Blood Free Fatty Acids Research Articles

Revisiting the metabolic syndrome and paving the way for microRNAs in non‐alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) comprises a spectrum of stages from simple steatosis to non-alcoholic steatohepatitis, which can progress to fibrosis, cirrhosis and, ultimately, hepatocellular carcinoma. Despite being one of the most common chronic liver diseases, NAFLD pathogenesis remains largely unknown. In this review, we discuss the key molecular mechanisms involved in NAFLD development and progression, focusing on the emerging role of microRNAs. NAFLD is intrinsically related to obesity and the metabolic syndrome. Changes in lipid metabolism increase free fatty acids in blood, which in turn induces peripheral insulin resistance and increases oxidative and endoplasmic reticulum stress. Although not yet considered in the diagnosis of NAFLD, recent reports also reinforce the crucial role of apoptosis in disease progression via activation of either death receptor or mitochondrial pathways and p53. In addition, the role of gut microbiota and the gut-liver axis has been recently associated with NAFLD. Finally, there is an accumulating and growing body of evidence supporting the role of microRNAs in NAFLD pathogenesis and progression, as well as hinting at their use as biomarkers or therapeutic tools. The ultimate goal is to review different molecular pathways that may underlie NAFLD pathogenesis in the hope of finding targets for new and efficient therapeutic interventions.

Polyphenol-rich fruits attenuate impaired endothelial function induced by glucose and free fatty acids in vitro in human endothelial cells

Elevated concentrations of plasma glucose and free fatty acids (FFA) are associated with impaired endothelial function increasing risk of cardiovascular diseases. Previous studies suggested that fruits rich in polyphenolic compounds modulate endothelial cell migration and capillary-like tube formation via a redox-sensitive mechanism. We hypothesized that polyphenol-rich extracts of strawberry (SB) and wild blueberry (WB) would attenuate relatively high concentrations of glucose and/or FFA-mediated impaired cell migration and capillary-like tube formation in vitro in human umbilical vein endothelial cells (HUVECs). HUVECs treated with high FFA and combina- tions of glucose and FFA showed significantly reduced cell migration and capillary-like tube formation compared to the PBS control (p<0.05). However, HUVEC pre-treated with SB or WB extracts significantly increased cell migration and capillary-like tube formation in cells treated with FFA or a combination of FFA and glucose compared to cells exposed to the same nutrients/combinations alone. The results from this study suggest that berry fruits may play a role in promoting cardiovascular health especially in individuals with high blood glucose and/or FFA levels.

Free-fatty-acid-regulating effects of fermented red ginseng are mediated by hormones and by the autonomic nervous system

BackgroundUnderstanding what causes changes in the flux of free fatty acids (FFA) is important to elucidate the etiology of metabolic syndrome. The first aim of this study was to test whether or not hormones and the autonomic nervous system influence blood FFA levels. A secondary aim was to test by means of a multiple group path analysis whether the consumption of fermented red ginseng (FRG; Panax ginseng) would influence those causal relationships. MethodsNinety-three postmenopausal women (age 50–73 yr) were randomly divided into two groups. One group (44 women; age, 58.4 ± 5.9 yr; body mass index, 23.6 ± 2.5 kg/m2) was supplied placebo capsules and the other group (49 women, age 58.4 ± 5.5 yr; body mass index, 22.9 ± 2.4 kg/m2) was supplied FRG capsules. Both prior to and after the study (2 wk), blood samples were collected from the participants and several blood variables were measured and analyzed. ResultsSquared multiple correlations of FFA were 0.699 in the placebo group and 0.707 in the FRG group. The unstandardized estimate of estradiol (E2) for FFA was 0.824 in both groups. ConclusionThe path coefficients of cortisol and the branchial pulse for FFA were significantly different between the FRG group and the placebo group.

