Decreased Plasma Free Fatty Acids Research Articles

Metabolic responses to albumin deficiency differ distinctly between partial and full ablation of albumin expression in mice

It had been observed that homozygous albumin knockout mice (Alb−/−) exhibit low plasma free fatty acid (FFA) concentration and improved blood glucose regulation. However, it was not yet known to what extent heterozygous albumin knockout (Alb+/−) mice would display a similar phenotype. Alb−/−, Alb+/−, and wild-type (WT) female mice were studied on a low-fat diet (LFD) or high-fat diet (HFD). On both diets, decreased plasma FFA concentration, and improved glucose tolerance test were observed in Alb−/−, but not in Alb+/−, compared to WT. Plasma adiponectin concentration showed greater elevation in Alb−/− than Alb+/−. Consistent with that, adiponectin gene expression was significantly higher in Alb−/− mice than in Alb+/− and WT mice. A dose-dependent response was observed for hepatic Acadl gene expression showing higher Acadl gene expression in Alb−/− mice than in Alb+/− and WT mice. In conclusion, although female Alb+/− mice exhibited some slight differences from WT mice (e.g., increased plasma adiponectin and hepatic Acadl gene expression), Alb+/− mice did not exhibit improved glucoregulation in comparison to WT mice, indicating that a minor suppression of albumin expression is not sufficient to improve glucoregulation. Furthermore, it is now clear that although the response of female mice to HFD might be unique from how males generally respond, still the complete albumin deficiency in Alb−/− mice and the associated FFA reduction is capable of improving glucoregulation in females on this diet. The present results have implications for the role of albumin and FFA in the regulation of metabolism.

Novel markers and networks related to restored skeletal muscle transcriptome after bariatric surgery.

The aim of this study was to discover novel markers underlying the improvement of skeletal muscle metabolism after bariatric surgery. Skeletal muscle transcriptome data of lean people and people with obesity, before and 1 year after bariatric surgery, were subjected to weighted gene co-expression network analysis (WGCNA) and least absolute shrinkage and selection operator (LASSO) regression. Results of LASSO were confirmed in a replication cohort. The expression levels of 440 genes differing between individuals with and without obesity were no longer different 1 year after surgery, indicating restoration. WGCNA clustered 116 genes with normalized expression in one major module, particularly correlating to weight loss and decreased plasma free fatty acids (FFA), 44 of which showed an obesity-related phenotype upon deletion in mice. Among the genes of the major module, 105 represented prominent markers for reduced FFA concentration, including 55 marker genes for decreased BMI in both the discovery and replication cohorts. Previously unknown gene networks and marker genes underlined the important role of FFA in restoring muscle gene expression after bariatric surgery and further suggest novel therapeutic targets for obesity.

Anti-adiposity and lipid-lowering effects of schisandrol A in diet-induced obese mice.

Lignan schisandrol A (SolA) is known to have antioxidant and anti-inflammatory effects. However, the impact of SolA on obesity is poorly understood. To test the hypothesis that SolA has anti-obesity effects, C57BL/6J mice were fed a high-fat diet with or without SolA (0.006%, w/w) for 16 weeks. SolA decreased visceral fat mass (10%) by increasing energy expenditure and upregulating white adipose tissue thermogenic genes mRNA expression. Furthermore, SolA upregulated adipose Lpl mRNA expression and decreased plasma free fatty acid (FFA), triglyceride (TG), apolipoprotein (apo) B, aspartate aminotransferase levels and TG/HDL-cholesterol and apoB/apoA1 ratios as well as hepatic lipid droplets. Increased hepatic β-oxidation and fecal FFA and TG levels were observed in the SolA-supplemented mice, suggesting an association of its lipid-lowering effect with increased hepatic β-oxidation, fecal fat excretion and adipose Lpl. Conclusionally, this study provides evidence on the protective effects of SolA against adiposity, dyslipidemia and nonalcoholic fatty liver disease in obese mice.

