Plasma Glycerol Research Articles

Exercise increases plasma THC concentrations in regular cannabis users

BackgroundThe major psychoactive ingredient of cannabis, Δ9-tetrahydrocannabinol (THC) accumulates in fat tissue from where it slowly diffuses back into blood. THC pre-treated rats can show elevated plasma cannabinoid levels when subjected to conditions that promote fat utilization, such as fasting. Here we examine whether fasting and exercise increase plasma THC concentrations in regular cannabis users. MethodsFourteen regular cannabis users completed 35min of exercise on a stationary bicycle in either a fed or overnight fasted state. Plasma cannabinoid levels were assessed prior to exercise, immediately post-exercise and 2h post-exercise. Plasma samples were also analyzed for indices of lipolysis (free fatty acids (FFA) and glycerol). ResultsExercise induced a small, statistically significant increase in plasma THC levels accompanied by increased plasma FFA and glycerol levels. Exercise-induced increases in plasma THC concentrations were positively correlated with body mass index. Fasting induced a significant increase in plasma FFA levels, and a lowering of blood glucose, but did not significantly alter plasma cannabinoid levels. ConclusionsHere we demonstrate that exercise enhances plasma THC levels in regular cannabis users. The lack of a fasting effect may reflect the modest duration of fasting used which was associated with only a modest increase in fat utilization relative to exercise. Overall, these results suggest that exercise may elevate blood THC levels by releasing dormant THC from fat stores. These data suggest the interpretation of blood THC levels in roadside and workplace tests might be complicated by recent exercise.

No Effect of 1 or 7 d of Green Tea Extract Ingestion on Fat Oxidation during Exercise

The aim of this study was to investigate the effects of 1 and 7 d of green tea extract (GTE) ingestion on whole body fat oxidation during moderate-intensity exercise. Thirty-one men completed two exercise trials (60-min cycle, 50% Wmax). After the baseline trial (day 0), subjects were randomly assigned to one of three conditions involving a week supplementation of the following: 1) 7 d of placebo, 2) 6 d of placebo followed by 1 d of GTE (GTE1), and 3) 7 d of GTE ingestion (GTE7). The morning after the supplementation week, subjects consumed an additional supplement and completed a second exercise trial (day 8). V˙O2 and V˙CO2 measurements were taken during exercise to calculate whole body fat oxidation rates. Blood samples, for analysis of plasma fatty acids (FA), glycerol, and epigallocatechin gallate, were collected at rest and during exercise. On day 8, the plasma kinetics and maximal plasma concentrations of epigallocatechin gallate were similar in the GTE1 and GTE7 group (206 ± 28 and 216 ± 25 ng·mL, respectively). One day of GTE ingestion did not affect markers of lipolysis during the exercise bout. Seven days of GTE ingestion significantly increased plasma glycerol during exercise (P = 0.045) and plasma FA during exercise (P = 0.020) as well as at rest (P = 0.046). However, fat oxidation did not change in any of the groups. There was no effect of 1 d of GTE ingestion on markers of lipolysis or fat oxidation during exercise. Seven days of GTE ingestion increased lipolysis, indicated by increased plasma FA and glycerol concentrations, but did not result in significant changes in fat oxidation.

Effect of oligomerized polyphenol supplementation on lipid metabolism during exercise in healthy men

Previous studies have shown that oligomerized polyphenol (OLG) supplementation reduced visceral fat in obese; however, role of OLG on lipid metabolism during exercise has not been tested. Therefore, the purpose of current study was to investigate the effect of OLG supplementation on lipid metabolism during a bout of aerobic exercise. OLG (100mg/day) and placebo (CON) were given for 14 days in 10 healthy young men by a double‐blind, randomized, cross‐over design. After an overnight fast on the 15th day, exercise test (50% VO2max for 30min on bicycle ergometer) was conducted. Blood samples were taken before, during, and up to 30min‐post exercise for analysis of hormones and metabolites. Insulin resistance as assessed by HOMA‐IR tended to be lower in OLG as compared to CON (P=0.09). Plasma glycerol as well as free fatty acid concentration increased significantly 15 to 30min post‐exercise in OLG as compared to CON (P<0.05). Moreover, % change in serum growth hormone was higher in OLG as compared to CON during exercise (P<0.05). In summary, 14 days of OLG supplementation significantly increased exercise‐induced GH response and subsequent lipolysis in response to a bout of aerobic exercise in young men.