Influencing the future: interactions of skeleton, energy, protein and calcium during late gestation and early lactation

Marked improvements in milk production, health and reproduction have resulted from manipulations of the pre-calving diet. An understanding of the underlying physiological changes resulting from manipulation of late gestational diets is needed in order to refine and enhance these responses. The physiology of late gestation and early lactation of the dairy cow is examined in the context of exploring the hypothesis that changes in physiology occur not only through homeostatic, but also homeorhetic change. Studies in mice and man have identified a pivotal role for skeleton, particularly through production of active forms of osteocalcin, in integrating energy metabolism. Skeleton appears to particularly influence lipid metabolism and vice versa. Further insights into the factors influencing skeletal function and calcium (Ca) metabolism are emerging, including the potential for negative dietary cation anion difference (DCAD) diets to upregulate the responses of the skeleton in metabolism through increased bone mobilisation and in enhancing responses to parathyroid hormone. The rumen appears to be an important site of absorption of Ca, but physiological mechanisms influencing this uptake are not clear. We provide quantitative evidence of the magnitude of responses that reflect relationships linking Ca metabolism, skeleton and production, using meta-analytic methods. Negative DCAD diets increase milk production in multiparous cattle, but not in heifers. Further, examination of concentrations of metabolites related to energy metabolism obtained from cattle exposed to a negative DCAD diet over calving identified a dominant role for Ca concentrations, which were associated with blood-free fatty acids (NEFA), blood 3-hydroxybutyrate, glucose and cholesterol. These relationships were homeostatic, occurring on the same day, but also homeorhetic with concentrations of Ca and NEFA being significantly associated over 21 days. The findings in cattle are consistent with those in the murine models. However, Ca and the skeleton are not the only significant factors in the transition period influencing future performance as hormonal treatments, metabolic demands and sex of the conceptus, and inflammation and the factors controlling this play a role in future performance. Homeorhetic, longer-term, adaptive responses are critical to achieving orchestrated longer-term adaptive responses to calving and lactation. We consider that the teleological question ‘why would a bone-specific hormone (osteocalcin) regulate energy metabolism?’ is answered by the specific needs for integrated metabolism to address the extreme metabolic demands of lactation in many species.

Ammonia-treated N-(1-naphthyl) ethylenediamine dihydrochloride as a novel matrix for rapid quantitative and qualitative determination of serum free fatty acids by matrix-assisted laser desorption/ionization-Fourier transform ion cyclotron resonance mass spectrometry

The blood free fatty acids (FFAs), which provide energy to the cell and act as substrates in the synthesis of fats, lipoproteins, liposaccharides, and eicosanoids, involve in a number of important physiological processes. In the present study, matrix-assisted laser desorption/ionization-Fourier transform ion cyclotron resonance mass spectrometry (MALDI-FTICR MS) with ammonia-treated N-(1-naphthyl) ethylenediamine dihydrochloride (ATNEDC) as a novel MALDI matrix in a negative ion mode was employed to directly quantify serum FFAs. Multiple point internal standard calibration curves between the concentration ratios of individual fatty acids to internal standard (IS, C17:0) versus their corresponding intensity ratios were constructed for C14:0, C16:1, C16:0, C18:0, C18:1, C18:2, C18:3, C20:4, and C22:6, respectively, in their mixture, with correlation coefficients between 0.991 and 0.999 and limits of detection (LODs) between 0.2 and 5.4μM, along with the linear dynamic range of more than two orders of magnitude. The results indicate that the multiple point internal standard calibration could reduce the impact of ion suppression and improve quantification accuracy in the MALDI mode. The quantitative results of nine FFAs from 339 serum samples, including 161 healthy controls, 118 patients with hyperglycemia and 60 patients without hyperglycemia show that FFAs levels in hyperglycemic patient sera are significantly higher than those in healthy controls and patients without hyperglycemia, and elevated FFA levels are also associated with increased levels of fasting blood glucose (FBG) in hyperglycemic patient sera. Serum FFAs were identified on the basis of the observed accurate molecular masses and reliable isotope distributions obtained by MALDI-FTICR MS.

