Reduced Triglyceride Content Research Articles

Tabata‐style functional exercise increases resting and postprandial fat oxidation but does not reduce triglyceride concentrations

What is the central question of this study? What are the metabolic impacts of high intensity functional Tabata exercise? What is the main finding and its importance? Tabata exercise with high intensity functional movements causes increases in fasted and postprandial fat oxidation the day after exercise without altering postprandial triglyceride concentrations. These results support the usage of a Tabata-style high intensity functional exercise to improve postprandial fat oxidation. We evaluated the effect of a high fat meal with and without prior high intensity functional exercise executed in a Tabata-style interval pattern on resting and postprandial substrate oxidation, as well as postprandial blood glucose and triglyceride concentrations. Eleven healthy males completed two trials (Tabata exercise (TE) and non-exercise control (CON)) in random order separated by 7days. A two-day protocol was used in which TE or CON was performed on the first day and a high fat meal was administered ∼13h later the following morning. Power output from the TE session was quantified using a kinematic approach by calculating external work performed per unit time for each of the four exercises (rowing, dumbbell thrusters, kettlebell swings and burpees). For the meal challenge, respiratory gases and blood samples were taken fasted and at 1, 2 and 3h postprandial. Fat oxidation was significantly higher after TE compared to CON at all time points (P<0.05). Carbohydrate oxidation was significantly lower after TE compared to CON at 1h postprandial (P<0.05). There were no significant effects of TE on fasting or postprandial glucose or triglyceride concentrations. Functional exercises performed in a high intensity TE pattern enhance fasting and postprandial fat oxidation on the following day with minimal influence on blood triglycerides or glucose levels.

EPA and DHA have divergent effects on serum triglycerides and lipogenesis, but similar effects on lipoprotein lipase activity: a randomized controlled trial

Comparative studies suggest that DHA may have stronger serum triglyceride-lowering effects than EPA; however, the molecular basis for this differential effect remains unexplored in humans. Differential regulation of lipogenesis and triglyceride clearance are 2 possible mechanisms of action. We compared the effects of EPA and DHA supplementation on serum triglycerides, markers of lipogenesis, and lipoprotein lipase (LPL) activity in adults participating in a double-blind, multiarm, placebo-controlled parallel-group randomized trial. Lipogenesis was assessed with the lipogenic index and compound specific isotope analysis (CSIA). Young, healthy normolipidemic men and women (n=89; 21.6±0.23 y; mean ± SEM) were randomly allocated into 1 of 3 supplement groups for 12 wk: 1) olive oil, 2) ∼3 g EPA/d, and 3) ∼3 g DHA/d. Omega-3 supplements were provided in triglyceride form. Blood was collected before and after supplementation for the analysis of fatty acids and preheparin LPL activity. Variations in the 13C:12C ratio (δ13C) of palmitate (16:0) and linoleate (18:2n-6) were measured by CSIA. DHA supplementation reduced blood triglycerides (0.85±0.04 mmol/L to 0.65±0.03 mmol/L; P<0.01), with no change seen with EPA supplementation. DHA supplementation did not change the lipogenic index or δ13C-16:0, whereas EPA supplementation increased the lipogenic index by 11% (P<0.01) and δ13C-16:0 (P=0.03) from -23.2±0.2 to -22.8±0.2 milliUrey±SEM. Reduced triglyceride concentrations after DHA supplementation are associated with increased LPL activity, whereas the null effect of EPA supplementation on blood triglycerides may stem from the concomitant increases in lipogenesis and LPL activity. Further investigation of the differential triglyceride-lowering effects of EPA and DHA is warranted in both normolipidemic and hyperlipidemic individuals. This trial was registered at clinicaltrials.gov as NCT03378232.

Angiotensin-converting enzyme 2 regulates endoplasmic reticulum stress and mitochondrial function to preserve skeletal muscle lipid metabolism

ObjectiveEndoplasmic reticulum (ER) stress and mitochondrial function affected intramuscular fat accumulation. However, there is no clear evident on the effect of the regulation of ER stress and mitochondrial function by Angiotensin-converting enzyme 2 (ACE2) on the prevention of intramuscular fat metabolism. We investigated the effects of ACE2 on ER stress and mitochondrial function in skeletal muscle lipid metabolism.MethodsThe triglyceride (TG) content in skeletal muscle of ACE2 knockout mice and Ad-ACE2-treated db/db mice were detected by assay kits. Meanwhile, the expression of lipogenic genes (ACCα, SREBP-1c, LXRα, CPT-1α, PGC-1α and PPARα), ER stress and mitochondrial function related genes (GRP78, eIF2α, ATF4, BCL-2, and SDH6) were analyzed by RT-PCR. Lipid metabolism, ER stress and mitochondrial function related genes were analyzed by RT-PCR in ACE2-overexpression C2C12 cell. Moreover, the IKKβ/NFκB/IRS-1 pathway was determined using lysate sample from skeletal muscle of ACE2 knockout mice.ResultsACE2 deficiency in vivo is associated with increased lipid accumulation in skeletal muscle. The ACE2 knockout mice displayed an elevated level of ER stress and mitochondrial dysfunctions in skeletal muscle. In contrast, activation of ACE2 can ameliorate ER stress and mitochondrial function, which slightly accompanied by reduced TG content and down-regulated the expression of skeletal muscle lipogenic proteins in the db/db mice. Additionally, ACE2 improved skeletal muscle lipid metabolism and ER stress genes in the C2C12 cells. Mechanistically, endogenous ACE2 improved lipid metabolism through the IKKβ/NFκB/IRS-1 pathway in skeletal muscle.ConclusionsACE2 was first reported to play a notable role on intramuscular fat regulation by improving endoplasmic reticulum and mitochondrial function. This study may provide a strategy for treating insulin resistance in skeletal muscle.