Detection of the endocannabinoid metabolome in human plasma and breast milk

The endocannabinoid metabolome (ENDOMET), endogenous cannabinoids that are lipid messengers, is critical for early development, including fertilization, implantation and pre‐ and postpartum (PP). The regulation underlying these physiological effects remains to be completely elucidated. We evaluated the ENDOMET in plasma of i) non‐pregnant (n=6) and pregnant women (20–22weeks‐ delivery, n=68) and ii) breast milk (BM) at 2 and 10 weeks PP (n= 20). The plasma and BM ENDOMETs [arachidonoyl ethanolamide (ET) (AEA), palmitoyl ET (PEA), oleoyl ET (OEA), docosahexaenoyl ET (DHEA), 2‐arachidonol glycerol (GLY) (2‐AG), 2‐palmitoyl GLY (PEA), and 2‐oleoyl GLY (2‐OG)] were measured using liquid chromatography‐mass spectrometry. ANOVA determined differences in the ENDOMET across time.Resultsplasma ETs increase with pregnancy and peak at delivery (AEA, PEA, OEA, DHEA, p<0.01); GLYs decrease during pregnancy and are stable (2‐AG, p=0.14; 2‐PG, p=0.07, 2‐OG, p=0.02). While BM ETs are considerably lower than plasma ET in pregnancy, BM levels remain stable during PP. BM GLYs are higher than plasma GLYs in late pregnancy. 2‐OG and 2‐AG decrease during PP (p=0.02; 0.05). Plasma and BM ETs are much lower in concentrations than GLYs. Our data point to a reciprocal relationship between ETs and GLYs during pregnancy and PP. Work is needed to better understand how maternal plasma and BM ENDOs regulate pre‐and postnatal outcomes.

Glycerol administration before endurance exercise: metabolism, urinary glycerol excretion and effects on doping‐relevant blood parameters

Glycerol is prohibited as a masking agent by the World Anti-Doping Agency and a urinary threshold has recently been recommended. However, little is known about urinary glycerol excretion after exercise, when (1) exogenous glycerol is metabolized increasingly and (2) endogenous glycerol levels are elevated. The purpose of the placebo-controlled cross-over study was to determine the effects of pre-exercise glycerol administration on glycerol metabolism, urinary excretion, and selected blood parameters. After administration of glycerol (G; 1.0 g/kg body weight (BW) + 25 ml fluid/kg BW) or placebo (P; 25 ml fluid/kg), 14 cyclists exercised 90 min at 60% VO2max . Samples were taken at 0 h (before administration), 2.5 h (before exercise), 4 h (after exercise) and 6.5 h and additional urine samples were collected until 24 h. Exercise increased endogenous plasma glycerol (0.51 ± 0.21 mmol/l) but peak concentrations were much higher in G (2.5 h: 15.6 ± 7.8 mmol/l). Urinary glycerol increased rapidly (58,428 ± 71,084 µg/ml after 2.5 h) and was significantly higher than in P until 13.6 ± 0.9 h (p < 0.01). In comparison with placebo administration, G caused significantly greater changes in plasma volume and haemoglobin concentrations after 2.5 h. BW and urine production were significantly different between P and G after 2.5 h and post-exercise. Despite exercise-induced increases in endogenous glycerol in the control group, urinary excretion remained well below the previously recommended threshold. In addition, exercise-related glycerol degradation did not appear to negatively affect the detection of exogenously administered glycerol.

