scholarly journals Response of Liver Metabolome to Dietary Folic Acid Alterations in WT and CerS6 Knockout Mice (P08-095-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Keri Barron ◽  
Natalia Krupenko
Keyword(s):  
Folic Acid ◽  
Fat Mass ◽  
Dietary Intervention ◽  
Acyl Chain ◽  
Principal Component ◽  
Lipid Classes ◽  
Whole Body ◽  
Ceramide Synthase ◽  
Wild Type ◽  
Whole Body Metabolism

Abstract Objectives To characterize metabolomic adjustments in response to alterations of dietary folate in the livers of wild type and Ceramide Synthase 6 (CerS6) deficient mice. Methods Ten-week-old CerS6 KO mice and wild-type controls were fed diets containing 0, 2, or 12 ppm of folic acid (FA) for 4 weeks. At the end of the dietary intervention, livers were snap-frozen in liquid nitrogen and tissue samples were subjected to untargeted metabolomics analysis by Metabolon®. Results Of the 736 measured compounds, 550 biochemicals were significantly different between male and female mice, while 273 metabolites differed by genotype (WT vs CerS6 KO) and 298 by diet (0, 2, or 12 ppm FA). Principal component analysis revealed distinct sex- and genotype-based separations and some diet-based separation. As expected, KO livers exhibited decreased levels of most ceramide-based sphingolipids with C14- or C16-acyl chains (ceramide, sphingomyelin, glycosyl- and lactosyl- ceramides) and elevated levels of longer acyl-chain sphingolipids. Importantly, genotype-based differences were also observed for other lipid classes, such as phosphatidylethanolamines, free fatty acids, and diacylglycerols, indicating global perturbations of lipid metabolism. Specifically, hepatic phosphatidylethanolamine levels were significantly higher in CerS6 KO mice. These KO mice also gained less weight and accumulated less fat mass over the course of this study, indicating significant changes in whole body metabolism and energetics. Additionally, significant alterations in energy producing pathways (glycolytic and TCA cycle intermediates), as well as acyl-choline and kynurenine pathways were found in CerS6 KO mice. Conclusions CerS6 is essential in maintaining the proper balance of several lipid classes and plays an important role in liver homeostasis under conditions of varying dietary folic acid intake. Our data also suggest that re-distribution of major lipid classes may contribute to the prevention of weight gain and fat mass increase in CerS6 KO mice. Funding Sources R01 CA193782-01.

scholarly journals Ceramide Synthase 6 Knockout Reprograms Energy Metabolism in Mice

2021 ◽  
Vol 5 (Supplement_2) ◽  
pp. 488-488
Author(s):  
Keri Barron ◽  
Natalia Krupenko
Keyword(s):  
Dietary Intervention ◽  
Metabolic Effects ◽  
Whole Body ◽  
Caloric Content ◽  
Significant Shift ◽  
Light Cycle ◽  
Ceramide Synthase ◽  
Bioactive Lipids ◽  
High Fat ◽  
Whole Body Metabolism

Abstract Objectives Ceramides, a group of bioactive lipids and important signaling molecules, have been implicated in the development of cardiometabolic disease, diabetes, and cancer. Recent studies have shown that targeting Ceramide Synthases (CerS), the enzymes producing ceramides, protected from glucose intolerance and diet induced obesity. We investigated metabolomic responses to high fat diet consumption in livers and plasma of wild type (WT) and CerS6 knockout (KO) mice to obtain mechanistic understanding of the protection provided by the enzyme knockout. Methods Upon weaning, male WT and CerS6 KO mice were placed on a high fat (HFD) or control (Ctrl) diet for 16 weeks. After 14 weeks on diet, mice were placed in calorimetry cages for 48 hours. Body composition was assessed before dietary intervention and before necropsy. Plasma and snap-frozen liver samples were subjected to untargeted metabolomic analysis at Metabolon®. Results CerS6 KO mice gained significantly less weight on HFD than WT mice. Calorimetry measurements revealed that over 24 hours CerS6 KO mice did not move more than WT in either x-, y- or z-planes. Interestingly, CerS6 KO mice on a HFD consumed significantly less food, and despite the higher caloric content of the diet, they also consumed fewer calories over the 24 hour period. No differences in fat excretion between WT and CerS6 KO mice were found, measured by fecal lipid content. Calorimetry data demonstrated that on HFD, regardless of genotype, animals oxidized fat for energy. On the Ctrl diet WT mice burned a mix of substrates while CerS6 KO mice preferentially oxidized glucose for energy during the light cycle. This indicates that during the active phase of the light cycle a switch in energy source occurred in KO but not WT mice. Untargeted metabolomics revealed significant differences in intermediates of glycolysis both in liver and plasma of the KO vs WT animals. Moreover, significant increases in multiple TCA cycle metabolites in KO vs WT plasma were seen in HFD fed mice. Conclusions We found a significant shift in tissue-level and whole-body energetics in CerS6 KO mice. This shift could be responsible for the beneficial metabolic effects of targeting CerS6 when HFD is consumed. Further studies will help determine how CerS6 and ceramides influence tissue and whole body metabolism. Funding Sources This work was funded by R01 CA193782 grant to NK.

