E. Šeböková

The hypotriglyceridemic effect of dietary n−3 FA is associated with increased β-oxidation and reduced leptin expression

To study the mechanisms responsible for the hypotriglyceridemic effect of marine oils, we monitored the effects of high dietary intake of n−3 PUFA on hepatic and muscular β-oxidation, plasma leptin concentration, leptin receptor gene expression, and in vivo insulin action. Two groups of male Wistar rats were fed either a high-fat diet [28% (w/w) of saturated fat] or a high-fat diet containing 10% n−3 PUFA and 18% saturated fat for 3 wk. The hypotriglyceridemic effect of n−3 PUFA was accompanied by increased hepatic oxidation of palmitoyl-CoA (125%, P<0.005) and palmitoyl-l-carnitine (480%, P<0.005). These findings were corroborated by raised carnitine palmitoyltransferase-2 activity (154%, P<0.001) and mRNA levels (91%, P<0.01) as well as by simultaneous elevation of hepatic peroxisomal acyl-CoA oxidase activity (144%, P<0.01) and mRNA content (82%, P<0.05). In contrast, hepatic carnitine palmitoyltransferase-1 activity remained unchanged despite a twofold increased mRNA level after n−3 PUFA feeding. Skeletal muscle FA oxidation was less affected by dietary n−3 PUFA, and the stimulatory effect was found only in peroxisomes. Dietary intake of n−3 PUFA was followed by increased acyl-CoA oxidase activity (48%, P<0.05) and mRNA level (83%, P<0.05) in skeletal muscle. The increased FA oxidation after n−3 PUFA supplementation of the high-fat diet was accompanied by lower plasma leptin concentration (−38%, P<0.05) and leptin mRNA expression (−66%, P<0.05) in retroperitoneal adipose tissue, and elevated hepatic mRNA level for the leptin receptor Ob-Ra (140%, P<0.05). Supplementation of the high-fat diet with n−3 PUFA enhanced in vivo insulin sensitivity, as shown by normalization of the glucose infusion rate during euglycemic hyperinsulinemic clamp.Our results indicate that the hypotriglyceridemic effect of dietary n−3 PUFA is associated with stimulation of FA oxidation in the liver and to a smaller extent in skeletal muscle. This may ameliorate dyslipidemia, tissue lipid accumulation, and insulin action, in spite of decreased plasma leptin level and leptin mRNA in adipose tissue.

High prevalence of prediabetes and diabetes in a population exposed to high levels of an organochlorine cocktail

Aims/hypothesisA heavily polluted area of Eastern Slovakia was targeted by the PCBRISK cross-sectional survey to search for possible links between environmental pollution and both prediabetes and diabetes.MethodsAssociations of serum levels of five persistent organic pollutants (POPs), namely polychlorinated biphenyls (PCBs), 2,2′-bis(4-chlorophenyl)-1,1-dichloroethylene (p,p′-DDE), 2,2′-bis(4-chlorophenyl)-1,1,1-trichloro-ethane (p,p′-DDT), hexachlorobenzene (HCB) and β-hexachlorocyclohexane (β-HCH), with prediabetes and diabetes were investigated in 2,047 adults. Diabetes and prediabetes were diagnosed by fasting plasma glucose in all participants and by OGTT in 1,220 compliant participants.ResultsOur population was stratified in terms of individual POPs quintiles and associations between environmental pollution, prediabetes and diabetes were investigated. Prevalence of prediabetes and diabetes increased in a dose-dependent manner, with individuals in upper quintiles of individual POPs showing striking increases in prevalence of prediabetes as shown by OR and 95% CI for PCBs (2.74; 1.92–3.90), DDE (1.86; 1.17–2.95), DDT (2.48; 1.77–3.48), HCB (1.86; 1.7–2.95) and β-HCH (1.97; 1.28–3.04). Interestingly, unlike PCBs, DDT and DDE, increased levels of HCB and β-HCH seemed not to be associated with increased prevalence of diabetes. Nevertheless, individuals in the 5th quintile of the variable expressing the cumulative effect of all five POPs (sum of orders) had a more than tripled prevalence of prediabetes and more than six times higher prevalence of diabetes when compared with the 1st referent quintile.Conclusions/interpretationIncreasing serum concentrations of individual POPs considerably increased prevalence of prediabetes and diabetes in a dose-dependent manner. Interaction of industrial and agricultural pollutants in increasing prevalence of prediabetes or diabetes is likely.