Albumin Knockout Mice Exhibit Reduced Plasma Free Fatty Acids but No Impairment in Whole Body Fat Oxidation

Abstract Objectives To improve understanding of the control of lipid metabolism, we aimed to determine whether lack of serum albumin decreases plasma free fatty acids (FFA), hepatic triacylglycerol (TAG), and whole body substrate oxidation in albumin knockout mice compared to wild type mice. Methods Male and female homozygous albumin knockout mice and C57BL/6J wild type controls, each on the 5k52 diet which contains a moderate fat content, were studied at 6–8 weeks of age. Body composition was tested by magnetic resonance. Substrate oxidation was measured by indirect calorimetry over 24 hours in metabolic cages. Plasma and tissues were collected after a 5-hour fast. Plasma FFA was measured by liquid chromatography/mass spectrometry (LC/MS). Hepatic TAG was measured by a colorimetric kit. Results In albumin knockout mice compared to the wild type mice, plasma FFA (P < 0.0001) and hepatic TAG content (P < 0.0001) were each reduced, while body fat percentage was increased (P < 0.01). In addition, female versus male showed higher hepatic TAG levels (P < 0.01). These results indicate that the lack of serum albumin decreases plasma FFA and hepatic TAG accumulation. However, the average 24-hour oxygen consumption, metabolic rate, and respiratory quotient (RQ) were not altered in albumin knockout mice, indicating that total fuel oxidation and relative contribution of lipid to whole body metabolism was not significantly unaltered. Conclusions We propose that lack of albumin reduces plasma FFA which diminishes hepatic TAG content through changes in the lipid supply to the liver. The results indicate that tissue lipid accumulation can be altered by targeting albumin without substantially disrupting whole body substrate oxidation, suggesting that metabolic control of FFA trafficking toward sites of ectopic lipid deposition and toward oxidation can be regulated independently of one another. Funding Sources McKinley Educational Initiative and the Purdue University College of Health and Human Sciences

Low-intensity exercise diverts cardiac fatty acid metabolism from triacylglycerol synthesis to beta oxidation in fructose-fed rats

Context Excessive fructose consumption causes ectopic lipid storage leading to metabolic disorders and cardiovascular diseases associated with defective substrate utilisation in the heart. Objective Examining the preventive impact of low-intensity exercise on alterations related to fructose-rich diet (FRD) on cardiac fatty acid (FA) transport and metabolism. Materials and methods Male Wistar rats were divided into control and two groups that received 10% fructose for 9 weeks, one of which was additionally exposed to exercise. Results FRD elevated plasma and cardiac TAG, FATP1 in plasma membrane, Lipin 1 in microsomes and HSL mRNA, while mitochondrial CPT1 was decreased. Exercise decreased plasma free FA level, raised CD36 in plasma membrane and FATP1 in lysate, mitochondrial CPT1 and decreased microsomal Lipin 1 in fructose-fed rats. Conclusions FRD changed plasma lipids and augmented partitioning of FA to TAG storage in the heart, whereas exercise in FRD rats switched metabolism of FA towards β-oxidation.

The Impact of Glucose-Based or Lipid-Based Total Parenteral Nutrition on the Free Fatty Acids Profile in Critically Ill Patients.

Introduction: Our study aim was to assess how the macronutrient intake during total parenteral nutrition (TPN) modulates plasma total free fatty acids (FFAs) levels and individual fatty acids in critically ill patients. Method: Adult patients aged 18–80, admitted to the intensive care unit (ICU), who were indicated for TPN, with an expected duration of more than three days, were included in the study. Isoenergetic and isonitrogenous TPN solutions were given with a major non-protein energy source, which was glucose (group G) or glucose and lipid emulsions (Smof lipid; group L). Blood samples were collected on days 0, 1, 3, 6, 9, 14, and 28. Results: A significant decrease (p < 0.001) in total FFAs occurred in both groups with a bigger decrease in group G (p < 0.001) from day 0 (0.41 ± 0.19 mmol∙L−1) to day 28 (0.10 ± 0.07 mmol∙L−1). Increased palmitooleic acid and decreased linoleic and docosahexaenoic acids, with a trend of increased mead acid to arachidonic acid ratio, on day 28 were observed in group G in comparison with group L. Group G had an insignificant increase in leptin with no differences in the concentrations of vitamin E, triacylglycerides, and plasminogen activator inhibitor-1. Conclusion: Decreased plasma FFA in critically ill patients who receive TPN may result from increased insulin sensitivity with a better effect in group G, owing to higher insulin and glucose dosing and no lipid emulsions. It is advisable to include a lipid emulsion at the latest from three weeks of TPN to prevent essential fatty acid deficiency.