Gluconeogenic pathway does not display metabolic cold adaptation in liver of Antarctic notothenioid fish

Antarctic notothenioid fish display specializations related to cope with their chronically cold environment, such as high triacylglycerol (TAG) content in tissues. The metabolic fate of glycerol, a product of TAG mobilization, has not been studied in Antarctic fish. To assess the importance of glycerol as a substrate for gluconeogenesis and to determine whether this pathway is metabolically cold adapted (MCA), key hepatic enzyme activities were measured in Antarctic (Notothenia coriiceps, Gobionotothen gibberifrons, and Chionodraco rastrospinosus) and non-Antarctic (Dissostichus eleginoides, Patagonotothen ramsayi, and Eleginops maclovinus) notothenioid fish. Fructose 1,6-biphosphatase (FBP), phosphoenolpyruvate carboxykinase (PEPCK), and glycerol kinase (GK) activities were similar in both groups at common temperatures (1, 6, 11, or 21 °C). In particular, thermal sensitivity for the reactions catalyzed by FBP and PEPCK was analogous between Antarctic and non-Antarctic species, reflected by similar values for Arrhenius energy of activation (E a) and Q10. Additionally, hepatic glycerol, glucose, and glycogen contents together with plasma glycerol and glucose concentrations were similar for all of the species studied. Our results do not support the concept of MCA in hepatic gluconeogenesis and may indicate that the use of glycerol as a precursor for glucose synthesis by this pathway is of low physiological importance in Antarctic fish.

The Acute Effects of L-arginine on Hormonal and Metabolic Responses During Submaximal Exercise in Trained Cyclists

L-arginine may enhance endurance performance mediated by two primary mechanisms including enhanced secretion of endogenous growth hormone (GH) and as a precursor of nitric oxide (NO); however, research in trained participants has been equivocal. The purpose was to investigate the effect of acute L-arginine ingestion on the hormonal and metabolic response during submaximal exercise in trained cyclists. Fifteen aerobically trained men (age: 28 ± 5 y; body mass: 77.4 ± 9.5 kg; height: 180.9 ± 7.9 cm; VO2max: 59.6 ± 5.9 ml·kg- 1·min-1) participated in a randomized, double-blind, crossover study. Subjects consumed L-arginine (ARG; 0. 075 g·kg-1 body mass) or a placebo (PLA) before performing an acute bout of submaximal exercise (60 min at 80% of power output achieved at ventilatory threshold). The ARG condition significantly increased plasma L-arginine concentrations (~146%), while no change was detected in the PLA condition. There were no differences between conditions for GH, nonesterified fatty acids (NEFA), lactate, glucose, VO2, VCO2, RER, CHO oxidation, and NOx. There was reduced fat oxidation at the start of exercise (ARG: 0.36 ± 0.25 vs. PLA: 0.42 ± 0.23 g·min-1, p < .05) and an elevated plasma glycerol concentrations at the 45-min time point (ARG: 340.3 vs. PLA: 288.5 μmol·L-1, p < .05) after L-arginine consumption. In conclusion, the acute ingestion of L-arginine did not alter any hormonal, metabolic, or cardio-respiratory responses during submaximal exercise except for a small but significant increase in glycerol at the 45-min time point and a reduction in fat oxidation at the start of exercise.

Plasma glycerol during the acute post-exercise recovery period: influence of exercise intensity

Intensity of exercise can influence substrate utilization, with increasing intensity resulting in lower rates of fat oxidation and the reliance on carbohydrate as the preferred fuel. Fat oxidation (or more specifically, mobilization) can be assessed via the measurement of circulating glycerol, with most prior research focusing on aerobic exercise and measurements obtained during the actual exercise bout. The present study determined the degree of fat oxidation/mobilization by measuring plasma glyctierol concentrations during the one hour post-exercise recovery period following three difference exercise bouts. On four different days, exercise trained men (n=12; 23.7±1.1 years) either rested quietly or performed aerobic cycle exercise (60 min at 70% heart rate reserve), 60 s cycle sprints at 100% max wattage obtained during graded exercise testing (GXT) - a total of five, or 15 s cycle sprints at 200% max wattage obtained during GXT - a total of 10. Blood was collected before and at 1, 30 and 60 min post-exercise. Haematocrit and haemoglobin were measured to correct for changes in plasma volume. Glycerol was analysed in plasma and the area under the curve was calculated. Glycerol increased across time (P&lt;0.0001) from pre-exercise (8.4±0.3 μg/dl) to 1 min (13.1±0.7 μg/dl), 30 min (11.3±0.6 μg/dl) and 60 min (9.1±0.5 μg/dl) post-exercise, with 1 min and 30 min post-exercise greater than pre-exercise and 60 min post-exercise (P&lt;0.05). Area under the curve was greater (P=0.0004) for aerobic exercise (24.7±2.0 μg/dl/h), 60 second sprints (23.4±1.9 μg/dl/h) and 15 sec sprints (24.4±1.5 μg/dl/h), as compared to rest (15.3±0.8 μg/dl/h), with no differences noted between exercise bouts (P≯0.05). All exercise bouts increase circulating glycerol, with no differences noted between bouts. Although previous data indicate that low intensity aerobic exercise results in greater fat oxidation than high intensity exercise (when assessed during the actual exercise session), our findings suggest that high intensity exercise may result in similar fat oxidation/mobilization as compared to aerobic exercise during the acute post-exercise period.