Biological Effects of Allium monanthum Extracts on Lipid Metabolism, Anti-oxidation and the Production of Pro-inflammatory Cytokines in Rats Fed a High-Fat Diet

This study is a basic study on the development of functional substances involved in obesity prevention, lipid metabolism, and immune regulation. Male Sprague-Dawley rats were fed a high-fat diet for 10 weeks. Allium monanthum extracts (AME) were administered orally to obesity-induced rats, and their lipid-lowering, antioxidative and various types of biological effects related to the immune system were examined. Blood free fatty acid and triglyceride concentrations decreased as the dose of AME increased. Total cholesterol and LDL cholesterol concentrations in the blood decreased as the dose of AME increased. The total cholesterol concentrations in the liver of the AME-treated groups were lower than the control group. The thiobarbituric acid reactive concentrations were lower in the plasma and liver of all AME-treated groups than the control group. Plasma AST and ALT activities did not show any significant differences among the treatment groups. IL-<TEX>$1{\beta}$</TEX> and IL-6 concentrations in the liver tended to decrease as the dose of AME increased. TNF-<TEX>${\alpha}$</TEX> and IL-10 concentrations did now show any significant differences compared to the control group. Lower expression levels of TNF-<TEX>${\alpha}$</TEX>, Apo-B and Apo-E genes were found in the AME-treated groups. Taken together, these results indicate that AME may show positive effects in lipid lowering, antioxidation and anti-inflammation.

Effects of sweet cassava polysaccharide extracts on endurance exercise in rats

BackgroundSweet cassava tubers have abundant carbohydrates consisting of monosaccharides and polysaccharides. In addition, polysaccharides extracted from plants improve sports performance, according to recent studies. We therefore examined whether the administration of sweet cassava polysaccharides (SCPs) benefited endurance performance in ratsMethodsMale Sprague–Dawley rats (n = 30, 7 weeks old) were divided into three groups: control (C), exercise (Ex), and exercise plus SCPs administration (ExSCP) (at a dose of 500 mg/kg body weight by gastric intubation for six days in addition to standard rat food and water). An exercise program was implemented in the Ex and ExSCP groups for five days (with no exercise on the sixth day), and then all rats were sacrificed to determine the glycogen content of the gastrocnemius and soleus muscles, and the blood metabolites after the ExSCP and Ex groups had completed exhaustive running.ResultsThe running time to exhaustion of the ExSCP group was significantly longer than that of the Ex group by 49% (64 vs. 43 min). After running to exhaustion, it was seen that although the glycogen content in the soleus and gastrocnemius muscles of the Ex and ExSCP groups was lower compared to the C group, values in the ExSCP group were significantly higher than in the Ex group (p > 0.05). In addition, blood glucose and free fatty acid (FFA) levels were significantly higher in the ExSCP than in the Ex group (p > 0.05). However, no significant differences for blood glucose or FFA were found between the ExSCP and C groups.ConclusionsSCP supplementation can prolong exercise endurance in rats. Higher muscle glycogen levels and stable glucose and FFA concentrations in the circulation contributed to the prolonged time to exhaustion.

Analysis of Free Fatty Acids in Blood of Healthy Person and that of Hepatitis Patient

Polyunsaturated fatty acids (PUFA) are highly susceptible to oxidation and their levels can rapidly decrease under oxidative stress [1]. A concomitant increase in monounsaturated fatty acids such as oleic and palmtoleic acids is often observed probably as a result of the activation of Δ9-desaturase [1]. Analysis of fatty acid profiles is therefore of importance. Here we describe the analysis of plasma free fatty acids (FFA) only, because the measurement of fatty acids in neutral lipids, phospholipids, and total lipids has already been well documented. Plasma FFA can, furthermore, be produced by oxidatively damaged tissues because hydrolysis of phospholipids is stimulated by oxidative stress [2].

Abdominal radiotherapy: a major determinant of metabolic syndrome in nephroblastoma and neuroblastoma survivors.