Improving insulin resistance with Antrodia cinnamomea mycelium powder to induce a hypoglycemic effect in dexamethasone‑induced insulin‑resistant rats.

Insulin resistance is a major factor in typeII diabetes development, occurring when insulin levels are normal, but do not have normal interactions with adipose, muscle or liver tissue. The present study aimed to explore the hypoglycemic effect of Antrodiacinnamomea (AC) mycelium powder by evaluating its impact on insulin resistance and plasma free fatty acid (FFA) levels in steroid‑induced insulin‑resistant (SIIR) rats. Male Wistar rats were administered dexamethasone for 5days to induce insulin resistance. The SIIR rats were subsequently randomly assigned into three experimental groups (EGs) and a control group (CG), where saline was orally administered. The EGs were orally administered different doses of AC (100, 200 or 500mg/kg) and an optimal dose for further study was determined. Changes in plasma insulin and glucose levels were calculated to investigate the hypoglycemic effect of AC. To evaluate insulin resistance, the homeostasis model assessment‑estimated insulin resistance of the SIIR rats was determined. Changes in plasma FFA levels were detected and levels of insulin signal proteins (IRS‑1, GLUT‑4 and PI3K) were analyzed by western blot to elucidate AC's mechanism of action. The SIIR rats exhibited significantly decreased plasma glucose levels in the first 30min, with plasma FFA levels displaying a marked downward trend (P<0.05) when they were administered the optimal dose of AC (200mg/kg). The decrease in plasma glucose and FFA levels was significantly larger in the EG compared to the CG, and insulin signal protein levels were also significantly increased (P<0.05). The hypoglycemic effect observed may be due to decreased plasma FFA levels and increased expression of intracellular insulin signal proteins. Furthermore, insulin sensitivity was enhanced, indicating that AC acts as an insulin sensitizer in insulin resistant animal models.

Insulin's direct hepatic effect explains the inhibition of glucose production caused by insulin secretion.

Insulin can inhibit hepatic glucose production (HGP) by acting directly on the liver as well as indirectly through effects on adipose tissue, pancreas, and brain. While insulin's indirect effects are indisputable, their physiologic role in the suppression of HGP seen in response to increased insulin secretion is not clear. Likewise, the mechanisms by which insulin suppresses lipolysis and pancreatic α cell secretion under physiologic circumstances are also debated. In this study, insulin was infused into the hepatic portal vein to mimic increased insulin secretion, and insulin's indirect liver effects were blocked either individually or collectively. During physiologic hyperinsulinemia, plasma free fatty acid (FFA) and glucagon levels were clamped at basal values and brain insulin action was blocked, but insulin's direct effects on the liver were left intact. Insulin was equally effective at suppressing HGP when its indirect effects were absent as when they were present. In addition, the inhibition of lipolysis, as well as glucagon and insulin secretion, did not require CNS insulin action or decreased plasma FFA. This indicates that the rapid suppression of HGP is attributable to insulin's direct effect on the liver and that its indirect effects are redundant in the context of a physiologic increase in insulin secretion.

Different regulation of insulin on glucose and lipid metabolism in 2 strains of gibel carp

To test the hypothesis that response to insulin by regulating glucose and lipid metabolism in gibel carp A strain may be different from that in DT strain, bovine insulin was injected into both strains of gibel carp after previous fasting for 48h. The results showed that insulin induced hypoglycemia at 3h in 2 strains, and that this was coupled with increased expression of glucose transporters (GLUT2 in the liver and GLUT1, GLUT4 in the muscle) and glycolytic enzyme (HK2 in the muscle) in both strains. Insulin induced increased glycolysis (GK) and fatty acid oxidation (ACO3 in the liver and CPT1a, ACO3 in the muscle) in the DT strain. Conversely, very strong lipogenic capacity, as indicated by higher mRNA levels of transcription factor of fatty acid anabolism (SREBP1) and lipogenic enzymes (ACC, ACLY, and FAS) and decrease lipolytic capacity as indicated by lower mRNA levels of fatty acid oxidation enzymes in the liver (ACO3) and muscle (CPT1a and ACO3) detected in the A strain after insulin injection. Higher plasma insulin levels and decreased plasma free fatty acid levels were detected at 8h post insulin injection in A strain induced hypoglycemia. However, plasma glucose levels returned to baseline and no effect on fatty acid levels in the DT strain was observed in response to insulin treatment at the same point in time. These insulin-strain interactions demonstrated that insulin induced different changes in glucose and lipid metabolism in these 2 strains as expected.