Porcine Adiponectin Receptor 1 Transgene Resists High-fat/Sucrose Diet-Induced Weight Gain, Hepatosteatosis and Insulin Resistance in Mice

Adiponectin and its receptors have been demonstrated to play important roles in regulating glucose and lipid metabolism in mice. Obesity, type II diabetes and cardiovascular disease are highly correlated with down-regulated adiponectin signaling. In this study, we generated mice overexpressing the porcine Adipor1 transgene (pAdipor1) to study its beneficial effects in metabolic syndromes as expressed in diet-induced obesity, hepatosteatosis and insulin resistance. Wild-type (WT) and pAdipor1 transgenic mice were fed ad libitum with a standard chow diet (Chow) or a high-fat/sucrose diet (HFSD) for 24 weeks, beginning at 6 to 7 weeks of age. There were 12 mice per genetic/diet/sex group. When challenged with HFSD to induce obesity, the pAdipor1 transgenic mice resisted development of weight gain, hepatosteatosis and insulin resistance. These mice had lowered plasma adiponectin, triglyceride and glycerol concentrations compared to WT mice. Moreover, we found that (indicated by mRNA levels) fatty acid oxidation was enhanced in skeletal muscle and adipose tissue, and liver lipogenesis was inhibited. The pAdipor1 transgene also restored HFSD-reduced phosphoenolpyruvate carboxykinase 1 (Pck1) and glucose transporter 4 mRNA in the adipose tissues, implying that the increased Pck1 may promote glyceroneogenesis to reduce glucose intolerance and thus activate the flux of glyceride-glycerol to resist diet-induced weight gain in the adipose tissues. Taken together, we demonstrated that pAdipor1 can prevent diet-induced weight gain and insulin resistance. Our findings may provide potential therapeutic strategies for treating metabolic syndromes and obesity, such as treatment with an ADIPOR1 agonist or activation of Adipor1 downstream targets.

Aquaglyceroporin-7 Overexpression in Women with the Polycystic Ovary Syndrome

Background: Aquaglyceroporin-7 (AQP7) is an adipose glycerol channel protein that has been suggested to be involved in whole-body glucose homeostasis and insulin sensitivity. The aim of this study was to investigate the expression of AQP7 in visceral adipose tissues from women with the polycystic ovary syndrome (PCOS). Methods:AQP7 mRNA and protein levels were measured in omental adipose tissue from 5 women with the PCOS and 4 healthy controls matched for body mass index and age; this was done by the real-time polymerase chain reaction (PCR) and Western blotting. -Results: The women with the PCOS had significantly higher homeostasis model insulin resistance indices (HOMA_IR) and their quantitative insulin sensitivity check indices were significantly lower compared to the controls (p < 0.05). No significant difference was noted between the two groups for the plasma glycerol concentration. AQP7 mRNA expression and protein levels in omental adipose tissue from women with the PCOS were significantly higher than those of the controls (p = 0.007). AQP7 expression showed a positive correlation with fasting insulin levels, insulin levels at 2 h after glucose loading and HOMA_IR in women with the PCOS. Conclusion:AQP7 overexpression may be related to insulin sensitivity and glucose homeostasis in women with the PCOS.