BackgroundReports on metabolic syndrome in nephroblastoma and neuroblastoma survivors are scarce. Aim was to evaluate the occurrence of and the contribution of treatment regimens to the metabolic syndrome.Patients and MethodsIn this prospective study 164 subjects participated (67 adult long-term nephroblastoma survivors (28 females), 36 adult long-term neuroblastoma survivors (21 females) and 61 control subjects (28 females)). Controls were recruited cross-sectionally. Waist and hip circumference as well as blood pressure were measured. Body composition and abdominal fat were assessed by dual energy X-ray absorptiometry (DXA-scan). Laboratory measurements included fasting triglyceride, high density lipoprotein-cholesterol (HDL-C), glucose, insulin, low-density lipoprotein-cholesterol (LDL-C) and free fatty acids (FFA) levels.ResultsMedian age at follow-up was 30 (range 19–51) years in survivors and 32 (range 18–62) years in controls. Median follow-up time in survivors was 26 (6–49) years. Nephroblastoma (OR = 5.2, P<0.0001) and neuroblastoma (OR 6.5, P<0.001) survivors had more components of the metabolic syndrome than controls. Survivors treated with abdominal irradiation had higher blood pressure, triglycerides, LDL-C, FFA and lower waist circumference. The latter can not be regarded as a reliable factor in these survivors as radiation affects the waist circumference. When total fat percentage was used as a surrogate marker of adiposity the metabolic syndrome was three times more frequent in abdominally irradiated survivors (27.5%) than in non-irradiated survivors (9.1%, P = 0.018).ConclusionsNephroblastoma and neuroblastoma survivors are at increased risk for developing components of metabolic syndrome, especially after abdominal irradiation. We emphasize that survivors treated with abdominal irradiation need alternative adiposity measurements for assessment of metabolic syndrome.

Effects of Sleep Restriction on Glucose Control and Insulin Secretion During Diet‐Induced Weight Loss

Insufficient sleep is associated with changes in glucose tolerance, insulin secretion, and insulin action. Despite widespread use of weight-loss diets for metabolic risk reduction, the effects of insufficient sleep on glucose regulation in overweight dieters are not known. To examine the consequences of recurrent sleep restriction on 24-hour blood glucose control during diet-induced weight loss, 10 overweight and obese adults (3F/7M; mean [SD] age 41 [5] y; BMI 27.4 [2.0] kg/m2) completed two 14-day treatments with hypocaloric diet and 8.5 or 5.5-h nighttime sleep opportunity in random order 7 [3] months apart. Oral and intravenous glucose tolerance test (IVGTT) data, fasting lipids and free-fatty acids (FFA), and 24-hour blood glucose, insulin, C-peptide, and counter-regulatory hormone measurements were collected after each treatment. Participants had comparable weight loss (1.0 [0.3] BMI units) during each treatment. Bedtime restriction reduced sleep by 131 [30] min/day. Recurrent sleep curtailment decreased 24-hour serum insulin concentrations (i.e. enhanced 24-hour insulin economy) without changes in oral glucose tolerance and 24-hour glucose control. This was accompanied by a decline in fasting blood glucose, increased fasting FFA which suppressed normally following glucose ingestion, and lower total and LDL cholesterol concentrations. Sleep-loss-related changes in counter-regulatory hormone secretion during the IVGTT limited the utility of the test in this study. In conclusion, sleep restriction enhanced 24-hour insulin economy without compromising glucose homeostasis in overweight individuals placed on a balanced hypocaloric diet. The changes in fasting blood glucose, insulin, lipid and FFA concentrations in sleep-restricted dieters resembled the pattern of human metabolic adaptation to reduced carbohydrate availability.

Abstract 8795: Cardiac Cachexia is Associated with Abnormal Liver Metabolism and Pro-Inflammatory Responses in a Rat Model of Heart Failure