Cytosolic citrate and malonyl-CoA regulation in rat muscle in vivo

In liver, insulin and glucose acutely increase the concentration of malonyl-CoA by dephosphorylating and activating acetyl-CoA carboxylase (ACC). In contrast, in incubated rat skeletal muscle, they appear to act by increasing the cytosolic concentration of citrate, an allosteric activator of ACC, as reflected by increases in the whole cell concentrations of citrate and malate [Saha, A. K., D. Vavvas, T. G. Kurowski, A. Apazidis, L. A. Witters, E. Shafrir, and N. B. Ruderman. Am. J. Physiol. 272 ( Endocrinol. Metab. 35): E641-E648, 1997]. We report here that sustained increases in plasma insulin and glucose may also increase the concentration of malonyl-CoA in rat skeletal muscle in vivo by this mechanism. Thus 70 and 125% increases in malonyl-CoA induced in skeletal muscle by infusions of glucose for 1 and 4 days, respectively, and a twofold increase in its concentration during a 90-min euglycemic-hyperinsulinemic clamp were all associated with significant increases in the sum of whole cell concentrations of citrate and/or malate. Similar correlations were observed in muscle of the hyperinsulinemic fa/fa rat, in denervated muscle, and in muscle of rats infused with insulin for 5 h. In muscle of 48-h-starved rats 3 and 24 h after refeeding, increases in malonyl-CoA were not accompanied by consistent increases in the concentrations of malate or citrate. However, they were associated with a decrease in the whole cell concentration of long-chain fatty acyl-CoA (LCFA-CoA), an allosteric inhibitor of ACC. The results suggest that increases in the concentration of malonyl-CoA, caused in rat muscle in vivo by sustained increases in plasma insulin and glucose or denervation, may be due to increases in the cytosolic concentration of citrate. In contrast, during refeeding after starvation, the increase in malonyl-CoA in muscle is probably due to another mechanism.In liver, insulin and glucose acutely increase the concentration of malonyl-CoA by dephosphorylating and activating acetyl-CoA carboxylase (ACC). In contrast, in incubated rat skeletal muscle, they appear to act by increasing the cytosolic concentration of citrate, an allosteric activator of ACC, as reflected by increases in the whole cell concentrations of citrate and malate [Saha, A. K., D. Vavvas, T. G. Kurowski, A. Apazidis, L. A. Witters, E. Shafrir, and N. B. Ruderman. Am. J. Physiol. 272 (Endocrinol. Metab. 35): E641-E648, 1997]. We report here that sustained increases in plasma insulin and glucose may also increase the concentration of malonyl-CoA in rat skeletal muscle in vivo by this mechanism. Thus 70 and 125% increases in malonyl-CoA induced in skeletal muscle by infusions of glucose for 1 and 4 days, respectively, and a twofold increase in its concentration during a 90-min euglycemic-hyperinsulinemic clamp were all associated with significant increases in the sum of whole cell concentrations of citrate and/or malate. Similar correlations were observed in muscle of the hyperinsulinemic fa/fa rat, in denervated muscle, and in muscle of rats infused with insulin for 5 h. In muscle of 48-h-starved rats 3 and 24 h after refeeding, increases in malonyl-CoA were not accompanied by consistent increases in the concentrations of malate or citrate. However, they were associated with a decrease in the whole cell concentration of long-chain fatty acyl-CoA (LCFA-CoA), an allosteric inhibitor of ACC. The results suggest that increases in the concentration of malonyl-CoA, caused in rat muscle in vivo by sustained increases in plasma insulin and glucose or denervation, may be due to increases in the cytosolic concentration of citrate. In contrast, during refeeding after starvation, the increase in malonyl-CoA in muscle is probably due to another mechanism.