Thermoneutral housing does not influence fat mass or glucose homeostasis in C57BL/6 mice

2018 ◽  
Vol 239 (3) ◽  
pp. 313-324 ◽  
Author(s):  
Lewin Small ◽  
Henry Gong ◽  
Christian Yassmin ◽  
Gregory J Cooney ◽  
Amanda E Brandon
Keyword(s):  
Glucose Metabolism ◽  
Ambient Temperature ◽  
Fat Mass ◽  
Glucose Homeostasis ◽  
Dietary Intervention ◽  
Whole Body ◽  
Housing Temperature ◽  
Brown Adipose ◽  
Normal Chow ◽  
Obesogenic Diet

One major factor affecting physiology often overlooked when comparing data from animal models and humans is the effect of ambient temperature. The majority of rodent housing is maintained at ~22°C, the thermoneutral temperature for lightly clothed humans. However, mice have a much higher thermoneutral temperature of ~30°C, consequently data collected at 22°C in mice could be influenced by animals being exposed to a chronic cold stress. The aim of this study was to investigate the effect of housing temperature on glucose homeostasis and energy metabolism of mice fed normal chow or a high-fat, obesogenic diet (HFD). Male C57BL/6J(Arc) mice were housed at standard temperature (22°C) or at thermoneutrality (29°C) and fed either chow or a 60% HFD for 13 weeks. The HFD increased fat mass and produced glucose intolerance as expected but this was not exacerbated in mice housed at thermoneutrality. Changing the ambient temperature, however, did alter energy expenditure, food intake, lipid content and glucose metabolism in skeletal muscle, liver and brown adipose tissue. Collectively, these findings demonstrate that mice regulate energy balance at different housing temperatures to maintain whole-body glucose tolerance and adiposity irrespective of the diet. Despite this, metabolic differences in individual tissues were apparent. In conclusion, dietary intervention in mice has a greater impact on adiposity and glucose metabolism than housing temperature although temperature is still a significant factor in regulating metabolic parameters in individual tissues.

scholarly journals Effects of supplements of folic acid, vitamin B12, and rumen-protected methionine on whole body metabolism of methionine and glucose in lactating dairy cows

2009 ◽  
Vol 92 (2) ◽  
pp. 677-689 ◽  
Author(s):  
A. Preynat ◽  
H. Lapierre ◽  
M.C. Thivierge ◽  
M.F. Palin ◽  
J.J. Matte ◽  
...  
Keyword(s):  
Folic Acid ◽  
Vitamin B12 ◽  
Dairy Cows ◽  
Whole Body ◽  
Lactating Dairy Cows ◽  
Whole Body Metabolism

scholarly journals Dietary Cocoa Flavanols Enhance Mitochondrial Function in Skeletal Muscle and Modify Whole-Body Metabolism in Healthy Mice

Nutrients ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 3466
Author(s):  
Frédéric Nicolas Daussin ◽  
Alexane Cuillerier ◽  
Julianne Touron ◽  
Samir Ben Said ◽  
Bruno Melo ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Mitochondrial Function ◽  
Tolerance Test ◽  
Whole Body ◽  
Oral Glucose ◽  
H2o2 Production ◽  
Wild Type ◽  
Nad Metabolism ◽  
Whole Body Metabolism ◽  
Cocoa Flavanols