Polyphenol-Rich Extracts from Toona sinensis Bark and Fruit Ameliorate Free Fatty Acid-Induced Lipogenesis through AMPK and LC3 Pathways.

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease found worldwide. The present study aimed to evaluate the mechanisms of inhibiting lipid accumulation in free fatty acid (FFA)-treated HepG2 cells caused by bark and fruit extracts of Toona sinensis (TSB and TSF). FFA induced lipid and triglyceride (TG) accumulation, which was attenuated by TSB and TSF. TSB and/or TSF promoted phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-coA carboxylase and peroxisome proliferator-activated receptor alpha upregulation. Furthermore, TSB and TSF suppressed FFA-induced liver X receptor, sterol regulatory element-binding transcription protein 1, fatty acid synthase, and stearoyl-CoA desaturase 1 protein expression. Moreover, TSB and/or TSF induced phosphorylation of Unc-51 like autophagy-activating kinase and microtubule-associated protein 1A/1B-light chain 3 expressions. Therefore, TSB and TSF relieve lipid accumulation by attenuating lipogenic protein expression, activating the AMPK pathway, and upregulating the autophagic flux to enhance lipid metabolism. Moreover, TSB and TSF reduced TG contents, implying the therapeutic use of TSB and TSF in NAFLD.

Fibroblast growth factor-21 (FGF21) administration to early-lactating dairy cows. II. Pharmacokinetics, whole-animal performance, and lipid metabolism

Dairy cows cope with severe energy insufficiency in early lactation by engaging in intense and sustained mobilization of fatty acids from adipose tissue. An unwanted side effect of this adaptation is excessive lipid accumulation in the liver, which in turn impairs hepatic functions. Mice experiencing increased hepatic fatty acid flux are protected from this condition through coordinated actions of the newly described hormone fibroblast growth factor-21 (FGF21) on liver and adipose tissue. The possibility of an analogous role for FGF21 in dairy cows is suggested by its rapid increase in plasma levels around parturition followed by chronically elevated levels in the first few weeks of lactation. To test this hypothesis, dairy cows were randomly assigned on d 12.6 ± 2.2 (± standard error) of lactation to receive either an excipient (control; n = 6) or recombinant human FGF21 (n = 7), first as an FGF21 bolus of 3 mg/kg of body weight (BW) followed 2 d later by a constant i.v. infusion of FGF21 at a rate of 6.3 mg/kg of metabolic BW for 9 consecutive days. After bolus administration, human FGF21 circulated with a half-life of 194 min, and its constant infusion increased total plasma concentration 117-fold over levels in excipient-infused cows. The FGF21 treatment had no effect on voluntary feed intake, milk yield, milk energy output, or net energy balance measured over the 9-d infusion or on final BW. Plasma fatty acids circulated at lower concentrations in the FGF21 group than in the control group for the 8-h period following bolus administration, but this reduction was not significant during the period of constant i.v. infusion. Treatment with FGF21 caused a 50% reduction in triglyceride content in liver biopsies taken at the end of the constant i.v. infusion without altering the mRNA abundance of key genes involved in the transport, acyl coenzyme A activation, or oxidation of fatty acids. In contrast, FGF21 treatment ablated the recovery of plasma insulin-like growth factor-1 seen in control cows during the 9-d i.v. infusion period despite a tendency for higher plasma growth hormone. This effect was associated with increased hepatic mRNA abundance of the intracellular inhibitor of growth hormone receptor trafficking, LEPROT. Overall, these data confirm the ability of FGF21 to reduce lipid accumulation in bovine liver and suggest the possibility that FGF21 does so by attenuating the hepatic influx of adipose tissue-derived fatty acids.

Suppression of Gene Juvenile Hormone Diol Kinase Delays Pupation in Heortia vitessoides Moore.