Angiotensin Receptor Blockade Recovers Hepatic UCP2 Expression and Aconitase and SDH Activities and Ameliorates Hepatic Oxidative Damage in Insulin Resistant Rats

Metabolic syndrome (MetS) is commonly associated with elevated renin-angiotensin system, oxidative stress, and steatohepatitis with down-regulation of uncoupling proteins (UCPs). However, the mechanisms linking renin-angiotensin system, steatosis, and UCP2 to hepatic oxidative damage during insulin resistance are not described. To test the hypothesis that angiotensin receptor activation contributes to decreased hepatic UCP2 expression and aconitase activity and to increased oxidative damage after increased glucose intake in a model of MetS, lean and obese Long Evans rats (n = 10/group) were randomly assigned to the following groups: 1) untreated Long Evans Tokushima Otsuka (lean, strain control), 2) untreated Otsuka Long Evans Tokushima Fatty (OLETF) (MetS model), 3) OLETF + angiotensin receptor blocker (ARB) (10 mg olmesartan/kg·d × 6 wk), 4) OLETF + high glucose (HG) (5% in drinking water × 6 wk), and 5) OLETF + ARB + HG (ARB/HG × 6 wk). HG increased body mass (37%), plasma triglycerides (TGs) (35%), plasma glycerol (87%), plasma free fatty acids (28%), and hepatic nitrotyrosine (74%). ARB treatment in HG decreased body mass (12%), plasma TG (15%), plasma glycerol (23%), plasma free fatty acids (14%), and hepatic TG content (42%), suggesting that angiotensin receptor type 1 (AT1) activation and increased adiposity contribute to the development of obesity-related dyslipidemia. ARB in HG also decreased hepatic nitrotyrosine and increased hepatic UCP2 expression (59%) and aconitase activity (40%), as well as antioxidant enzyme activities (50-120%), suggesting that AT1 activation also contributes to protein oxidation, impaired lipid metabolism, and antioxidant metabolism in the liver. Thus, in addition to promoting obesity-related hypertension, AT1 activation may also impair lipid metabolism and antioxidant capacity, resulting in steatosis via decreased UCP2 and tricarboxylic acid cycle activity.

Hepatic glucose production pathways after three days of a high-fat diet

ObjectiveA three-day high-fat diet induces hepatic steatosis and hepatic insulin resistance in rats without altering fasting plasma glucose concentration or the rate of glucose production. However, as the nutrient profile available to the liver is substantially altered by a high-fat diet, we hypothesized that the relative fluxes supporting hepatic glucose production would be altered. Materials/MethodsTo test this hypothesis, we used multiple tracers ([3,4-13C2]glucose, 2H2O, and [U-13C3]propionate) followed by NMR analysis of blood glucose to quantify net glucose production and the contributions of glycogen and key gluconeogenesis precursors in 4–5-h fasted rats. ResultsNMR analysis demonstrated that the majority of blood glucose was derived from glycogen and the citric acid cycle, while a smaller fraction of glucose was derived from glycerol in both controls and high-fat-fed animals. High-fat feeding was associated with a two-fold increase in plasma glycerol concentration and an increase in the contribution (both fractional and absolute) of glycerol-gluconeogenesis. The increase in gluconeogenesis from glycerol tended to be balanced by a decrease in glycogenolysis. The absolute fluxes associated with the citric acid cycle including gluconeogenesis from the cycle intermediates, pyruvate cycling and the citric acid cycle flux itself, were not altered by this short high-fat diet. ConclusionsA short term high-fat diet altered the specific pathways for hepatic glucose production without influencing the overall rate of glucose production or flux in the citric acid cycle.

Homozygosity for aquaporin 7 G264V in three unrelated children with hyperglyceroluria and a mild platelet secretion defect

