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    TFAM Enhances Fat Oxidation and Attenuates High-Fat Diet-Induced Insulin Resistance in Skeletal Muscle. Koh Jin-Ho,Johnson Matthew L,Dasari Surendra,LeBrasseur Nathan K,Vuckovic Ivan,Henderson Gregory C,Cooper Shawna A,Manjunatha Shankarappa,Ruegsegger Gregory N,Shulman Gerald I,Lanza Ian R,Nair K Sreekumaran Diabetes Diet-induced insulin resistance (IR) adversely affects human health and life span. We show that muscle-specific overexpression of human mitochondrial transcription factor A (TFAM) attenuates high-fat diet (HFD)-induced fat gain and IR in mice in conjunction with increased energy expenditure and reduced oxidative stress. These TFAM effects on muscle are shown to be exerted by molecular changes that are beyond its direct effect on mitochondrial DNA replication and transcription. TFAM augmented the muscle tricarboxylic acid cycle and citrate synthase facilitating energy expenditure. TFAM enhanced muscle glucose uptake despite increased fatty acid (FA) oxidation in concert with higher β-oxidation capacity to reduce the accumulation of IR-related carnitines and ceramides. TFAM also increased pAMPK expression, explaining enhanced PGC1α and PPARβ, and reversing HFD-induced GLUT4 and pAKT reductions. TFAM-induced mild uncoupling is shown to protect mitochondrial membrane potential against FA-induced uncontrolled depolarization. These coordinated changes conferred protection to TFAM mice against HFD-induced obesity and IR while reducing oxidative stress with potential translational opportunities. 10.2337/db19-0088
    Atlas of metabolism reveals palmitic acid results in mitochondrial dysfunction and cell apoptosis by inhibiting fatty acid β-oxidation in Sertoli cells. Frontiers in endocrinology In recent years, the impact of lipotoxicity on male fertility has received extensive attention, especially on Sertoli cells (SCs). In SCs, energy metabolism is important as disorders of energy metabolism result in infertility eventually. However, the underlying mechanism of lipotoxicity on energy metabolism in SCs remains unknown. Advances in high-throughput metabolomics and lipidomics measurement platforms provide powerful tools to gain insights into complex biological systems. Here, we aimed to explore the potential molecular mechanisms of palmitic acid (PA) regulating energy metabolism in SCs based on metabolomics and lipidomics. The results showed that glucose metabolism-related metabolites were not significantly changed, which suggested that PA treatment had little effect on glucose metabolism and may not influence the normal energy supply from SCs to germ cells. However, fatty acid β-oxidation was inhibited according to accumulation of medium- and long-chain acylcarnitines in cells. In addition, the pool of amino acids and the levels of most individual amino acids involved in the tricarboxylic acid (TCA) cycle were not changed after PA treatment in SCs. Moreover, PA treatment of SCs significantly altered the lipidome, including significant decreases in cardiolipin and glycolipids as well as remarkable increases in ceramide and lysophospholipids, which indicated that mitochondrial function was affected and apoptosis was triggered. The increased apoptosis rate of SCs was verified by elevated protein expression levels of Cleaved Caspase-3 and Bax as well as decreased Bcl-2 protein expression level. Together, these findings indicated that PA may result in mitochondrial dysfunction and increased apoptosis by inhibiting fatty acid β-oxidation of SCs. 10.3389/fendo.2022.1021263
