Lipid Metabolism Is Dysregulated before, during and after Pregnancy in a Mouse Model of Gestational Diabetes

The aim of the current study was to test the hypothesis that maternal lipid metabolism was modulated during normal pregnancy and that these modulations are altered in gestational diabetes mellitus (GDM). We tested this hypothesis using an established mouse model of diet-induced obesity with pregnancy-associated loss of glucose tolerance and a novel lipid analysis tool, Lipid Traffic Analysis, that uses the temporal distribution of lipids to identify differences in the control of lipid metabolism through a time course. Our results suggest that the start of pregnancy is associated with several changes in lipid metabolism, including fewer variables associated with de novo lipogenesis and fewer PUFA-containing lipids in the circulation. Several of the changes in lipid metabolism in healthy pregnancies were less apparent or occurred later in dams who developed GDM. Some changes in maternal lipid metabolism in the obese-GDM group were so late as to only occur as the control dams’ systems began to switch back towards the non-pregnant state. These results demonstrate that lipid metabolism is modulated in healthy pregnancy and the timing of these changes is altered in GDM pregnancies. These findings raise important questions about how lipid metabolism contributes to changes in metabolism during healthy pregnancies. Furthermore, as alterations in the lipidome are present before the loss of glucose tolerance, they could contribute to the development of GDM mechanistically.

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A nutrient cocktail prevents lipid metabolism alterations induced by 20 days of daily steps reduction and fructose overfeeding: result from a randomized study

Journal of Applied Physiology ◽

10.1152/japplphysiol.00018.2018 ◽

2019 ◽

Vol 126 (1) ◽

pp. 88-101 ◽

Cited By ~ 2

Author(s):

Anthony Damiot ◽

Rémi Demangel ◽

John Noone ◽

Isabelle Chery ◽

Alexandre Zahariev ◽

...

Keyword(s):

Lipid Metabolism ◽

Insulin Sensitivity ◽

Glucose Tolerance ◽

Physical Inactivity ◽

De Novo ◽

Fat Oxidation ◽

De Novo Lipogenesis ◽

Sedentary Behaviors ◽

Protein Ubiquitination ◽

Total Fat

Physical inactivity and sedentary behaviors are independent risk factors for numerous diseases. We examined the ability of a nutrient cocktail composed of polyphenols, omega-3 fatty acids, vitamin E, and selenium to prevent the expected metabolic alterations induced by physical inactivity and sedentary behaviors. Healthy trained men ( n = 20) (averaging ∼14,000 steps/day and engaged in sports) were randomly divided into a control group (no supplementation) and a cocktail group for a 20-day free-living intervention during which they stopped exercise and decreased their daily steps (averaging ∼3,000 steps/day). During the last 10 days, metabolic changes were further triggered by fructose overfeeding. On days 0, 10, and 20, body composition (dual energy X-ray), blood chemistry, glucose tolerance [oral glucose tolerance test (OGTT)], and substrate oxidation (indirect calorimetry) were measured. OGTT included 1% fructose labeled with (U-13C) fructose to assess liver de novo lipogenesis. Histological changes and related cellular markers were assessed from muscle biopsies collected on days 0 and 20. While the cocktail did not prevent the decrease in insulin sensitivity and its muscular correlates induced by the intervention, it fully prevented the hypertriglyceridemia, the drop in fasting HDL and total fat oxidation, and the increase in de novo lipogenesis. The cocktail further prevented the decrease in the type-IIa muscle fiber cross-sectional area and was associated with lower protein ubiquitination content. The circulating antioxidant capacity was improved by the cocktail following the OGTT. In conclusion, a cocktail of nutrient compounds from dietary origin protects against the alterations in lipid metabolism induced by physical inactivity and fructose overfeeding. NEW & NOTEWORTHY This is the first study to test the efficacy of a novel dietary nutrient cocktail on the metabolic and physiological changes occurring during 20 days of physical inactivity along with fructose overfeeding. The main findings of this study are that 1) reduction in daily steps leads to decreased insulin sensitivity and total fat oxidation, resulting in hyperlipemia and increased de novo lipogenesis and 2) a cocktail supplement prevents the alterations on lipid metabolism.