Juvenile hormone diol kinase (JHDK) is a critical enzyme involved in juvenile hormone degradation in insects. In this study, HvJHDK in the Heortia vitessoides Moore (Lepidoptera: Crambidae) transcriptional library was cloned. Stage-specific expression patterns of HvJHDK, HvJHEH, and HvJHE as well as juvenile hormone titers were determined. The three tested enzymes participated in juvenile hormone degradation. Moreover, juvenile hormone titers peaked after larval–larval molts, consistent with a role for juvenile hormone in inhibition of metamorphosis. HvJHDK was subsequently suppressed using RNA interference (RNAi) to reveal its functions. Different concentrations of dsJHDK elicited the optimal interference efficiency at different life stages of H. vitessoides. Suppression of HvJHDK decreased HvJHDK content and increased the juvenile hormone titer, thereby resulting in reduced triglyceride content, sharply declined survival rate, clearly lethal phenotypes, and extended larval growth. Moreover, suppression of HvJHDK upregulated HvJHEH and HvJHE expression levels, suggesting that there is feedback regulation in the juvenile hormone metabolic pathway. Taken together, our findings provide molecular references for the selection of novel insecticidal targets.

Nutrient and hormone composition of milk is altered in rodent dams post-bariatric surgery.

Although bariatric surgery is approved for a woman of child-bearing age with an interest in subsequent pregnancy, reports of in utero growth issues during pregnancy have garnered a closer look at the impact of maternal surgical weight loss on the pre- and postpartum periods. Offspring of dams having received vertical sleeve gastrectomy (VSG) are born small-for-gestational age and have increased risk for metabolic syndrome later in life. Here, we aimed to determine whether the postnatal catch-up growth trajectory of bariatric offspring may be affected by milk composition. Milk samples were collected at postnatal day 15/16 from dams having received VSG surgery and fed a high-fat diet (HFD) (H-VSG), Sham surgery and fed chow (C-Sham), or Sham surgery and fed HFD (H-Sham). Milk obtained from H-VSG dams had elevated glucose (P < 0.05) and significantly reduced triglyceride content (P < 0.01). Milk from H-Sham dams had the lowest amount of milk protein (P < 0.05). Fatty acid composition measured by fractionation was largely not affected by surgery but rather maternal diet. No difference was observed in milk leptin levels; however, insulin, adiponectin, and growth hormone levels were significantly increased in milk from H-VSG animals. H-Sham had the lowest level of immunoglobulin (Ig)A, whereas IgG was significantly reduced in H-VSG. Taken together, the quality of milk from H-VSG dams suggests that milk composition could be a factor in reducing the rate of growth during the lactation period.

TRNA-Derived Small Non-Coding RNAs as Novel Epigenetic Molecules Regulating Adipogenesis

tRNA-derived fragments (tRFs), a novel type of non-coding RNA derived from tRNAs, play an important part in governing gene expressions at a post-transcriptional level. To date, the regulatory mechanism of tRFs governing fat deposition and adipogenesis is completely unknown. In this study, high fat diet was employed to induce an obese rat model, and tRFs transcriptome sequencing was conducted to identify differentially expressed tRFs that response to obesity. We found out that tRFGluTTC, which promoted preadipocyte proliferation by increasing expressions of cell cycle regulatory factors, had the highest fold change in the 296 differentially expressed tRFs. Moreover, tRFGluTTC also suppressed preadipocyte differentiation by reducing triglyceride content and lipid accumulation, and by decreasing expressions of genes that related to fatty acid synthesis. According to results of luciferase activity analysis, tRFGluTTC directly targeted Kruppel-like factor (KLF) 9, KLF11, and KLF12, thus significantly suppressing mRNA expressions of these target genes. Moreover, tRFGluTTC suppressed adipogenesis, accompanying by suppressing expressions of adipogenic transcription factors (aP2, PPARγ, and C/EBPα). In conclusion, these results imply that tRFGluTTC may act as a novel epigenetic molecule regulating adipogenesis and could provide a new strategy for the intervention treatment of obesity.

Effects of marked hypertriglyceridemia and lipid clearance techniques on canine biochemistry testing.

Triglyceride concentrations in dogs with hyperlipidemic disorders can exceed concentrations used by assay manufacturers for interference testing. High-speed centrifugation or the polar solvent LipoClear reduce triglyceride concentrations, but efficacy requires evaluation in veterinary species. We determined the effect of marked hypertriglyceridemia on canine biochemistry testing; assessed the ability of high-speed centrifugation or LipoClear to correct lipemic interferences; and determined if LipoClear introduces inaccuracy into biochemistry assays. Fifteen pooled canine serum samples were aliquoted and spiked with equal volumes of water or Intralipid [triglyceride concentration 33.9 mmol/L (3,000 mg/dL)]. Intralipid aliquots underwent lipid removal by high-speed centrifugation or LipoClear treatment, and a water-spiked aliquot underwent LipoClear treatment. Biochemistry panels were performed using a Vitros 4600 chemistry analyzer. Results were compared by paired t-test or Wilcoxon test. Total observed errors were considered clinically acceptable if below veterinary allowable total error (TEa) guidelines. Statistically significant (p ≤ 0.05) interferences were introduced by Intralipid for 15 of 15 analytes. Median observed error exceeded TEa for potassium and enzymatic carbon dioxide, neither of which were identified by the manufacturer as susceptible to lipemic interference. After centrifugation, median observed error exceeded TEa for potassium and chloride. LipoClear treatment resulted in median errors that exceeded TEa for total protein, chloride, and phosphorus. Given that severe lipemia can occur in dogs with primary or secondary hyperlipidemia, veterinary laboratories should perform their own interference testing at triglyceride concentrations relevant to their patient population and provide this information to clinicians to ensure optimal case management.