Aquaporin 7 (AQP7) belongs to the aquaglyceroporin family, which transports glycerol and water. AQP7-deficient mice develop obesity, insulin resistance, and hyperglyceroluria. However, AQP7's pathophysiologic role in humans is not yet known. Three children with psychomotor retardation and hyperglyceroluria were screened for AQP7 mutations. The children were from unrelated families. Urine and plasma glycerol levels were measured using a three-step enzymatic approach. Platelet morphology and function were studied using electron microscopy, aggregations, and adenosine triphosphate (ATP) secretion tests. The index patients were homozygous for AQP7 G264V, which has previously been shown to inhibit transport of glycerol in Xenopus oocytes. We also detected a subclinical platelet secretion defect with reduced ATP secretion, and the absence of a secondary aggregation wave after epinephrine stimulation. Electron microscopy revealed round platelets with centrally located granules. Immunostaining showed AQP7 colocalization, with dense granules that seemed to be released after strong platelet activation. Healthy relatives of these patients, who were homozygous (not heterozygous) for G264V, also had hyperglyceroluria and platelet granule abnormalities. The discovery of an association between urine glycerol loss and a platelet secretion defect is a novel one, and our findings imply the involvement of AQPs in platelet secretion. Additional studies are needed to define whether AQP7 G264V is also a risk factor for mental disability.

Decreased expression of adipose CD36 and FATP1 are associated with increased plasma non-esterified fatty acids during prolonged fasting in northern elephant seal pups (Mirounga angustirostris)

The northern elephant seal pup (Mirounga angustirostris) undergoes a 2-3 month post-weaning fast, during which it depends primarily on the oxidation of fatty acids to meet its energetic demands. The concentration of non-esterified fatty acids (NEFAs) increases and is associated with the development of insulin resistance in late-fasted pups. Furthermore, plasma NEFA concentrations respond differentially to an intravenous glucose tolerance test (ivGTT) depending on fasting duration, suggesting that the effects of glucose on lipid metabolism are altered. However, elucidation of the lipolytic mechanisms including lipase activity during prolonged fasting in mammals is scarce. To assess the impact of fasting and glucose on the regulation of lipid metabolism, adipose tissue and plasma samples were collected before and after ivGTTs performed on early (2 weeks, N=5) and late (6-8 weeks; N=8) fasted pups. Glucose administration increased plasma triglycerides and NEFA concentrations in late-fasted seals, but not plasma glycerol. Fasting decreased basal adipose lipase activity by 50%. Fasting also increased plasma lipase activity twofold and decreased the expressions of CD36, FAS, FATP1 and PEPCK-C by 22-43% in adipose tissue. Plasma acylcarnitine profiling indicated that late-fasted seals display higher incomplete LCFA β-oxidation. Results suggest that long-term fasting induces shifts in the regulation of lipolysis and lipid metabolism associated with the onset of insulin resistance in northern elephant seal pups. Delineation of the mechanisms responsible for this shift in regulation during fasting can contribute to a more thorough understanding of the changes in lipid metabolism associated with dyslipidemia and insulin resistance in mammals.

Oral contraception and energy intake in women: Impact on substrate oxidation during exercise

Oral contraception (OC) and energy intake may play a role in fuel selection during exercise. The aim of this study was to investigate the effect of OCs (OC+ vs. OC-) in fed and fasting conditions on substrate oxidation and metabolic and hormonal responses in women during exercise. Substrate oxidation (respiratory exchange ratio and lipid and carbohydrates oxidation rates), metabolic (glycerol, free fatty acids (FFA), and glucose), and hormonal (insulin, adrenaline, and noradrenaline) responses were determined in 21 women: 10 regularly menstruating women (OC-) and 11 women using OCs (OC+: low-dose monophasic pill; ethinyl estradiol ≤ 30 µg) during 45 min at 65% of maximal oxygen consumption in fasting and postprandial states. At rest, OC+ presented higher low-density lipoprotein cholesterol, total cholesterol, and triglyceride plasma concentrations as compared with OC-. OC status had no influence on substrate oxidation and metabolic and hormonal responses during exercise. In the fasting state, whatever the OC status, women exhibited greater reliance on fat than in postprandial condition. This occurred in the presence of lower plasma insulin concentrations and higher plasma FFA and glycerol levels. The results indicated that the use of low-dose monophasic combined with OCs did not modify fuel selection and metabolic and hormonal responses during exercise in women. The fasting condition, compared with the fed condition, decreased carbohydrate oxidation during exercise, leading to a greater lipid mobilization and utilization whatever the OC status. Thus, in women, the realization of an exercise in either the fed or fasting conditions had a greater impact on substrate oxidation than OC status.