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Carrot Supplementation Improves Blood Pressure and Reduces Aortic Root Lesions in an Atherosclerosis-Prone Genetic Mouse Model

Nutrients ◽

10.3390/nu13041181 ◽

2021 ◽

Vol 13 (4) ◽

pp. 1181

Author(s):

Raffaella Soleti ◽

Marine Coué ◽

Charlotte Trenteseaux ◽

Gregory Hilairet ◽

Lionel Fizanne ◽

...

Keyword(s):

Blood Pressure ◽

Mouse Model ◽

Aortic Root ◽

De Novo ◽

Body Weight Gain ◽

Density Lipoprotein ◽

De Novo Lipogenesis ◽

Hemodynamic Parameters ◽

Cellular Models ◽

Genetic Mouse Model

Epidemiological studies have shown that carrot consumption may be associated with a lower risk of developing several metabolic dysfunctions. Our group previously determined that the Bolero (Bo) carrot variety exhibited vascular and hepatic tropism using cellular models of cardiometabolic diseases. The present study evaluated the potential metabolic and cardiovascular protective effect of Bo, grown under two conditions (standard and biotic stress conditions (BoBS)), in apolipoprotein E-knockout (ApoE−/−) mice fed with high fat diet (HFD). Effects on metabolic/hemodynamic parameters and on atherosclerotic lesions have been assessed. Both Bo and BoBS decreased plasma triglyceride and expression levels of genes implicated in hepatic de novo lipogenesis and lipid oxidation. BoBS supplementation decreased body weight gain, secretion of very-low-density lipoprotein, and increased cecal propionate content. Interestingly, Bo and BoBS supplementation improved hemodynamic parameters by decreasing systolic, diastolic, and mean blood pressure. Moreover, Bo improved cardiac output. Finally, Bo and BoBS substantially reduced the aortic root lesion area. These results showed that Bo and BoBS enriched diets corrected most of the metabolic and cardiovascular disorders in an atherosclerosis-prone genetic mouse model and may therefore represent an interesting nutritional approach for the prevention of cardiovascular diseases.

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Glial Hedgehog and lipid metabolism regulate neural stem cell proliferation in Drosophila

10.1101/2020.05.18.100990 ◽

2020 ◽

Author(s):

Qian Dong ◽

Michael Zavortink ◽

Francesca Froldi ◽

Sofya Golenkina ◽

Tammy Lam ◽

...

Keyword(s):

Lipid Metabolism ◽

Cell Cycle Progression ◽

De Novo ◽

De Novo Lipogenesis ◽

Post Translational Modification ◽

Final Size ◽

Neural Lineage ◽

Signalling Molecule ◽

Lipid Metabolism Genes ◽

And Function

AbstractThe final size and function of the adult central nervous system (CNS) is determined by neuronal lineages generated by neural stem cells (NSCs) in the developing brain. In Drosophila, NSCs called neuroblasts (NBs) reside within a specialised microenvironment called the glial niche. Here, we explore non-autonomous glial regulation of NB proliferation. We show that lipid droplets (LDs) which reside within the glial niche are closely associated with the signalling molecule Hedgehog (Hh). Under physiological conditions, cortex glial Hh is autonomously required to sustain niche chamber formation, and non-autonomously restrained to prevent ectopic Hh signalling in the NBs. In the context of cortex glial overgrowth, induced by Fibroblast Growth Factor (FGF) activation, Hh and lipid storage regulators Lsd-2 and Fasn1 were upregulated, resulting in activation of Hh signalling in the NBs; which in turn disrupted NB cell cycle progression and reduced neuronal production. We show that the LD regulator Lsd-2 modulates Hh’s ability to signal to NBs, and de novo lipogenesis gene Fasn1 regulates Hh post-translational modification via palmitoylation. Together, our data suggest that the glial niche non-autonomously regulates NB proliferation and neural lineage size via Hh signaling that is modulated by lipid metabolism genes.