1990-P: STAT1 Knockdown in CD11c+ Cells Prevents Adipose Tissue Inflammation and Metabolic Dysfunction in Mice on High-Fat Diet

Background: Classically activated M1-like CD11c+ macrophages/dendritic cells (MDCs) are increased in obese adipose tissue (AT) and may contribute to AT inflammation and the development of insulin resistance in obesity. STAT1 is a key transcription factor for MDC polarization into M1-like phenotypes. Here, we examined the role of STAT1 in obesity-induced AT MDC polarization and inflammation and insulin resistance in mice. Methods: Mice with specific knockout (KO) of STAT1 in CD11c+ MDCs were generated by crossbreeding STAT1fl/fl and CD11c-Cre mice. CD11c/STAT1 KO and littermate controls were fed high-fat diet (HFD, 16 weeks) to induce obesity and evaluated for immune cells and browning/beige adipogenesis in perigonadal (pAT) and inguinal (iAT) AT and metabolic functions. Results: Compared to control mice, KO mice on HFD had similar body weight. Analyses of AT immune cells revealed that compared to controls, KO mice had a decrease in M1-like proinflammatory polarization but an increase in M2-like polarization of macrophages and reduced CD8+ T cell number in pAT, and significant increases in the proportion of IL-5+ Th2 cells and eosinophils (CD170+) in pAT and iAT (p&amp;lt;0.05). Furthermore, compared to control mice, KO mice showed significantly increased iAT expression of browning markers (Ucp-1, Cidea, and prdm16) and had increased oxygen consumption rate but lower respiratory exchange ratio, indicating higher energy expenditure and increased fat utilization as energy source. Moreover, KO mice, as compared to controls, had significant reductions in triglyceride content in the liver and skeletal muscle and exhibited improved insulin sensitivity and glucose tolerance examined by insulin and glucose tolerance test (p&amp;lt;0.05). Conclusion: STAT1 plays an important role in obesity-induced MDC M1-like polarization and AT inflammation and contributes to insulin resistance and metabolic dysfunctions in obese mice. Disclosure A. Kalathookunnel Antony: None. X. Perrard: None. Z. Lian: None. J. Perrard: None. C.M. Ballantyne: Consultant; Self; Abbott, Akcea Therapeutics, Amarin Corporation, Amgen Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Esperion, Gilead Sciences, Inc., Matinas BioPharma, Merck &amp; Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Regeneron Pharmaceuticals, Roche Diagnostic USA, Sanofi. Research Support; Self; Abbott, Akcea Therapeutics, Amarin Corporation, Amgen Inc., Esperion, Novartis Pharmaceuticals Corporation, Regeneron Pharmaceuticals, Roche Diagnostic USA, Sanofi. Other Relationship; Self; Roche Diagnostic USA. H. Wu: None. Funding American Diabetes Association (1-17-IBS-082 to H.W.)

Platycodi Radix Beverage Reduced the Postprandial Lipemia Response to a High-fat Load in Randomized Controlled Trials of Healthy Subjects (P12-009-19)

ObjectivesHigh postprandial lipemia is a characteristic of metabolic abnormality recognized as a risk factor inducing cardiovascular disease. The objective of this study was to investigate the effects of Platycodi radix (PR) beverage on postprandial lipemia response after challenging with a high-fat/sugar load using both single-dose cross-over and 8-week repeated paralleled designs in healthy subjects. MethodsA total of 52 and 96 subjects were included in the two studies, respectively. Postprandial blood samples were collected at designated time points from 0 to 6 hours after a high-fat load at each visit to determine triglyceride (TG) and lipoprotein lipase (LPL) activity and mass in plasma, chylomicron and very low-density lipoprotein (VLDL). A general linear mixed-effect model analysis of time point values and area under the curves (AUCs) was performed to estimate the effect of PR beverage on postprandial lipemia response. ResultsIn a single-dose cross-over design study, PR beverage consumption significantly increased lipoprotein lipase mass (P = 0.011, β estimate = 4.295) and reduced TG concentration in VLDL (P = 0.038, β estimate = –52.69) at 6-hour as compared to those in placebo consumption with a high-fat load. Postprandial TG responses as measured by AUC for 6 hours were significantly correlated with a high-fat dietary score MEDFICTS in chylomicron (r = 0.276, P = 0.008) and VLDL (r = 0.213, P = 0.040). In a 8-week repeated parallel design study, postprandial lipemia responses were compared considering the interaction between group and week. PR beverage consumption decreased postprandial serum TG response (AUCn, P = 0.039; total AUC, P = 0.088). In addition, PR increased plasma LPL mass (AUCn, P = 0.076) that is a clearing factor that hydrolyzed TG of chylomicron and VLDL in the lipoprotein metabolism. ConclusionsIn both of single and long-term intake, PR beverage consumption improved the degradation of postprandial TG level with increasing postprandial LPL mass. However, detail LPL mechanisms of PR consumption should be further analyzed. Funding SourcesThis work was carried out with the support of “Cooperative Research Program for Agriculture Science & Technology Development” Rural Development Administration, Republic of Korea and the BK21 PLUS program of the Ministry of Education.