Alpha-mangostin from mangosteen (Garcinia mangostana Linn.) pericarp extract reduces high fat-diet induced hepatic steatosis in rats by regulating mitochondria function and apoptosis.

BackgroundNon-alcoholic fatty liver disease (NAFLD) is caused by multiple factors including hepatic oxidative stress, lipotoxicity, and mitochondrial dysfunction. Obesity is among the risk factors for NAFLD alongside type 2 diabetes mellitus and hyperlipidemia. α- mangostin (α-MG) extracts from the pericarps of mangosteen (Garcinia mangostana Linn.) may regulate high fat diet-induced hepatic steatosis; however the underlying mechanisms remain unknown. The aim of this study was to investigate the regulatory effect of α-MG on high fat diet-induced hepatic steatosis and the underlying mechanisms related to mitochondrial functionality and apoptosis in vivo and in vitro.MethodsSprague Dawley (SD) rats were fed on either AIM 93-M control diet, a high-fat diet (HFD), or high-fat diet supplemented with 25 mg/day mangosteen pericarp extract (MGE) for 11 weeks. Thereafter, the following were determined: body weight change, plasma free fatty acids, liver triglyceride content, antioxidant enzymes (superoxide dismutase, SOD; glutathione, GSH; glutathione peroxidase, GPx; glutathione reductase GRd; catalase, CAT) and mitochondrial complex enzyme activities. In the in vitro study, primary liver cells were treated with 1 mM free fatty acid (FFA) (palmitate: oleate acid = 2:0.25) to induce steatosis. Thereafter, the effects of α-MG (10 μM, 20 μM, 30 μM) on total and mitochondria ROS (tROS, mitoROS), mitochondria bioenergetic functions, and mitochondrial pathway of apoptosis were examined in the FFA-treated primary liver cells.ResultsThe MGE group showed significantly decreased plasma free fatty acids and hepatic triglycerides (TG) and thiorbarbituric acid reactive substances (TBARS) levels; increased activities of antioxidant enzymes (SOD, GSH, GPx, GRd, CAT); and enhanced NADH-cytochrome c reductase (NCCR) and succinate-cytochrome c reductase (SCCR) activities in the liver tissue compared with HFD group. In the in vitro study, α-MG significantly increased mitochondrial membrane potential, enhanced cellular oxygen consumption rate (OCR), decreased tROS (total ROS) and mitoROS (mitochondrial ROS) levels ; reduced Ca2+ and cytochrome c (cyt c) release from mitochondria, and reduced caspases 9 and 3 activities compared with control group.ConclusionThese findings demonstrate α-MG attenuated hepatic steatosis in high fat-diet fed rats potentially through enhanced cellular antioxidant capacity and improved mitochondrial functions as well as suppressed apoptosis of hepatocytes. The findings of study represent a novel nutritional approach on the use of α-MG in the prevention and management of NAFLD.

Exploring the Lean Phenotype of Glutathione-Depleted Mice: Thiol, Amino Acid and Fatty Acid Profiles.

BackgroundAlthough reduced glutathione (rGSH) is decreased in obese mice and humans, block of GSH synthesis by buthionine sulfoximine (BSO) results in a lean, insulin-sensitive phenotype. Data is lacking about the effect of BSO on GSH precursors, cysteine and glutamate. Plasma total cysteine (tCys) is positively associated with stearoyl-coenzyme A desaturase (SCD) activity and adiposity in humans and animal models.ObjectiveTo explore the phenotype, amino acid and fatty acid profiles in BSO-treated mice.DesignMale C3H/HeH mice aged 11 weeks were fed a high-fat diet with or without BSO in drinking water (30 mmol/L) for 8 weeks. Amino acid and fatty acid changes were assessed, as well as food consumption, energy expenditure, locomotor activity, body composition and liver vacuolation (steatosis).ResultsDespite higher food intake, BSO decreased particularly fat mass but also lean mass (both P<0.001), and prevented fatty liver vacuolation. Physical activity increased during the dark phase. BSO decreased plasma free fatty acids and enhanced insulin sensitivity. BSO did not alter liver rGSH, but decreased plasma total GSH (tGSH) and rGSH (by ~70%), and liver tGSH (by 82%). Glutamate accumulated in plasma and liver. Urine excretion of cysteine and its precursors was increased by BSO. tCys, rCys and cystine decreased in plasma (by 23–45%, P<0.001 for all), but were maintained in liver, at the expense of decreased taurine. Free and total plasma concentrations of the SCD products, oleic and palmitoleic acids were decreased (by 27–38%, P <0.001 for all).ConclusionCounterintuitively, block of GSH synthesis decreases circulating tCys, raising the question of whether the BSO-induced obesity-resistance is linked to cysteine depletion. Cysteine-supplementation of BSO-treated mice is warranted to dissect the effects of cysteine and GSH depletion on energy metabolism.