Mitochondrial dysfunction is widely reported in various diseases and contributes to their pathogenesis. We assessed the effect of cocoa flavanols supplementation on mitochondrial function and whole metabolism, and we explored whether the mitochondrial deacetylase sirtuin-3 (Sirt3) is involved or not. We explored the effects of 15 days of CF supplementation in wild type and Sirt3-/- mice. Whole-body metabolism was assessed by indirect calorimetry, and an oral glucose tolerance test was performed to assess glucose metabolism. Mitochondrial respiratory function was assessed in permeabilised fibres and the pyridine nucleotides content (NAD+ and NADH) were quantified. In the wild type, CF supplementation significantly modified whole-body metabolism by promoting carbohydrate use and improved glucose tolerance. CF supplementation induced a significant increase of mitochondrial mass, while significant qualitative adaptation occurred to maintain H2O2 production and cellular oxidative stress. CF supplementation induced a significant increase in NAD+ and NADH content. All the effects mentioned above were blunted in Sirt3-/- mice. Collectively, CF supplementation boosted the NAD metabolism that stimulates sirtuins metabolism and improved mitochondrial function, which likely contributed to the observed whole-body metabolism adaptation, with a greater ability to use carbohydrates, at least partially through Sirt3.

scholarly journals Accelerated developmental adipogenesis programs adipose tissue dysfunction and cardiometabolic risk in offspring born to dams with metabolic dysfunction

2021 ◽  
Author(s):  
Anna Mikolajczak ◽  
Nada A Sallam ◽  
Radha D Singh ◽  
Taylor B Scheidl ◽  
Emma J. Walsh ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Fat Mass ◽  
Cardiometabolic Risk ◽  
Late Gestation ◽  
Whole Body ◽  
Distribution Analysis ◽  
Metabolic Dysfunction ◽  
Wild Type ◽  
Cell Size Distribution ◽  
Differentiation Potential

This study determined if a perturbation in in utero adipogenesis leading to later-life adipose tissue (AT) dysfunction underlies programming of cardiometabolic risk in offspring born to dams with metabolic dysfunction. Female mice heterozygous for the leptin receptor deficiency (Hetdb) had 2.4-fold higher pre-pregnancy fat mass and in late gestation had higher plasma insulin and triglycerides, compared to wild-type (Wt) females (p < 0.05). To isolate the role of the intrauterine milieu, wild-type (Wt) offspring from each pregnancy were studied. Differentiation potential in isolated progenitors and cell size distribution analysis revealed accelerated adipogenesis in Wt pups born to Hetdb dams, accompanied by a higher accumulation of neonatal fat mass. In adulthood, whole-body fat mass by NMR was higher in male (69%) and female (20%) Wt offspring born to Hetdb vs. Wt pregnancies, along with adipocyte hypertrophy and hyperlipidemia (all p < 0.05). Lipidomic analyses by gas chromatography revealed an increased lipogenic index (16:0/18:2n6) after high fat/fructose diet (HFFD). Postprandial insulin, ADIPO-IR and ex vivo AT lipolytic responses to isoproterenol, were all higher in Wt offspring born to Hetdb dams (p < 0.05). Intrauterine metabolic stimuli may direct a greater proportion of progenitors toward terminal differentiation, thereby predisposing to hypertrophy-induced adipocyte dysfunction.

scholarly journals MicroRNA-27a/b-3p and PPARG regulate SCAMP3 through a feed- forward loop during adipogenesis

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Agné Kulyté ◽  
Kelvin Ho Man Kwok ◽  
Michiel de Hoon ◽  
Piero Carninci ◽  
Yoshihide Hayashizaki ◽  
...  
Keyword(s):  
Fat Mass ◽  
Late Phase ◽  
Whole Body ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Peroxisome Proliferator Activated Receptor ◽  
Feed Forward ◽  
Feed Forward Loop ◽  
Whole Body Metabolism ◽  
Pparg Expression