High Dietary Glucose Intake Increases Hepatic Triglyceride Content and Oxidative Stress: Contributions of Angiotensin Receptor

Excessive glucose intake exacerbates the deposition of adipose and plasma lipid levels and can subsequently increase organ‐specific oxidative damage during insulin resistance. To test our hypothesize that angiotensin receptor contributes to increased hepatic triglyceride content and oxidative stress following increased glucose intake in a model of metabolic syndrome, we studied 5 groups of rats: 1) LETO (lean control strain), 2) OLETF (15 wk), 3) OLETF + ARB (10 mg olmesartan mg/kg/d), 4) OLETF + high glucose (HG; 5% in water) and 5) OLETF + ARB + HG. HG had increased plasma triglycerides (TG) (35%), plasma glycerol (87%), free fatty acids (FFA) (28%) and body mass (BM) (37%), indicative of dislipidemia, as well as increased (74%) hepatic lipid peroxidation (4‐HNE). ARB treatment in HG reduced plasma TG (15%), plasma glycerol (23%), FFA (14%), BM (12%), and hepatic TG content (42%). ARB treatment in HG also decreased hepatic nitrotyrosine and increased UCP2 protein expression (59%), aconitase (40%) and antioxidant enzyme activities 50–120% suggesting that AT1 activation contributes to protein oxidation, lipid metabolism, fat deposition and lipid‐associated hepatic oxidative stress. Thus, besides the antihypertensive effects of ARB treatment, ARBs can also improve the condition of metabolic syndrome by improving the lipid profile and reducing adiposity and oxidative stress. Funded by NIH NCMHD 9T37MD001480 &amp; P20MD005049.

Effect of Alipogene Tiparvovec (AAV1-LPLS447X) on Postprandial Chylomicron Metabolism in Lipoprotein Lipase-Deficient Patients

Lipoprotein lipase-deficient (LPLD) individuals display marked chylomicronemia and hypertriglyceridemia associated with increased pancreatitis risk. The aim of this study was to determine the effect of i.m. administration of an adeno-associated viral vector (AAV1) for expression of LPL(S447X) in muscle (alipogene tiparvovec, AAV1-LPL(S447X)) on postprandial chylomicron metabolism and on nonesterified fatty acid (NEFA) and glycerol metabolism in LPLD individuals. In an open-label clinical trial (CT-AMT-011-02), LPLD subjects were administered alipogene tiparvovec at a dose of 1 × 10(12) genome copies per kilogram. Two weeks before and 14 wk after administration, chylomicron metabolism and plasma palmitate and glycerol appearance rates were determined after ingestion of a low-fat meal containing (3)H-palmitate, combined with (continuous) iv infusion of [U-(13)C]palmitate and [1,1,2,3,3-(2)H]glycerol. After administration of alipogene tiparvovec, the triglyceride (TG) content of the chylomicron fraction and the chylomicron-TG/total plasma TG ratio were reduced throughout the postprandial period. The postprandial peak chylomicron (3)H level and chylomicron (3)H area under the curve were greatly reduced (by 79 and 93%, 6 and 24 h after the test meal, respectively). There were no significant changes in plasma NEFA and glycerol appearance rates. Plasma glucose, insulin, and C-peptide also did not change. Intramuscular administration of alipogene tiparvovec resulted in a significant improvement of postprandial chylomicron metabolism in LPLD patients, without inducing large postprandial NEFA spillover.

Fasting Energy Homeostasis in Mice with Adipose Deficiency of Desnutrin/Adipose Triglyceride Lipase