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AMPK Activation Reduces Hepatic Lipid Content by Increasing Fat Oxidation In Vivo

International Journal of Molecular Sciences ◽

10.3390/ijms19092826 ◽

2018 ◽

Vol 19 (9) ◽

pp. 2826 ◽

Cited By ~ 21

Author(s):

Marc Foretz ◽

Patrick Even ◽

Benoit Viollet

Keyword(s):

Lipid Metabolism ◽

De Novo ◽

Fat Oxidation ◽

De Novo Lipogenesis ◽

Acid Oxidation ◽

Ampk Activation ◽

Hepatic Lipid ◽

Adenoviral Delivery ◽

Body Production

The energy sensor AMP-activated protein kinase (AMPK) is a key player in the control of energy metabolism. AMPK regulates hepatic lipid metabolism through the phosphorylation of its well-recognized downstream target acetyl CoA carboxylase (ACC). Although AMPK activation is proposed to lower hepatic triglyceride (TG) content via the inhibition of ACC to cause inhibition of de novo lipogenesis and stimulation of fatty acid oxidation (FAO), its contribution to the inhibition of FAO in vivo has been recently questioned. We generated a mouse model of AMPK activation specifically in the liver, achieved by expression of a constitutively active AMPK using adenoviral delivery. Indirect calorimetry studies revealed that liver-specific AMPK activation is sufficient to induce a reduction in the respiratory exchange ratio and an increase in FAO rates in vivo. This led to a more rapid metabolic switch from carbohydrate to lipid oxidation during the transition from fed to fasting. Finally, mice with chronic AMPK activation in the liver display high fat oxidation capacity evidenced by increased [C14]-palmitate oxidation and ketone body production leading to reduced hepatic TG content and body adiposity. Our findings suggest a role for hepatic AMPK in the remodeling of lipid metabolism between the liver and adipose tissue.

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Hepatic Transcriptomics Reveals that Lipogenesis Is a Key Signaling Pathway in Isocitrate Dehydrogenase 2 Deficient Mice

Genes ◽

10.3390/genes10090728 ◽

2019 ◽

Vol 10 (9) ◽

pp. 728

Author(s):

Jeong Hoon Pan ◽

Jingsi Tang ◽

Mersady C. Redding ◽

Kaleigh E. Beane ◽

Cara L. Conner ◽

...

Keyword(s):

Lipid Metabolism ◽

Isocitrate Dehydrogenase ◽

De Novo ◽

Nicotinamide Adenine Dinucleotide Phosphate ◽

Tca Cycle ◽

De Novo Lipogenesis ◽

Oxidative Decarboxylation ◽

Qpcr Analysis ◽

Isocitrate Dehydrogenase 2 ◽

Mice Liver

Mitochondrial nicotinamide adenine dinucleotide phosphate (NADP+)-dependent isocitrate dehydrogenase (IDH2) plays a key role in the intermediary metabolism and energy production via catalysing oxidative decarboxylation of isocitrate to α-ketoglutarate in the tricarboxylic acid (TCA) cycle. Despite studies reporting potential interlinks between IDH2 and various diseases, there is lack of effort to comprehensively characterize signature(s) of IDH2 knockout (IDH2 KO) mice. A total of 6583 transcripts were identified from both wild-type (WT) and IDH2 KO mice liver tissues. Afterwards, 167 differentially expressed genes in the IDH2 KO group were short-listed compared to the WT group based on our criteria. The online bioinformatic analyses indicated that lipid metabolism is the most significantly influenced metabolic process in IDH2 KO mice. Moreover, the TR/RXR activation pathway was predicted as the top canonical pathway significantly affected by IDH2 KO. The key transcripts found in the bioinformatic analyses were validated by qPCR analysis, corresponding to the transcriptomics results. Further, an additional qPCR analysis confirmed that IDH2 KO caused a decrease in hepatic de novo lipogenesis via the activation of the fatty acid β-oxidation process. Our unbiased transcriptomics approach and validation experiments suggested that IDH2 might play a key role in homeostasis of lipid metabolism.