OR20-6 Ketones and Sepsis-Induced Muscle Weakness: Signal or Fuel for Protection?

Background: Septic patients often develop muscle weakness, contributing to ICU morbidity and mortality. We recently observed that obese septic mice and patients do not develop such weakness, explained by increased lipolysis and hepatic conversion of fatty acids into the ketone bodies. Furthermore, in lean septic mice, supplementing nutrition with 3-hydroxybutyrate (3HB) reproduced the protection against muscle weakness seen with obesity. The aim of the current study was to investigate underlying mechanisms of the 3HB-protection. Methods: We performed a mouse study (n=49) in a centrally-catheterized fluid-resuscitated model of prolonged (5 days) abdominal sepsis (cecal ligation and puncture). Lean septic mice received standard parenteral nutrition (PN) supplemented with either D,L-3HB (5 mg/kg/day) or isocaloric glucose (gluc). Healthy pair-fed mice served as controls. The use of 3HB as energy substrate in the muscle was assessed by quantifiying protein, triglyceride and glycogen content and markers of muscle ketolysis, proteolysis and fatty acid oxidation (FAO). Signaling function of 3HB was assessed by markers of muscle autophagy activation, inflammation and regeneration. Results: Although 3HB infusion abated sepsis-induced upregulation of ubiquitin-proteasome system marker Fxbo32 (p=0.002), loss of muscle mass was not prevented (p=0.8). Sepsis reduced triglyceride content (p≤0.01) equally in PN+gluc and PN+3HB mice (p=0.9), but did not affect markers of muscle FAO (Cd36, Cpt1b, Acadl, Hadha mRNA) in PN+gluc and PN+3HB mice (p≥0.2). Muscle glycogen content was unaltered by sepsis (p=0.1), and the illness-induced decrease in plasma glucose concentrations at day 5 (p≤0.004) was similar in PN+gluc and PN+3HB mice (p=1). Gene expression of the ketolysis enzyme Oxct1 was lower in PN+3HB compared to PN+gluc septic mice and healthy controls (p≤0.05). Also, ketone body transporter Mct1 mRNA was elevated by sepsis (p≤0.01) but attenuated by 3HB (p=0.05) compared to glucose. Sepsis-induced elevation of inflammation markers (Tnfα, IL-1β, Nlrp3 mRNA levels; p≥0.4) and autophagy (Atg5, Atg7 mRNA; p≥0.4; LC3 II/I, p-ULK1/ULK1 protein; p≥0.4) were not countered by 3HB infusion compared to glucose. However, PN+3HB septic mice did show enhanced markers of muscle regeneration (Myod1, Myf5 and Myog mRNA; p≤0.04) compared to PN+gluc septic mice and healthy controls. Also, sepsis-induced elevation of expression of Hdac4, an inhibitor of myoblast differentiation stimulator Mef2c, was reduced by 3HB (p=0.03) and resulted in increased Mef2c mRNA levels (p=0.01) compared to glucose. Conclusion: In conclusion, the observed protection against sepsis-induced muscle weakness with 3HB infusion coincided with enhanced markers of muscle regeneration, but not with changes in substrate handling. Supplemented 3HB during sepsis thus acted as a signaling molecule rather than as an energy source.

Beneficial Effects of Pomegranate Peel Extract and Probiotics on Pre-adipocyte Differentiation.