Effects of dry period length and dietary energy source on milk yield, energy balance, and metabolic status of dairy cows over 2 consecutive years: Effects in the second year

The objective of the current study was to evaluate the effect of dry period (DP) length on milk yield, energy balance (EB), and metabolic status in cows fed a lipogenic or glucogenic diet in the second year after implementation of DP and dietary treatments. Holstein-Friesian dairy cows (n=167) were assigned randomly to 1 of 3 DP lengths (0, 30, or 60d) and 1 of 2 early lactation diets (glucogenic or lipogenic) for 2 consecutive years. Results of the first year were reported previously. In the second year, 19 cows in the 0-d DP group were attributed to a new group (0→67d DP) because these cows had a milk yield of <4kg/d at least 30d before expected calving date and were dried off. Milk yield was recorded and EB was calculated from wk –8 to 9 relative to calving. Blood samples were taken weekly from wk –3 to 8 relative to calving. Liver samples were taken in wk –2, 2, and 4 relative to calving. At the onset of lactation, cows with a 0-d or 0→67-d DP had greater body condition score (BCS) than cows with a 60-d DP. During the first 9wk, cows with a 0- or 30-d DP produced 5.0 and 4.3kg less milk per day, respectively, but had similar EB compared with cows with a 60-d DP. Cows with a 0- or 30-d DP produced additional milk precalving, which could compensate milk yield losses in the first 9wk postcalving. Cows with a 0-d DP did not have milk yield losses or improve EB in the second year as much as in the first year. Cows with a 0-d DP had greater plasma insulin and insulin-like growth factor-I (IGF-I) and lower liver triacylglycerol concentrations than cows with other DP lengths. Cows with a 0→67-d DP had lower EB, and greater plasma free fatty acids (FFA) and β-hydroxybutyrate (BHB) concentrations than cows with other DP lengths. Feeding a glucogenic diet increased plasma glucose, IGF-I, and insulin concentrations, and decreased plasma FFA, BHB, and urea concentrations compared with a lipogenic diet, independent of DP length. In conclusion, omitting the DP or feeding a glucogenic diet improved metabolic status in early lactation of the second year after implementation of DP length and dietary treatments, although effects of omitting the DP were less pronounced in the second year than in the first year. The less pronounced improvement of EB in the second year was related to the high BCS at the onset of lactation and reduced milk yield losses in cows with a 0-d DP.

α-Linolenic acid increases the G0/G1 switch gene 2 mRNA expression in peripheral blood mononuclear cells from obese patients: a pilot study