    Palmitic acid feeding increases ceramide supply in association with increased milk yield, circulating nonesterified fatty acids, and adipose tissue responsiveness to a glucose challenge. Rico J E,Mathews A T,Lovett J,Haughey N J,McFadden J W Journal of dairy science Reduced insulin action is a key adaptation that facilitates glucose partitioning to the mammary gland for milk synthesis and enhances adipose tissue lipolysis during early lactation. The progressive recovery of insulin sensitivity as cows advance toward late lactation is accompanied by reductions in circulating nonesterified fatty acids (NEFA) and milk yield. Because palmitic acid can promote insulin resistance in monogastrics through sphingolipid ceramide-dependent mechanisms, palmitic acid (C16:0) feeding may enhance milk production by restoring homeorhetic responses. We hypothesized that feeding C16:0 to mid-lactation cows would enhance ceramide supply and ceramide would be positively associated with milk yield. Twenty multiparous mid-lactation Holstein cows were enrolled in a study consisting of a 5-d covariate, 49-d treatment, and 14-d posttreatment period. All cows were randomly assigned to a sorghum silage-based diet containing no supplemental fat (control; n=10; 138±45 d in milk) or C16:0 at 4% of ration dry matter (PALM; 98% C16:0; n=10; 136±44 d in milk). Blood and milk were collected at routine intervals. Liver and skeletal muscle tissue were biopsied at d 47 of treatment. Intravenous glucose tolerance tests (300mg/kg of body weight) were performed at d -1, 24, and 49 relative to start of treatment. The plasma and tissue concentrations of ceramide and glycosylated ceramide were determined using liquid chromatography coupled with tandem mass spectrometry. Data were analyzed as repeated measures using a mixed model with fixed effects of treatment and time, and milk yield served as a covariate. The PALM treatment increased milk yield, energy-corrected milk, and milk fat yield. The most abundant plasma and tissue sphingolipids detected were C24:0-ceramide, C24:0-monohexosylceramide (GlcCer), and C16:0-lactosylceramide. Plasma concentrations of total ceramide and GlcCer decreased as lactation advanced, and ceramide and GlcCer were elevated in cows fed PALM. Palmitic acid feeding increased hepatic ceramide levels, a response not observed in skeletal muscle tissue. Plasma ceramides (e.g., C24:0-ceramide) were positively correlated with plasma NEFA and milk yield, and positively correlated with NEFA levels following a glucose challenge. Our data demonstrate a remodeled plasma and hepatic sphingolipidome in mid-lactation dairy cows fed PALM. The potential involvement in ceramide in homeorhetic nutrient partitioning to support lactation requires further consideration. 10.3168/jds.2016-11296
    Insulin Resistance, Obesity and Lipotoxicity. Yazıcı Dilek,Sezer Havva Advances in experimental medicine and biology Lipotoxicity , originally used to describe the destructive effects of excess fat accumulation on glucose metabolism, causes functional impairments in several metabolic pathways, both in adipose tissue and peripheral organs, like liver, heart, pancreas and muscle. Lipotoxicity has roles in insulin resistance and pancreatic beta cell dysfunction. Increased circulating levels of lipids and the metabolic alterations in fatty acid utilization and intracellular signaling, have been related to insulin resistance in muscle and liver. Different pathways, like novel protein kinase c pathways and the JNK-1 pathway are involved as the mechanisms of how lipotoxicity leads to insulin resistance in nonadipose tissue organs, such as liver and muscle. Mitochondrial dysfunction plays a role in the pathogenesis of insulin resistance. Endoplasmic reticulum stress, through mainly increased oxidative stress, also plays important role in the etiology of insulin resistance, especially seen in non-alcoholic fatty liver disease. Visceral adiposity and insulin resistance both increase the cardiometabolic risk and lipotoxicity seems to play a crucial role in the pathophysiology of these associations. 10.1007/978-3-319-48382-5_12
    Exposure to environmental contaminants is associated with altered hepatic lipid metabolism in non-alcoholic fatty liver disease. Sen Partho,Qadri Sami,Luukkonen Panu K,Ragnarsdottir Oddny,McGlinchey Aidan,Jäntti Sirkku,Juuti Anne,Arola Johanna,Schlezinger Jennifer J,Webster Thomas F,Orešič Matej,Yki-Järvinen Hannele,Hyötyläinen Tuulia Journal of hepatology BACKGROUND & AIMS:Recent experimental models and epidemiological studies suggest that specific environmental contaminants (ECs) contribute to the initiation and pathology of non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanisms linking EC exposure with NAFLD remain poorly understood and there is no data on their impact on the human