The beneficial effects of pomegranate are due to the ellagitannins and anthocyanins content, which are protective toward a wide variety of diseases including inflammatory diseases. Many investigators have reported that pomegranate waste (peel and seeds) extracts, made from waste product of industrial processing, show free radical scavenger and a potent antioxidant capacity. Pomegranate extracts (PEs) were also reported to possess noteworty antibacterial, antiviral, hypolipidemic, and anti-inflammatory bioactivities thanks to the polyphenolic compounds content, which includes punicalagins, gallic acid, and ellagic acid derivatives. The focus of the present manuscript was to study the prebiotic potentiality of a PE, soluble in water, and characterized through HPLC–PDA–ESI/MSn for its phenolic content. Moreover, since it has been reported that pomegranate extracts decreased the level of lipids in the blood and that a number of probiotic strains have been shown to affect adipogenesis in cell culture, this study was also performed to test the in vitro effects of PE and probiotic L. rhamnosus GG ATCC 53103 strain (LGG) on 3T3-L1 cell line. PE and probiotics substantially reduced the triglyceride content and intracellular lipid increase, compared to the control group. However, the combination treatment of PE and LGG filtered spent broth (SB) was the most effective in reducing triglyceride content and intracellular lipid accumulation. The mRNA expression levels of the main transcriptional factors implicated in adipocyte differentiation were substantially lower in 3T3-L1 cells treated with PE and LGG filtered SB. These results evidenced that a synergistic effect of probiotics and polyphenols contained in PE may affect in vitro adipogenesis and may contribute in development of new nutraceutical/probiotic-based remedies to prevent and to treat obesity.

Genetic deletion of soluble 5′-nucleotidase II reduces body weight gain and insulin resistance induced by a high-fat diet

We previously investigated whether inhibition of AMP-metabolizing enzymes could enhance AMP-activated protein kinase (AMPK) activation in skeletal muscle for the treatment of type 2 diabetes. Soluble 5′-nucleotidase II (NT5C2) hydrolyzes IMP and its inhibition could potentially lead to a rise in AMP to activate AMPK. In the present study, we investigated effects of NT5C2 deletion in mice fed a normal-chow diet (NCD) or a high-fat diet (HFD). On a NCD, NT5C2 deletion did not result in any striking metabolic phenotype. On a HFD however, NT5C2 knockout (NT5C2−/−) mice displayed reduced body/fat weight gain, improved glucose tolerance, reduced plasma insulin, triglyceride and uric acid levels compared with wild-type (WT) mice. There was a tendency towards smaller and fewer adipocytes in epididymal fat from NT5C2−/− mice compared to WT mice, consistent with a reduction in triglyceride content. Differences in fat mass under HFD could not be explained by changes in mRNA expression profiles of epididymal fat from WT versus NT5C2−/− mice. However, rates of lipolysis tended to increase in epididymal fat pads from NT5C2−/− versus WT mice, which might explain reduced fat mass. In incubated skeletal muscles, insulin-stimulated glucose uptake and associated signalling were enhanced in NT5C2−/− versus WT mice on HFD, which might contribute towards improved glycemic control. In summary, NT5C2 deletion in mice protects against HFD-induced weight gain, adiposity, insulin resistance and associated hyperglycemia.

A 7-day high-PUFA diet reduces angiopoietin-like protein 3 and 8 responses and postprandial triglyceride levels in healthy females but not males: a randomized control trial

BackgroundPolyunsaturated fatty acids (PUFAs) have beneficial effects on hypertriglyceridemia although their effect on angiopoietin-like proteins (ANGPTLs), specifically ANGPTL3, ANGPTL4 and ANGPTL8 is unknown.ObjectiveTo determine whether a high-PUFA diet improves postprandial triglyceride (TG) levels through reducing ANGPTL responses following high saturated fat (SFA) meals.MethodsTwenty-six adults were randomized into a PUFA diet (n = 16) or a control diet group (n = 10). Participants completed a pre-diet visit (v1) where they were given two SFA-rich, high-fat meals. Blood draws were taken at fasting and every 2 h postprandially for a total of 8 h. After v1, participants completed a 7d diet of the same macronutrient proportions (50% carbohydrate, 35% fat, 15% protein) but with different fatty acid (FA) compositions (PUFA = 21% of total energy from PUFAs vs. Control = 7% of total energy from PUFA). All participants then completed the post-diet visit (v2) identical to v1.ResultsIn the PUFA group, females, but not males, reduced TG concentrations (Area under the curve (AUC): 141.2 ± 18.7 vs. 80.7 ± 6.5 mg/dL/h, p = 0.01, for v1 vs. v2, respectively). Fasting and postprandial AUC levels of ANGPTL3 and 8, but not ANGPTL4, also decreased from v1 to v2 in PUFA females, but not males. No changes from v1 to v2 were seen in either sex in the control group.ConclusionsA PUFA-rich diet improves TG levels in response to high-SFA meals with reductions in ANGPTL3 and ANGPTL8. PUFAs may be more protective against hypertriglyceridemia in females, compared to males since no diet effect was observed in males.Trial registrationNCT02246933.

Lipoprotein Subclass Profile after Progressive Energy Deficits Induced by Calorie Restriction or Exercise.