Introduction: Cachexia, namely body wasting, is a common complication in heart failure (HF). Although neurohumoral and immune abnormalities are associated with the condition, the mechanism by which the imbalance of catabolism and anabolism occurs is not known. Hypothesis: We assessed the hypothesis that the liver is important in the pathogenesis of cardiac cachexia, since the liver plays a critical role in systemic metabolic regulation. Methods: We analyzed markers of cachexia in Dahl salt-sensitive rats fed a high salt diet which develop hypertension and, subsequently, HF. Dahl rats fed a low salt diet were used as a control. Glucose uptake of the liver was estimated using 18 F-deoxyglucose ( 18 FDG). The amount of metabolites in glycolysis and the Krebs cycle was measured employing metabolome analysis. Results and Conclusion: The body weight of HF rats was decreased compared with control rats (354±9 vs. 425±13 g, n=6, p&lt;0.05). Food intake was reduced compared with controls by 29% (p&lt;0.05). Blood sugar and insulin levels were decreased by 34 and 54%, respectively (p&lt;0.05). Blood retinol binding protein (RBP), a hepatic protein, was decreased by 53% (p&lt;0.05). The blood levels of tumor necrosis factor (TNF)-α and interleukin (IL)-1β were increased. These results indicate that Dahl rats serve as a model of cardiac cachexia. Despite the apparent fasting condition, blood free fatty acid levels were decreased by 53% (p&lt;0.05) and triglyceride (TG) levels were increased 2.0-fold (p&lt;0.05). Next, we analyzed the livers of HF rats. 18 FDG uptake was increased 1.7-fold (p&lt;0.05). The concentrations of some metabolites in the glycolytic pathway increased, and those in the Krebs cycle decreased. Gene expression related to lipogenesis increased and the TG content of the liver increased 1.8-fold (p&lt;0.05). Gene expressions of sterol regulatory element-binding protein (SREBP)-1c and SREBP-2, key enzymes in lipogenesis, increased 3.1- and 1.9-fold, respectively (p&lt;0.05). The protein levels of SREBP-1c and SREBP-2 also increased. The gene and protein expressions of TNF-α and IL-1β increased in the liver. In conclusion, cardiac cachexia was associated with abnormal lipogenesis and proinflammatory responses in the liver, which might act as a maladaptive response in HF.

Effect of aging on insulin receptor in islet beta-cells of Wistar rats

Objective To evaluate the effect of aging on the insulin receptor in islet beta-cells of Wistar rats,so as to investigate the mechanism of impaired glucose tolerance in elderly population.Methods Thirty healthy male Wistar rats were divided into young group(4-month old,n=15) and elderly group(24-monfh old,n=15).The fasting blood glucose,blood insulin,free fatty acid,and blood lipid were observed.Insulin sensitivity and the function of islet cells were assessed by the euglycaemic-hyperinsulinaemic clamp technique.The insulin receptor in islet beta-cells was observed using immunofluorescence staining,and the fluorescence intensity was analyzed using software.Results The body mass of rats in young group and elderly group was(490.60±7.72)g and(728.90±7.57)g respectively(P0.01).There was no significant difference in fasting blood glucose between the two groups(P0.05).The fasting blood insulin was(0.59±0.14)ng/ml and(2.37±0.04)ng/ml in young group and elderly group respectively(P0.01).The blood free fatty acid was significantly lower in young group than in elderly group[(0.76±0.14) vs (1.51±0.04) mmol/L,P0.01].The euglycaemic-hyperinsulinaemic clamp test displayed that the glucose infusion rate was significantly higher in young group than in elderly group[(26.02±2.83) vs(10.73±0.72)mg/(kg·mm),P0.01].Homeostasis model insulin resistance index(HOMA-IR) was(3.09±0.80) and(13.14±1.59) in young group and elderly group(P0.01).The fluorescence intensity was(63.55±5.20) and(23.26±2.50) respectively in young group and elderly group respectively(P0.01).Conclusion The elderly rats present with insulin resistance and compensatory high level insulin secretion.Meanwhile,insulin receptor in islet beta-cells is decreased.It is possible that the peripheral insulin resistance and the insulin resistance in islet beta-cells itself coexist in elderly rats.