BackgroundRecent evidence has demonstrated that the G0/G1 switch gene 2 (G0S2) is an important negative regulator of the rate-limiting lipolytic enzyme adipose triglyceride lipase-mediated lipolysis. It has been revealed that α-linolenic acid (ALA), a plant-based essential omega-3 polyunsaturated fatty acids, reduces adipose tissue lipolysis. However, it is not known whether G0S2 is implicated in ALA-induced inhibition of lipolysis. The purpose of this pilot study is to investigate the effect of ALA on G0S2 gene expression in peripheral blood mononuclear cells (PBMC) of obese patients and the potential influence of G0S2 gene expression in ALA-induced inhibition of lipolysis.MethodsA total of 26 obese patients were randomly assigned to be treated with or without ALA treatment (~4.0 g daily) for 12 weeks: the ALA-treated group (n = 14) or the untreated control group (n = 12). Plasma triglyceride (TG), free fatty acids (FFA), glycerol, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), as well as the mRNA expression levels of proliferator-activated receptor gamma (PPAR-γ), G0S2, and G protein-coupled receptor 120 (GPR120) in PBMC were repeatedly examined from fasting obese patients before and after ALA treatment.ResultsALA significantly decreased plasma TG, FFA, glycerol, IL-6, and TNF-α levels and increased the mRNA expression levels of PPAR-γ, G0S2, and GPR120 in PBMC, compared with the untreated control group. In obese patients from the ALA-treated group, decreased plasma FFA (a biomarker for lipolysis) level was significantly correlated with increased PPAR-γ (a functional omega-3 fatty acids receptor) and G0S2 (a direct target gene of PPAR-γ) mRNA expression in PBMC, while decreased plasma FFA level was not correlated with increased GPR120 (another functional omega-3 fatty acids receptor) mRNA expression in PBMC.ConclusionThis study shows that ALA increases G0S2 gene expression in PBMC in parallel with the decrease of plasma FFA level in obese patients. Increased G0S2 gene expression might contribute to the beneficial anti-lipolytic effect of ALA in obese patients.

Endothelin regulates intermittent hypoxia-induced lipolytic remodelling of adipose tissue and phosphorylation of hormone-sensitive lipase.

Obstructive sleep apnoea syndrome is characterized by repetitive episodes of upper airway collapse during sleep resulting in chronic intermittent hypoxia (IH). Obstructive sleep apnoea syndrome, through IH, promotes cardiovascular and metabolic disorders. Endothelin-1 (ET-1) secretion is upregulated by IH, and is able to modulate adipocyte metabolism. Therefore, the present study aimed to characterize the role of ET-1 in the metabolic consequences of IH on adipose tissue in vivo and in vitro. Wistar rats were submitted to 14 days of IH-cycles (30 s of 21% FiO2 and 30 s of 5% FiO2 ; 8 h day(-1) ) or normoxia (air-air cycles) and were treated or not with bosentan, a dual type A and B endothelin receptor (ETA-R and ETB-R) antagonist. Bosentan treatment decreased plasma free fatty acid and triglyceride levels, and inhibited IH-induced lipolysis in adipose tissue. Moreover, IH induced a 2-fold increase in ET-1 transcription and ETA-R expression in adipose tissue that was reversed by bosentan. In 3T3-L1 adipocytes, ET-1 upregulated its own and its ETA-R transcription and this effect was abolished by bosentan. Moreover, ET-1 induced glycerol release and inhibited insulin-induced glucose uptake. Bosentan and BQ123 inhibited these effects. Bosentan also reversed the ET-1-induced phosphorylation of hormone-sensitive lipase (HSL) on Ser(660) . Finally, ET-1-induced lipolysis and HSL phosphorylation were also observed under hypoxia. Altogether, these data suggest that ET-1 is involved in IH-induced lipolysis in Wistar rats, and that upregulation of ET-1 production and ETA-R expression by ET-1 itself under IH could amplify its effects. Moreover, ET-1-induced lipolysis could be mediated through ETA-R and activation of HSL by Ser(660) phosphorylation.

Free fatty acid availability is closely related to myocardial lipid storage and cardiac function in hypoglycemia counterregulation.

Hypoglycemia, a major side effect of intensive glucose-lowering therapy, was recently linked to increased cardiovascular risk in patients with diabetes. Whether increased circulating free fatty acids (FFA) owing to catecholamine-induced lipolysis affect myocardial energy metabolism and thus link hypoglycemia to cardiac vulnerability is unclear. Therefore, this study investigated the impact of hypoglycemia counterregulation (± inhibition of lipolysis) on myocardial lipid content (MYCL) and left ventricular function in healthy subjects. Nine healthy men were studied in randomized order: 1) insulin/hypoglycemia test (IHT; ins+/aci-), 2) IHT during inhibition of adipose tissue lipolysis by acipimox (ins+/aci+), 3) normoglycemia with acipimox (ins-/aci+), and 4) normoglycemia with placebo (ins-/aci-). MYCL and cardiac function were assessed by employing magnetic resonance spectroscopy/imaging at baseline and at 2 and 6 h. In response to acute hypoglycemia, plasma FFA (P<0.0001) and ejection fraction (EF; from 63.2±5.5 to 69.6±6.3%, P=0.0001) increased significantly and were tightly correlated with each other (r=0.68, P=0.0002); this response was completely blunted by inhibition of adipose tissue lipolysis. In the presence of normoglycemia, inhibition of lipolysis was associated with a drop in EF (from 59.2±5.5 to 53.9±6.9%,P=0.005) and a significant decrease in plasma FFA, triglycerides, and MYCL (by 48.5%, P=0.0001). The present data indicate that an intact interorgan cross-talk between adipose tissue and the heart is a prerequisite for catecholamine-mediated myocardial contractility and preservation of myocardial lipid stores in response to acute hypoglycemia.