Weight loss, induced by chronic energy deficit, improves the blood lipid profile. However, the effects of an acute negative energy balance and the comparative efficacy of diet and exercise are not well-established. We determined the effects of progressive, acute energy deficits (20% or 40% of daily energy requirements) induced by a single day of calorie restriction (n = 19) or aerobic exercise (n = 13) in healthy subjects (age: 26 ± 9 years; body mass index (BMI): 21.8 ± 2.9 kg/m2). Fasting plasma concentrations of very low-, intermediate-, low-, and high-density lipoprotein (VLDL, LDL, IDL, and HDL, respectively) particles and their subclasses were determined using nuclear magnetic resonance. Total plasma triglyceride and VLDL-triglyceride concentrations decreased after calorie restriction and exercise (all p ≤ 0.025); the pattern of change was linear with an increasing energy deficit (all p < 0.03), with no evidence of plateauing. The number of circulating large and medium VLDL particles decreased after diet and exercise (all p < 0.015), with no change in small VLDL particles. The concentrations of IDL, LDL, and HDL particles, their relative distributions, and the particle sizes were not altered. Our data indicate that an acute negative energy balance induced by calorie restriction and aerobic exercise reduces triglyceride concentrations in a dose-dependent manner, by decreasing circulating large and medium VLDL particles.

LPS-induced reduction of triglyceride synthesis and secretion in dairy cow mammary epithelial cells via decreased SREBP1 expression and activity.

Sterol regulatory element binding protein 1 (SREBP1) has a central regulatory effect on milk fat synthesis. Lipopolysaccharides (LPS) can induce mastitis and cause milk fat depression in cows. SREBP1 is also known to be associated with inflammatory regulation. Thus, in the current study, we hypothesized that LPS-induced milk fat depression in dairy cow mammary epithelial cells (DCMECs) operates via decreased SREBP1 expression and activity. To examine the hypothesis, DCMECs were isolated and purified from dairy cow mammary tissue and treated with LPS (10 µg/ml). LPS treatment of DCMECs suppressed lipid-metabolism-related transcription factor SREBP1 mRNA expression, nuclear translocation and protein expression, leading to reduced triglyceride content. The transcription levels of acetyl-CoA carboxylase-1 and fatty acid synthetase were significantly down-regulated in DCMECs after LPS treatment, suggesting that acetyl-CoA carboxylase-1 and fatty acid synthetase involved in de novo milk fat synthesis was regulated by SREBP1. In summary, these results suggest that LPS induces milk fat depression in dairy cow mammary epithelial cells via decreased expression of SREBP1 in a time-dependent manner.

Treatment with volanesorsen (VLN) reduced triglycerides and pancreatitis in patients with familial chylomicronemia syndrome (FCS) and severe hypertriglyceridemia (sHTG) vs placebo: Results of the approach and compass studies

Volanesorsen is an antisense oligonucleotide that targets hepatic apolipoprotein C-III synthesis and reduces plasma triglyceride concentration. The aim of this study was to explore the safety and efficacy of volanesorsen in patients with multifactorial chylomicronaemia syndrome.The COMPASS trial was a randomised, placebo-controlled, double-blind, phase 3 study done at 38 international clinical sites in Canada, France, Germany, the Netherlands, UK, and USA. Eligible patients were aged 18 years or older with multifactorial severe hypertriglyceridaemia or familial chylomicronaemia syndrome, who had a BMI of 45 kg/m2 or less and fasting plasma triglyceride of 500 mg/dL or higher. Patients were randomly assigned (2:1) with an interactive response system using an allocation sequence and permuted block randomisation to receive subcutaneous volanesorsen (300 mg) or a matched volume of placebo (1·5 mL) once a week for 26 weeks. After 13 weeks of treatment, dosing was changed to 300 mg of volanesorsen or placebo every 2 weeks for all patients, except those who had completed 5 months or more of treatment as of May 27, 2016. Participants, investigators, sponsor personnel, and clinical research staff were all masked to the treatment assignments. The primary outcome was percentage change from baseline to 3 months in fasting triglyceride in the full analysis set (all patients who were randomly assigned and received at least one dose of study drug and had a baseline fasting triglyceride assessment). This trial is registered with ClinicalTrials.gov, NCT02300233 (completed).Between Feb 5, 2015, and Jan 24, 2017, 408 patients were screened for eligibility. 294 were excluded and 114 randomly assigned to receive either volanesorsen (n=76) or placebo (n=38). One patient in the volanesorsen group discontinued before receiving the study drug. The total number of dropouts was 28 (four in the placebo group and 24 in the treatment group). Volanesorsen reduced mean plasma triglyceride concentration by 71·2% (95% CI −79·3 to −63·2) from baseline to 3 months compared with 0·9% (−13·9 to 12·2) in the placebo group (p<0·0001), representing a mean absolute reduction of fasting plasma triglycerides of 869 mg/dL (95% CI −1018 to −720; 9·82 mmol/L [–11·51 to −8·14]) in volanesorsen compared with an increase in placebo of 74 mg/dL (−138 to 285; 0·83 mmol/L [–1·56 to 3·22]; p<0·0001). In the key safety analysis, five adjudicated events of acute pancreatitis occurred during the study treatment period, all in three of 38 patients in the placebo group. The most common adverse events were related to tolerability and included injection-site reactions (average of 24% of all volanesorsen injections vs 0·2% of placebo injections), which were all mild or moderate. One participant in the volanesorsen group had a platelet count reduction to less than 50 000 per μL and one patient had serum sickness, both of which were regarded as serious adverse events.Volanesorsen significantly reduced triglyceride concentrations in patients with multifactorial chlyomicronaemia and might reduce acute pancreatitis events in these patients.Ionis Pharmaceuticals and Akcea Therapeutics.