Combination Therapy with Metformin and Fenofibrate for Insulin Resistance in Obesity

This randomized controlled study investigated metformin and fenofibrate, compared with metformin alone, for the treatment of peripheral insulin resistance in patients with simple obesity with hyperinsulinaemia but not diabetes. Participants were randomized to receive metformin (500 mg orally three times daily) plus either fenofibrate (200 mg orally once daily; n = 44) or placebo (n = 43) for 6 months. Blood pressure, free fatty acids (FFA), body mass index (BMI), lipid and insulin levels were recorded pre- and post-treatment. β-Cell function and insulin resistance were measured by the homeostasis model assessment for insulin resistance (HOMA-IR) index. Both groups showed significant decreases in blood pressure, FFA, BMI and HOMA-IR relative to baseline. In addition, combined metformin and fenofibrate therapy showed significantly decreased fasting and postmeal insulin levels relative to baseline and relative to the placebo group. Both treatments were well tolerated. Metformin and fenofibrate can increase insulin sensitivity and recover β-cell function in patients with simple obesity accompanied by insulin resistance.

Interaction Between Insulin and Estradiol in Regulation of Cardiac Glucose and Free Fatty Acid Transporters

The estrogen binding to specific extranuclear receptors (ER) activates several intracellular pathways that are activated by insulin as well. Moreover, insulin and estradiol (E2) influence cardiac energy substrates, blood glucose and free fatty acids (FFAs), and both hormones exert cardio-beneficial effects. In view of these facts, we suggest that cross-talk between their signaling pathways might have an important role in regulation of cardiac energy substrate transport. Ovariectomized rats were treated with insulin, estradiol (E2), or their combination 20, 30, or 40 min before analysis of blood glucose and FFA level, as well as cardiac plasma membranes (PM) and low density microsomes (LDM) content of glucose (GLUT4 and GLUT1) and FFA (CD36) transporters. Insulin, given alone, or in combination with E2, decreased plasma glucose level at all time points, but did not influence FFA level, while E2 treatment itself did not change glucose and FFA concentration. Insulin increased PM GLUT4 and GLUT1 content 30 and 40 min after treatment and the increases were partially accompanied by decrease in transporter LDM content. E2 increased PM content and decreased LDM content only of GLUT4 at 30 min. Insulin generally, and E2 at 20 min increased CD36 content in PM fraction. Both hormones decreased CD36 LDM content 20 min after administration. Effect of combined treatment mostly did not differ from single hormone treatment, but occasionally, particularly in distribution of GLUT4, combined treatment emphasized single hormone effect, suggesting that insulin and E2 act synergistically in regulation of energy substrate transporters in cardiac tissue.

Effect of Thiamin Derivative on Carbohydrate Metabolism at Rest in Mice

Thiamin is known to activate carbohydrate metabolism by the activation of pyruvate dehydrogenase (PDH). We previously reported that thiamin tetrahydrofurfuryl disulfide (TTFD), which is a derivative of thiamin, inhibits oxidation of exogenous glucose at rest, but not during exercise. Furthermore, concentrations of muscle and liver glycogen tended to be lower after TTFD ingestion during recovery from endurance exercise. Therefore, it could be hypothesized that administration of a thiamin derivative inhibited glycogen synthesis from glucose in muscle and liver and changed liver cytosolic glucose-induced lipogenesis via pentosephosphate pathway, which involves the other thiamin sensitive transketolase (TK) reaction. PURPOSE: To investigate the effect of TTFD on carbohydrate metabolism in liver and skeletal muscles at rest. METHODS: Seven-week-old male ICR mice were randomly assigned to a TTFD ingestion group or a water ingestion group. Mice orally ingested glucose (0.8 mg/g BW) plus water or TTFD (0.1 mg/g BW). Concentrations of blood substrates, muscle and liver glycogen and liver TK activity were measured at rest. RESULTS: No significant effect of TTFD was found in concentrations of blood lactate and glucose at rest. Blood free fatty acid concentrations were significantly lower in TTFD group than in water group (P<0.01). Concentration of muscle glycogen was significantly lower in TTFD mice than in control mice (P<0.05), but no significant difference was found in liver glycogen. Liver TK activity was lower in TTFD group (P<0.05). Therefore, single treatment of TTFD and glucose might suppress liver glucose-induced lipogenesis via pentose phosphate pathway. CONCLUSIONS: These results indicate that TTFD, a derivative of thiamin, which has been known to activate glucose metabolism, decreased glycogen concentration in skeletal muscle and blood free fatty acid concentration at rest.