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DHT Causes Liver Steatosis via Transcriptional Regulation of SCAP in Lean female Mice

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.1642 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A807-A807

Author(s):

Stanley Andrisse ◽

Jessie Myer ◽

Dilip “Bobby” Bogle ◽

Nicole Eregha ◽

Taylor Lofton

Keyword(s):

Lipid Metabolism ◽

Protein Expression ◽

Low Dose ◽

De Novo ◽

Polycystic Ovary ◽

Liver Steatosis ◽

De Novo Lipogenesis ◽

Alcoholic Fatty Liver ◽

Female Mice ◽

Real Time Quantitative Pcr

Abstract Hyperandrogenemia (HA) and insulin resistance are hallmarks of polycystic ovary syndrome (PCOS). These hallmarks are also integral elements of non-alcoholic fatty liver disease (NALFD). Administering low dose dihydrotestosterone (DHT) induced a lean PCOS-like female mouse model. The molecular mechanism of HA-induced NAFLD has not been determined. We hypothesized that low dose DHT would interrupt hepatic lipid metabolism leading to NAFLD. We extracted white adipose tissue (WAT), liver, and skeletal muscle from control and low dose DHT female mice; and performed histological and biochemical lipid profiles, Western blot, immunoprecipitation, chromatin immunoprecipitation, and real-time quantitative PCR analyses. DHT lowered the 65 kD form of cytosolic SREBP1 in the liver and WAT compared to controls. However, DHT did not alter the levels of the active and inactive forms of SREBP2 in the liver and WAT. DHT increased SCAP protein expression and SCAP-SREBP1 binding via AR binding to intron-8 of SCAP leading to increased SCAP mRNA. FAS mRNA and protein expression was increased in liver of DHT mice. p-ACC levels were unaltered in liver but decreased in WAT. Other lipid metabolism pathways were examined in liver and WAT, but no changes were observed. Our findings suggest that DHT increased de novo lipogenic proteins resulting in increased NAFLD via regulation of SREBP1 in liver. We show that in the presence of DHT the SCAP-SREBP1 interaction is elevated leading to increased nuclear SREBP1 resulting in increased de novo lipogenesis. We propose that the mechanism of action is increased AR binding to an ARE in SCAP intron-8.

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Real-World Gestational Diabetes Screening: Problems with the Oral Glucose Tolerance Test in Rural and Remote Australia

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph16224488 ◽

2019 ◽

Vol 16 (22) ◽

pp. 4488 ◽

Cited By ~ 8

Author(s):

Emma L. Jamieson ◽

Erica P. Spry ◽

Andrew B. Kirke ◽

David N. Atkinson ◽

Julia V. Marley

Keyword(s):

Gestational Diabetes ◽

Glucose Tolerance ◽

Oral Glucose Tolerance Test ◽

Time Course ◽

Glucose Tolerance Test ◽

Tolerance Test ◽

Oral Glucose ◽

Oral Glucose Tolerance ◽

Rural And Remote ◽

Glucose Levels

Gestational diabetes mellitus (GDM) is the most common antenatal complication in Australia. All pregnant women are recommended for screening by 75 g oral glucose tolerance test (OGTT). As part of a study to improve screening, 694 women from 27 regional, rural and remote clinics were recruited from 2015–2018 into the Optimisation of Rural Clinical and Haematological Indicators for Diabetes in pregnancy (ORCHID) study. Most routine OGTT samples were analysed more than four hours post fasting collection (median 5.0 h, range 2.3 to 124 h), potentially reducing glucose levels due to glycolysis. In 2019, to assess pre-analytical plasma glucose (PG) instability over time, we evaluated alternative sample handling protocols in a sample of participants. Four extra samples were collected alongside routine room temperature (RT) fluoride-oxalate samples (FLOXRT): study FLOXRT; ice slurry (FLOXICE); RT fluoride-citrate-EDTA (FC Mix), and RT lithium-heparin plasma separation tubes (PST). Time course glucose measurements were then used to estimate glycolysis from ORCHID participants who completed routine OGTT after 24 weeks gestation (n = 501). Adjusting for glycolysis using FLOXICE measurements estimated 62% under-diagnosis of GDM (FLOXRT 10.8% v FLOXICE 28.5% (95% CI, 20.8–29.5%), p < 0.001). FC Mix tubes provided excellent glucose stability but gave slightly higher results (Fasting PG: +0.20 ± 0.05 mmol/L). While providing a realistic alternative to the impractical FLOXICE protocol, direct substitution of FC Mix tubes in clinical practice may require revision of GDM diagnostic thresholds.