Abstract P036: Effects of Exercise Training and Increasing Non-Exercise Physical Activity on Lipoprotein Subclass and Size: Results From the I-CAN Study

Introduction: Previous studies have shown that lipoprotein particle size and lipoprotein subclasses are associated with cardiovascular and type 2 diabetes risk, and have independent prognostic value above traditional lipid concentrations. The impact of exercise training and increasing non-exercise physical activity on lipoprotein subclasses and size has not been previously investigated. Methods: In this pilot study, 35 obese adults were randomized to aerobic exercise training (50-75% of VO 2 max) (AERO, n=11), aerobic training and increasing non-exercise physical activity (AERO-PA, n=10, ~3,000 steps above baseline levels), or a non-exercise control group (n=14) for 6 months. Baseline and follow-up blood samples were analyzed for lipoprotein subclass, size, and lipoprotein insulin resistance score (LP-IR) using nuclear magnetic resonance spectroscopy (Liposcience, NC). Analysis of covariance was used to evaluate the change in outcome variables following the intervention across groups with adjustment for baseline value and age. Participants who changed lipid medications during the intervention (n=2) or who were non-adherent to exercise training (n=2) were excluded from the analysis. Results: Significant reductions were observed for mean VLDL size in the AERO-PA group (-4.7 nm, CI: -8.7 to -0.8) compared to control group (0.7 nm, CI: -2.7 to 4.4) and the AERO group (1.1 nm, CI: -2.9 to 5.0). Reductions in triglyceride concentrations were observed in the AERO-PA group (-28.3 mg/dL, CI: -50.3 to -6.4) compared to control (4.1 mg/dL, CI: -14.6 to 22.8). Additionally, we observed a trend for LP-IR index (p=0.055) and the concentration of small HDL particles (p=0.093) to decrease in the AERO-PA group compared to controls, with no differences compared to the AERO group (p&gt;0.10). No significant changes were observed for other notable lipoprotein measures, such as LDL size, HDL size, concentration of small LDL particles, or chylomicron measures (p&gt;0.05). In the AERO-PA group, the change in steps was associated with the change in LP-IR index (r= -0.71, p=0.013), but not with change in VLDL size (r= -0.24, p=0.463) or triglyceride concentrations (r=-0.28, p=0.388). Conclusions: Aerobic training combined with increasing non-exercise physical activity leads to favorable changes in the lipoprotein profile, specifically reductions in VLDL size and triglycerides, and may have promise for other lipoprotein traits (reductions in LP-IR and small HDL particles) that were not observed with aerobic training alone.

Serum microRNA miR-206 is decreased in hyperthyroidism and mediates thyroid hormone regulation of lipid metabolism in HepG2 human hepatoblastoma cells.

The actions of thyroid hormone (TH) on lipid metabolism in the liver are associated with a number of genes involved in lipogenesis and lipid metabolism; however, the underlying mechanisms through which TH impacts on lipid metabolism remain to be elucidated. The present study aimed to investigate the effects of hyperthyroidism on the serum levels of the microRNA (miR) miR-206 and the role of miR-206 on TH-regulated lipid metabolism in liver cells. Serum was obtained from 12 patients diagnosed with hyperthyroidism and 10 healthy control subjects. Human hepatoblastoma (HepG2) cells were used to study the effects of triiodothyronine (T3) and miR-206 on lipid metabolism. Expression of miR-206 in serum and cells was determined by reverse transcription-quantitative polymerase chain reaction analysis. Lipid accumulation in HepG2 cells was assessed with Oil Red O staining. Suppression or overexpression of miR-206 was performed via transfection with a miR-206 mimic or miR-206 inhibitor. Serum miR-206 was significantly decreased in patients with hyperthyroidism compared with euthyroid controls. Treatment of HepG2 cells with T3 led to reduced total cholesterol (TC) and triglyceride (TG) content, accompanied by reduced miR-206 expression. Inhibition of endogenous miR-206 expression decreased intracellular TG and TC content in HepG2 cells. By contrast, overexpression of miR-206 in HepG2 partially prevented the reduction in TG content induced by treatment with T3. In conclusion, serum miR-206 expression is reduced in patients with hyperthyroidism. In addition, miR-206 is involved in T3-mediated regulation of lipid metabolism in HepG2 cells, indicating a role for miR-206 in thyroid hormone-induced disorders of lipid metabolism in the liver.