Abstract MicroRNAs (miRNA) modulate gene expression through feed-back and forward loops. Previous studies identified miRNAs that regulate transcription factors, including Peroxisome Proliferator Activated Receptor Gamma (PPARG), in adipocytes, but whether they influence adipogenesis via such regulatory loops remain elusive. Here we predicted and validated a novel feed-forward loop regulating adipogenesis and involved miR-27a/b-3p, PPARG and Secretory Carrier Membrane Protein 3 (SCAMP3). In this loop, expression of both PPARG and SCAMP3 was independently suppressed by miR-27a/b-3p overexpression. Knockdown of PPARG downregulated SCAMP3 expression at the late phase of adipogenesis, whereas reduction of SCAMP3 mRNA levels increased PPARG expression at early phase in differentiation. The latter was accompanied with upregulation of adipocyte-enriched genes, including ADIPOQ and FABP4, suggesting an anti-adipogenic role for SCAMP3. PPARG and SCAMP3 exhibited opposite behaviors regarding correlations with clinical phenotypes, including body mass index, body fat mass, adipocyte size, lipolytic and lipogenic capacity, and secretion of pro-inflammatory cytokines. While adipose PPARG expression was associated with more favorable metabolic phenotypes, SCAMP3 expression was linked to increased fat mass and insulin resistance. Together, we identified a feed-forward loop through which miR-27a/b-3p, PPARG and SCAMP3 cooperatively fine tune the regulation of adipogenesis, which potentially may impact whole body metabolism.

scholarly journals Gremlin1 plays a key role in kidney development and renal fibrosis

2017 ◽  
Vol 312 (6) ◽  
pp. F1141-F1157 ◽  
Author(s):  
Rachel H. Church ◽  
Imran Ali ◽  
Mitchel Tate ◽  
Deborah Lavin ◽  
Arjun Krishnakumar ◽  
...  
Keyword(s):  
Folic Acid ◽  
Limb Development ◽  
Renal Fibrosis ◽  
Kidney Development ◽  
Left Kidney ◽  
Acute Injury ◽  
Whole Body ◽  
Normal Lung ◽  
Wild Type

Gremlin1 (Grem1), an antagonist of bone morphogenetic proteins, plays a key role in embryogenesis. A highly specific temporospatial gradient of Grem1 and bone morphogenetic protein signaling is critical to normal lung, kidney, and limb development. Grem1 levels are increased in renal fibrotic conditions, including acute kidney injury, diabetic nephropathy, chronic allograft nephropathy, and immune glomerulonephritis. We demonstrate that a small number of grem1−/− whole body knockout mice on a mixed genetic background (8%) are viable, with a single, enlarged left kidney and grossly normal histology. The grem1−/− mice displayed mild renal dysfunction at 4 wk, which recovered by 16 wk. Tubular epithelial cell-specific targeted deletion of Grem1 ( TEC-grem1-cKO) mice displayed a milder response in the acute injury and recovery phases of the folic acid model. Increases in indexes of kidney damage were smaller in TEC-grem1-cKO than wild-type mice. In the recovery phase of the folic acid model, associated with renal fibrosis, TEC-grem1-cKO mice displayed reduced histological damage and an attenuated fibrotic gene response compared with wild-type controls. Together, these data demonstrate that Grem1 expression in the tubular epithelial compartment plays a significant role in the fibrotic response to renal injury in vivo.

Adipokines as key players in β cell function and failure

2019 ◽  
Vol 133 (22) ◽  
pp. 2317-2327 ◽  
Author(s):  
Nicolás Gómez-Banoy ◽  
James C. Lo
Keyword(s):  
Metabolic Diseases ◽  
Cell Function ◽  
Whole Body ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Cell Axis ◽  
Β Cell Function ◽  
Prevalence Of Obesity ◽  
Specific Factors ◽  
Whole Body Metabolism

Abstract The growing prevalence of obesity and its related metabolic diseases, mainly Type 2 diabetes (T2D), has increased the interest in adipose tissue (AT) and its role as a principal metabolic orchestrator. Two decades of research have now shown that ATs act as an endocrine organ, secreting soluble factors termed adipocytokines or adipokines. These adipokines play crucial roles in whole-body metabolism with different mechanisms of action largely dependent on the tissue or cell type they are acting on. The pancreatic β cell, a key regulator of glucose metabolism due to its ability to produce and secrete insulin, has been identified as a target for several adipokines. This review will focus on how adipokines affect pancreatic β cell function and their impact on pancreatic β cell survival in disease contexts such as diabetes. Initially, the “classic” adipokines will be discussed, followed by novel secreted adipocyte-specific factors that show therapeutic promise in regulating the adipose–pancreatic β cell axis.

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