Chronic Reduction of Plasma Free Fatty Acid Improves Mitochondrial Function and Whole-Body Insulin Sensitivity in Obese and Type 2 Diabetic Individuals

Insulin resistance and dysregulation of free fatty acid (FFA) metabolism are core defects in type 2 diabetic (T2DM) and obese normal glucose tolerant (NGT) individuals. Impaired muscle mitochondrial function (reduced ATP synthesis) also has been described in insulin-resistant T2DM and obese subjects. We examined whether reduction in plasma FFA concentration with acipimox improved ATP synthesis rate and altered reactive oxygen species (ROS) production. Eleven NGT obese and 11 T2DM subjects received 1) OGTT, 2) euglycemic insulin clamp with muscle biopsy, and 3) 1H-magnetic resonance spectroscopy of tibialis anterior muscle before and after acipimox (250 mg every 6 h for 12 days). ATP synthesis rate and ROS generation were measured in mitochondria isolated from muscle tissue ex vivo with chemoluminescence and fluorescence techniques, respectively. Acipimox 1) markedly reduced the fasting plasma FFA concentration and enhanced suppression of plasma FFA during oral glucose tolerance tests and insulin clamp in obese NGT and T2DM subjects and 2) enhanced insulin-mediated muscle glucose disposal and suppression of hepatic glucose production. The improvement in insulin sensitivity was closely correlated with the decrease in plasma FFA in obese NGT (r = 0.81) and T2DM (r = 0.76) subjects (both P < 0.001). Mitochondrial ATP synthesis rate increased by >50% in both obese NGT and T2DM subjects and was strongly correlated with the decrease in plasma FFA and increase in insulin-mediated glucose disposal (both r > 0.70, P < 0.001). Production of ROS did not change after acipimox. Reduction in plasma FFA in obese NGT and T2DM individuals improves mitochondrial ATP synthesis rate, indicating that the mitochondrial defect in insulin-resistant individuals is, at least in part, reversible.

Angiopoietin-like 4: An endogenous break of intestinal lipid digestion

Angiopoietin-like 4: An endogenous break of intestinal lipid digestion

Abstract 75: Chronic Treatment With At2 Receptor Agonist Rescues High Fat Diet-induced Obesity in Female Mice.

Obesity in itself is a disease condition and a major risk factor in the development of hypertension, dyslipidemia, and hyperglycemia. Therefore, successful strategies for improving obesity and related metabolic risk factors are needed. Role of renin-angiotensin system (RAS) has been implicated in obesity and metabolic dysfunction. Recently, we have shown that AT2R knock-out in female mice caused a greater body weight gain and hyperinsulimia in response to high fat diet (HFD). In the present study, we hypothesize that AT2R activation rescues diet-induced obesity in females. To test this hypothesis, we injected AT2R non-peptide agonist C21 (0.3mg/kg/day i.p) in C57BL6 female mice on HFD for 12 weeks. C21-treatment did not affect the HFD calorie intake (HFD: 937±18 Kcal; C21HFD: 886±37 Kcal) but caused lesser body weight gain compared to control (HFD: 4.4± 0.4g; C21HFD: 3.06± 0.4g). Similar to the body weight gain pattern, gonadal fat weight and adipocyte size were decreased significantly in C21-treated mice on HFD compared to control HFD group (HFD: 4.4± 0.4 g; C21 HFD: 3.06± 0.4g) and (HFD: 6404±161.6μm2 ; C21HFD: 3874±103.2μm2 ) respectively. Moreover, the C21-treated females on HFD had lower levels of plasma insulin, improved glucose tolerance, and decreased plasma free fatty acids and hepatic triglycerides. Western blot revealed that phospho-Ser79-acetyl CoA carboxylase (p-Ser79-ACC-1) was reduced, an index of increased lipogenic activity and decreased β-oxidation process, in both adipose (Adi) and hepatic (Hep) tissues of HFD fed groups (Adi: 86% and Hep: 73% of 100% controls); C21-treatment revered the decrease in p-ser79-ACC-1 in Adi (104% of control) and caused an increase in Hep (122% of control) respectively. The HFD feeding lowered the estradiol level (ND: 38.8±2.6 vs HFD:11.3±1.2ng), which was modestly reversed by C21 treatment (C21HFD:17.4± 1.5ng) in HFD mice. Our results strongly suggest that stimulation of AT2R in female mice positively contribute, predominantly independent of estrogen, to rescue body weight gain and adipocyte size increase in response to HFD. We propose reduced lipogenesis and enhanced lipid β-oxidation as potential mechanisms linked to AT2R action in reducing obesity and its related metabolic disorders in females.