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Central Resistin Regulates Hypothalamic and Peripheral Lipid Metabolism in a Nutritional-Dependent Fashion

Endocrinology ◽

10.1210/en.2007-1708 ◽

2008 ◽

Vol 149 (9) ◽

pp. 4534-4543 ◽

Cited By ~ 72

Author(s):

María J. Vázquez ◽

C. Ruth González ◽

Luis Varela ◽

Ricardo Lage ◽

Sulay Tovar ◽

...

Keyword(s):

Fatty Acid ◽

Lipid Metabolism ◽

Mrna Expression ◽

Fatty Acid Synthase ◽

De Novo ◽

Acid Synthesis ◽

Inhibitory Effect ◽

De Novo Lipogenesis ◽

Dependent Manner ◽

Fed State

Evidence suggests that the adipocyte-derived hormone resistin (RSTN) directly regulates both feeding and peripheral metabolism through, so far, undefined hypothalamic-mediated mechanisms. Here, we demonstrate that the anorectic effect of RSTN is associated with inappropriately decreased mRNA expression of orexigenic (agouti-related protein and neuropeptide Y) and increased mRNA expression of anorexigenic (cocaine and amphetamine-regulated transcript) neuropeptides in the arcuate nucleus of the hypothalamus. Of interest, RSTN also exerts a profound nutrition-dependent inhibitory effect on hypothalamic fatty acid metabolism, as indicated by increased phosphorylation levels of both AMP-activated protein kinase and its downstream target acetyl-coenzyme A carboxylase, associated with decreased expression of fatty acid synthase in the ventromedial nucleus of the hypothalamus. In addition, we also demonstrate that chronic central RSTN infusion results in decreased body weight and major changes in peripheral expression of lipogenic enzymes, in a tissue-specific and nutrition-dependent manner. Thus, in the fed state central RSTN is associated with induced expression of fatty acid synthesis enzymes and proinflammatory cytokines in liver, whereas its administration in the fasted state does so in white adipose tissue. Overall, our results indicate that RSTN controls feeding and peripheral lipid metabolism and suggest that hepatic RSTN-induced insulin resistance may be mediated by central activation of de novo lipogenesis in liver.

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Effect of Central Corticotropin-Releasing Factor on Hepatic Lipid Metabolism and Inflammation-Related Gene Expression in Rats

International Journal of Molecular Sciences ◽

10.3390/ijms22083940 ◽

2021 ◽

Vol 22 (8) ◽

pp. 3940

Author(s):

Yukiomi Nakade ◽

Rena Kitano ◽

Taeko Yamauchi ◽

Satoshi Kimoto ◽

Kazumasa Sakamoto ◽

...

Keyword(s):

Gene Expression ◽

Lipid Metabolism ◽

De Novo ◽

Corticotropin Releasing Factor ◽

De Novo Lipogenesis ◽

Control Group ◽

Mrna Levels ◽

Related Gene ◽

Hepatic Lipid Metabolism ◽

Hepatic Lipid

Corticotropin-releasing factor (CRF) in the brain acts on physiological and pathophysiological modulation of the hepatobiliary system. Central CRF administration aggravates experimental acute liver injury by decreasing hepatic blood flow. Conversely, minimal evidence is available regarding the effect of centrally acting CRF on hepatic lipid metabolism and inflammation. We examined whether central CRF affects hepatic lipid metabolism and inflammation-related gene expression in rats. Male Long Evans rats were intracisternally injected with CRF (10 μg) or saline. Rats were sacrificed 2 h, 6 h, and 24 h after the CRF injection, the liver was isolated, and mRNA was extracted. Next, hepatic lipid metabolism and inflammation-related gene expression were examined. Hepatic SREBF1 (sterol regulatory element-binding transcription factor 1) mRNA levels were significantly increased 6 h and 24 h after intracisternal CRF administration when compared with those in the control group. Hepatic TNFα and IL1β mRNA levels increased significantly 6 h after intracisternal CRF administration. Hepatic sympathectomy or guanethidine treatment, not hepatic branch vagotomy or atropine treatment, inhibited central CRF-induced increase in hepatic SREBF1, TNFα and IL1β mRNA levels. These results indicated that central CRF affects hepatic de novo lipogenesis and inflammation-related gene expression through the sympathetic-noradrenergic nervous system in rats.

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