Adipose triglyceride lipase (ATGL) catalyzes the first step of lipolysis of cytoplasmic triacylglycerols in white adipose tissue (WAT) and several other organs. We created adipose-specific ATGL-deficient (ATGLAKO) mice. In these mice, in vivo lipolysis, measured as the increase of plasma nonesterified fatty acid and glycerol levels after injection of a β3-adrenergic agonist, was undetectable. In isolated ATGLAKO adipocytes, β3-adrenergic-stimulated glycerol release was 10-fold less than in controls. Under fed conditions, ATGLAKO mice had normal viability, mild obesity, low plasma nonesterified fatty acid levels, increased insulin sensitivity, and increased daytime food intake. After 5 h of fasting, ATGLAKO WAT showed phosphorylation of the major protein kinase A-mediated targets hormone-sensitive lipase and perilipin A and ATGLAKO liver showed low glycogen and triacylglycerol contents. During a 48-h fast, ATGLAKO mice developed striking and complex differences from controls: progressive reduction of oxygen consumption, high respiratory exchange ratio, consistent with reduced fatty acid availability for energy production, lethargy, hypothermia, and undiminished fat mass, but greater loss of lean mass than controls. Plasma of 48 h-fasted ATGLAKO mice had a unique pattern: low 3-hydroxybutyrate, insulin, adiponectin, and fibroblast growth factor 21 with elevated leptin and corticosterone. ATGLAKO WAT, liver, skeletal muscle, and heart showed increased levels of mRNA related to autophagy and proteolysis. In murine ATGL deficiency, adipose lipolysis is critical for fasting energy homeostasis, and fasting imposes proteolytic stress on many organs, including heart and skeletal muscle.

Impact of Intensive High-Fat Ingestion in the Early Stage of Recovery from Exercise Training on Substrate Metabolism during Exercise in Humans

Not only increasing body carbohydrate (CHO) stores before exercise but also suppressing CHO oxidation during exercise is important for improving endurance performance. We tested the hypothesis that intensive high-fat ingestion in the early stage of recovery from exercise training (ET) for 2 d would suppress CHO oxidation during exercise by increasing whole body lipolysis and/or fat oxidation. In a randomized crossover design, on days 1 and 2, six male subjects performed cycle ET at 50% peak oxygen consumption (VO(2 peak)) for 60-90 min, and consumed a control diet (CON: 1,224 kcal, 55% carbohydrate, 30% fat) or the same diet supplemented with high fat (HF: 1,974 kcal, 34% carbohydrate, 56% fat) 1 h after ET, with the diet other than post-ET similar in both trials. On day 3, subjects performed cycle exercise at 65% VO(2 peak) until exhaustion. Exercise time to exhaustion was longer in the HF trial than in the CON trial (CON: 48.9 ± 6.7 vs. HF: 55.8 ± 7.7 min, p<0.05). In the HF trial, total fat oxidation until exhaustion was higher, accompanied by higher post-exercise plasma glycerol concentration, than in the CON trial (CON: 213 ± 54 vs. HF: 286 ± 63 kcal, p<0.05), whereas total carbohydrate oxidation until exhaustion was not different between trials. These results suggest that intensive high-fat ingestion in the early stage of recovery from ET for a few days until the day before exercise was an effective means of eliciting a CHO-sparing effect during exercise by enhancing fat metabolism.

Expression Analysis of Glycerol Synthesis–Related Liver Transcripts in Rainbow Smelt (Osmerus mordax) Exposed to a Controlled Decrease in Temperature

Rainbow smelt (Osmerus mordax) accumulate high glycerol levels to avoid freezing at subzero temperatures. Glyceroneogenesis is activated by low temperature and occurs in liver via a branch in glycolysis and gluconeogenesis. In this study, carbohydrate and liver transcript levels of 21 genes potentially associated with glycerol production were assessed during a controlled warm to cold transition. Smelt were held at 8°C (warm smelt; non-glycerol accumulating) or subjected to a controlled decrease in water temperature from 8° to 0°C (cold smelt; glycerol accumulating) and sampled at the end of the temperature decrease and 1 mo later. In cold smelt compared with warm smelt, liver glycogen levels were lower and phosphoglucomutase transcript levels were higher. Plasma glycerol levels were higher and increased over time in cold smelt; in cold smelt, liver phosphofructokinase and pyruvate dehydrogenase kinase transcript levels increased over time. These findings imply that glycerol production is being fueled by glycogen degradation and inhibition of pyruvate oxidation serves to channel metabolic flux toward glycerol as opposed to complete glycolysis. Plasma glucose and liver glucose-6-phosphatase transcript levels were higher. Lipoprotein lipase transcript levels were higher, suggesting enhanced lipid breakdown to fuel energy metabolism. Glutamine synthetase transcript levels were higher, perhaps to store nitrogen for biosynthesis in spring.