Estradiol enhances effects of fructose rich diet on cardiac fatty acid transporter CD36 and triglycerides accumulation

Fructose rich diet increases hepatic triglycerides production and has deleterious cardiac effects. Estrogens are involved in regulation of lipid metabolism as well, but their effects are cardio beneficial. In order to study effects of fructose rich diet on the main heart fatty acid transporter CD36 and the role of estrogens, we subjected ovariectomized female rats to the standard diet or fructose rich diet, with or without estradiol (E2) replacement. The following parameters were analyzed: feeding behavior, visceral adipose tissue mass, plasma lipids, cardiac CD36 expression, localization and insulin regulation, as well as the profile of cardiac lipids. Results show that fructose rich diet significantly increased plasma triglycerides and decreased plasma free fatty acid (FFA) concentration, while E2 additionally emphasized FFA decrease. The fructose diet increased cardiac plasma membrane content of CD36 in the basal and insulin-stimulated states, and decreased its low density microsomes content. The E2 in fructose-fed rats raised the total cardiac protein content of CD36, its presence in plasma membranes and low density microsomes, and cardiac deposition of triglycerides, as well. Although E2 counteracts fructose in some aspects of lipid metabolism, and separately they have opposite cardiac effects, in combination with fructose rich diet, E2 additionally enhances CD36 presence in plasma membranes of cardiac cells and triglycerides accumulation, which paradoxically might promote deleterious effects of fructose diet on cardiac lipid metabolism. Taken together, the results presented in this work are of high importance for clinical administration of estrogens in females with a history of type 2 diabetes.

Acute hyperinsulinemia and reduced plasma free fatty acid levels decrease intramuscular triglyceride synthesis

ObjectiveTo investigate the effect of acute hyperinsulinemia and the resulting decrease in plasma free fatty acid (FFA) concentrations on intramuscular TG synthesis. Materials/MethodsU-13C16-palmitate was infused for 3 h in anesthetized rabbits after overnight food deprivation. Arterial blood and leg muscle were sampled during the tracer infusion. Plasma samples were analyzed for free and TG-bound palmitate enrichments and concentrations. The enrichments and concentrations of palmitoyl-CoA and palmitoyl-carnitine as well as the enrichment of palmitate bound to TG were measured in muscle samples. Fractional synthetic rate (FSR) of intramuscular TG was calculated using the tracer incorporation method. The rabbits were divided into a control group and a hyperinsulinemic euglycemic clamp group. Insulin infusion decreased the rate of appearance of plasma free palmitate (2.00±0.15 vs 0.68±0.20μmol⋅kg−1⋅min−1; P<.001), decreased plasma FFA concentration (327±61 vs 72±25nmol/mL; P<.01), decreased the total concentration of intramuscular fatty acyl-CoA plus fatty acyl-carnitine (12.1±1.6 vs 7.0±0.7nmol/g; P<.05), and decreased intramuscular TG FSR (0.48±0.05 vs 0.21±0.06%/h; P<.01) in comparison with the control group. Intramuscular TG FSR was correlated (P<.01) with both plasma FFA concentrations and intramuscular fatty acyl-CoA concentrations. ConclusionsFatty acid availability is a determinant of intramuscular TG synthesis. Insulin infusion decreases plasma and intramuscular fatty acid availability and thereby decreases TG synthesis.