (HbA1c), 1 h glucose load plasma insulin (INS) level, and 2 h INS level were independent risk factors for the development of insulin resistance after delivery. This study has identified a high prevalence of AGM after GDM. Insulin resistance appears to be the major contributor. Any treatment to reduce the postpartum BMI and lipids level may be beneficial to decrease insulin resistance.