Oleic Acid Prevents Detrimental Effects of Saturated Fatty Acids on Bovine Oocyte Developmental Competence1

Mobilization of fatty acids from adipose tissue during metabolic stress will increase the amount of free fatty acids in blood and follicular fluid and, thus, may affect oocyte quality. In this in vitro study, the three predominant fatty acids in follicular fluid (saturated palmitic and stearic acid and unsaturated oleic acid) were presented to maturing oocytes to test whether fatty acids can affect lipid storage of the oocyte and developmental competence postfertilization. Palmitic and stearic acid had a dose-dependent inhibitory effect on the amount of fat stored in lipid droplets and a concomitant detrimental effect on oocyte developmental competence. Oleic acid, in contrast, had the opposite effect, causing an increase of lipid storage in lipid droplets and an improvement of oocyte developmental competence. Remarkably, the adverse effects of palmitic and stearic acid could be counteracted by oleic acid. These results suggest that the ratio and amount of saturated and unsaturated fatty acid is relevant for lipid storage in the maturing oocyte and that this relates to the developmental competence of maturing oocytes.

Glucose-Dependent Insulinotropic Polypeptide May Enhance Fatty Acid Re-esterification in Subcutaneous Abdominal Adipose Tissue in Lean Humans

OBJECTIVEGlucose-dependent insulinotropic polypeptide (GIP) has been implicated in lipid metabolism in animals. In humans, however, there is no clear evidence of GIP effecting lipid metabolism. The present experiments were performed in order to elucidate the effects of GIP on regional adipose tissue metabolism.RESEARCH DESIGN AND METHODSEight healthy subjects were studied on four different occasions. Abdominal subcutaneous adipose tissue metabolism was assessed by measuring arterio-venous concentration differences and regional adipose tissue blood flow during GIP (1.5 pmol/kg/min) or saline infused intravenously alone or in combination with a hyperinsulinemic-hyperglycemic (HI-HG) clamp.RESULTSDuring GIP and HI-HG clamp, abdominal subcutaneous adipose tissue blood flow, hydrolysis of circulating triacylglycerol (TAG) (P = 0.009), and glucose uptake (P = 0.03) increased significantly while free fatty acid (FFA) output (P = 0.04) and FFA/glycerol release ratio (P = 0.02) decreased compared with saline and HI-HG clamp.CONCLUSIONSIn conclusion, GIP in combination with hyperinsulinemia and slight hyperglycemia increased adipose tissue blood flow, glucose uptake, and FFA re-esterification, thus resulting in increased TAG deposition in abdominal subcutaneous adipose tissue.

Effect of Thiamin Derivative on Carbohydrate Metabolism in Recovery Period from Endurance Exercise in Mice

Thiamin is known to activate carbohydrate metabolism by the activation of pyruvate dehydrogenase (PDH). We previously reported that thiamin tetrahydrofurfuryl disulfide (TTFD), which is a derivative of thiamin, inhibits oxidation of exogenous glucose without affecting muscle and liver glycogen concentrations at rest, but not during exercise. It could be speculated that the carbohydrate metabolism through glycogen synthesis from glucose was activated after administration of a thiamin derivative at rest without changing in overall oxidation of carbohydrates. PURPOSE: To investigate the effect of TTFD on energy metabolism in recovery period following endurance exercise. METHODS: Eight-week-old male ICR mice were randomly assigned to a TTFD ingestion group or a water ingestion group. Immediately after 60 min of endurance treadmill running (20 m/min), mice orally ingested glucose (0.8 mg/g BW) plus water or TTFD (0.1 mg/g BW). After 1h, 3h, 6h and 12h of recovery period, muscle and liver glycogen concentrations were measured. The rate of oxidation of exogenous glucose during 1h recovery was measured using 13C-glucose (0.8mg/g BW) ingested in mice immediately after the exercise. RESULTS: The average percent of 13C atom in total 12C + 13C (13C atom %) in expired air after ingestion of 13C-glucose was not significantly different in TTFD group from water group. No significant effect of TTFD was found in concentrations of blood lactate and glucose. Blood free fatty acid concentrations were lower in TTFD group than in water group at 3h of recovery (P<0.01). Recovery of muscle and liver glycogen concentrations after the exercise tended to be lower in TTFD mice than in control mice at during 12h of recovery (P<0.06 and P<0.08 1h). CONCLUSION: These results suggest that TTFD, a derivative of thiamin, which has been known to activate glucose metabolism does not increase but rather tended to decrease glycogen resynthesis from glucose after endurance exercise.