liver metabolome. Herein, we hypothesized that exposure to ECs, particularly perfluorinated alkyl substances (PFAS), impacts liver metabolism, specifically bile acid metabolism. METHODS:In a well-characterized human NAFLD cohort of 105 individuals, we investigated the effects of EC exposure on liver metabolism. We characterized the liver (via biopsy) and circulating metabolomes using 4 mass spectrometry-based analytical platforms, and measured PFAS and other ECs in serum. We subsequently compared these results with an exposure study in a PPARa-humanized mouse model. RESULTS:PFAS exposure appears associated with perturbation of key hepatic metabolic pathways previously found altered in NAFLD, particularly those related to bile acid and lipid metabolism. We identified stronger associations between the liver metabolome, chemical exposure and NAFLD-associated clinical variables (liver fat content, HOMA-IR), in females than males. Specifically, we observed PFAS-associated upregulation of bile acids, triacylglycerols and ceramides, and association between chemical exposure and dysregulated glucose metabolism in females. The murine exposure study further corroborated our findings, vis-à-vis a sex-specific association between PFAS exposure and NAFLD-associated lipid changes. CONCLUSIONS:Females may be more sensitive to the harmful impacts of PFAS. Lipid-related changes subsequent to PFAS exposure may be secondary to the interplay between PFAS and bile acid metabolism. LAY SUMMARY:There is increasing evidence that specific environmental contaminants, such as perfluorinated alkyl substances (PFAS), contribute to the progression of non-alcoholic fatty liver disease (NAFLD). However, it is poorly understood how these chemicals impact human liver metabolism. Here we show that human exposure to PFAS impacts metabolic processes associated with NAFLD, and that the effect is different in females and males. 10.1016/j.jhep.2021.09.039
    Ceramide metabolism mediates the impaired glucose homeostasis following short-term black carbon exposure: A targeted lipidomic analysis. The Science of the total environment BACKGROUND:Ambient particulate matter (PM), especially its carbonaceous composition black carbon (BC) increases cardiometabolic risks, yet the underlying mechanisms are incompletely understood. Ceramides (Cer; a class of sphingolipids) are biological intermediates in glucose metabolism. OBJECTIVES:To explore whether Cer metabolism mediates impaired glucose homeostasis following short-term PM exposure. METHODS:In a panel study in Beijing, China, 112 participants were followed-up between 2016 and 2017. Targeted lipidomic analyses quantified 26 sphingolipids in 387 plasma samples. Ambient BC and PM with aerodynamic diameter ≤ 2.5 μm (PM) were continuously monitored in a station. We examined the associations of sphingolipid levels with average BC and PM concentrations 1-14 days before clinical visits using linear mixed-effects models, and explored the mediation effects of sphingolipids on PM-associated fasting blood glucose (FBG) difference using mediation analyses. RESULTS:Increased levels of FBG and multiple sphingolipids in Cer metabolic pathways were associated with BC exposure in 1-14-day time window, but not with PM exposure. For each 10 μg/m increase in the average BC concentration 1-14 days before the clinical visits, species in the Cer C24:1 pathway (Cer, dihydroceramide, hexosylceramide, lactosylceramide, and sphingomyelin C24:1) increased in levels ranging from 11.8% (95% confidence interval [CI]: -6.2-33.2) to 48.7% (95% CI: 8.8-103.4), as did the Cer C16:0, C18:0, and C20:0 metabolic pathway species, ranging from 3.2% (95% CI: -5.6-12.9) to 32.4% (95% CI: 7.0-63.8), respectively. The Cer C24:1 metabolic pathway species mediated 6.5-25.5% of the FBG increase associated with BC exposure in 9-day time window. The Cer C16:0, C18:0, and C20:0 metabolic pathway species mediated 5.4-26.2% of the BC-associated FBG difference. CONCLUSIONS:In conclusion, Cer metabolism may mediate impaired glucose homeostasis following short-term BC exposure. The current findings are preliminary, which need to be corroborated by further studies. 10.1016/j.scitotenv.2022.154657