GPR40 is partially required for insulin secretion following activation of β 3-adrenergic receptors

The free fatty acid (FFA) receptor GPR40, expressed by pancreatic β-cells, may be responsible for insulin release following β 3 adrenoceptor (Adrb3) activation. To test this hypothesis, we first studied the effects of Adrb3 agonists SR58611A and CL316,243 in GPR40 knockout (GPR40 −/−) mice. Both drugs increased blood FFA levels in wild-type (GPR40 +/+) and GPR40 −/− mice, indicating that lipolysis is not GPR40-dependent. However, the magnitude of the insulin response after agonist treatment was decreased by ∼50% in GPR40 −/− mice. Analysis of the time-course revealed that the change in FFAs (5–10 min post-treatment) in response to SR58611A preceded insulin secretion (10–15 min post-treatment). While reduced by agonist treatment, glucose levels in GPR40 −/− mice remained significantly higher than in GPR40 +/+ mice. Energy expenditure, food intake, or body weight was not affected in GPR40 −/− mice, whereas SR58611A increased energy metabolism. Furthermore, CL316,243 did not potentiate glucose-stimulated insulin secretion in isolated mouse islets or activate a cAMP reporter in transgenic mice. Our data indicate that insulin secretion, a secondary event following stimulation of Adrb3 receptors, is partially mediated by GPR40 and suggest that GPR40 is integral to the anti-diabetes effects of Adrb3 agonists.

Plasma anandamide and other N-acylethanolamines are correlated with their corresponding free fatty acid levels under both fasting and non-fasting conditions in women

N-acylethanolamines (NAEs), such as anandamide (AEA), are a group of endogenous lipids derived from a fatty acid linked to ethanolamine and have a wide range of biological activities, including regulation of metabolism and food intake. We hypothesized that i) NAE plasma levels are associated with levels of total free fatty acids (FFAs) and their precursor fatty acid in fasting and non-fasting conditions and ii) moderate alcohol consumption alters non-fasting NAE levels. In a fasting and non-fasting study we sampled blood for measurements of specific NAEs and FFAs. In the fasting study blood was drawn after an overnight fast in 22 postmenopausal women. In the non-fasting study blood was sampled before and frequently after a standardized lunch with beer or alcohol-free beer in 19 premenopausal women. Fasting AEA levels correlated with total FFAs (r = 0.84; p < 0.001) and arachidonic acid levels (r = 0.42; p < 0.05). Similar results were observed for other NAEs with both total FFAs and their corresponding fatty acid precursors. In addition, AEA (r = 0.66; p < 0.01) and OEA levels (r = 0.49; p <0.02) positively related with BMI. Changes over time in non-fasting AEA levels were correlated with changes in total FFA levels, both after a lunch with beer (r = 0.80; 95% confidence interval: 0.54-0.92) and alcohol-free beer (r = 0.73; 0.41-0.89). Comparable correlations were found for other NAEs, without differences in correlations of each NAE between beer and alcohol free beer with lunch. In conclusion, i) in fasting and non-fasting states circulating anandamide and other N-acylethanolamines were associated with free fatty acid levels and ii) moderate alcohol consumption does not affect non-fasting NAE levels. This suggests that similar physiological stimuli cause the release of plasma N-acylethanolamines and free fatty acids in blood. The trials are registered at ClinicalTrials.gov numbers: NCT00524550 and NCT00652405.