Medium-chain fatty acids ameliorate insulin resistance caused by high-fat diets in rats.

Background High dietary intake of saturated fat impairs insulin sensitivity and lipid metabolism. The influence of fatty acid chain length, however, is not yet fully understood, but evidence exists for different effects of saturated long‐chain (LC) versus saturated medium‐chain (MC) fatty acids (FA).

High Prevalence of Anti-Glutamic Acid Decarboxylase (Anti-GAD) Antibodies in Employees at a Polychlorinated Biphenyl Production Factory

Abstract An increased prevalence of thyroid antibodies was seen in employees of a factory that formerly produced polychlorinated biphenyls (PCBs). In this study, the authors expand the evaluation of possible long-term PCB effects by comparing the prevalence of glutamic acid decarboxylase (anti-GAD) antibodies with the development of diabetes mellitus. The sera of 240 factory employees and 704 control subjects were analyzed. Anti-GAD antibody values exceeded 1.20 U/ml in all employees (40.4%), was 4 times higher (p < .001) than in all controls (10.5%), and were 5 times higher in employees aged 51-60 yr (53.2%) than in age-matched controls (10.5%) (p < .001). Although the prevalence of diabetes could not be determined from this retrospective study, this is the first report of a possible relationship between xenobiotics and the prevalence of anti-GAD antibodies, and it supports the concept of an immunomodulatory effect of PCBs. However, such antibodies may be present decades before the development of clinical diabetes, and not all anti-GAD antibody-positive individuals become diabetic. Presently, it is unknown whether there is an increased prevalence of diabetes among the former factory employees.

Muscle GLUT 4 protein levels and impaired triglyceride metabolism in streptozotocin diabetic rats. Effect of a high sucrose diet and fish oil supplementation.

Our data indicate that (a) the existence of a defect in the clearance of circulating TG and persistence of muscle TG deposition in the high sucrose-fed neonatal streptozotocin diabetic rat, which (b) can only be partially corrected by raised dietary n-3 PUFA intake. (c) Skeletal muscle of STZ type II-like diabetic rats contains about 40% less glucose transporters, and (d) this situation cannot be changed by any of the dietary treatments employed. (e) These findings indicate that muscle TG accumulation may have no direct relation to glucose transport in muscle.

Increased thyroid volume, prevalence of thyroid antibodies and impaired fasting glucose in young adults from organochlorine cocktail polluted area: Outcome of transgenerational transmission?

In 137 females (F) and 94 males (M) aged 21-35 years from organochlorines (OCs) polluted area (POLL) increased thyroid volume (ThV), prevalence of antibodies to thyroperoxidase (TPOab), thyrotropin receptor (TRab) and of impaired fasting glucose (IFG) was found compared to 116 F and 107 M from background pollution area (BCGR). In F and M from POLL also strikingly increased level of PCBs, DDE and HCB was found. Such findings were compared to the generation of their parents aged 41-55 years consisting of 320F/213M from POLL and 406F/231M from BCGR. However, in spite of strikingly lower level of those OCs in young adults from POLL, they showed about the same prevalence of adverse health signs as the old generation. From such reason 44 young F and 40 young M with lowest PCBs level from POLL were selected to obtain nearly the same PCB level as found in all young F and M from BCGR. In such PCB adjusted groups the prevalence of TPOab, TRab, IFG and increased ThV was still significantly higher than that in all young subjects from BCGR. At the same time, also the level of DDE and HCB in such PCBs adjusted groups was considerably lower. It was concluded that such adverse effects in young adults from POLL possibly did not result from their actual OCs levels, but very likely from their exposure to high OCs levels of their mothers during their prenatal and perinatal life. Thus, the data may be compatible with present views on transgenerational transmission of endocrine disruptors action.

Endocrine Regulation of Subcutaneous Fat Metabolism during Cold Exposure in Humans

Abstract: Increased oxidation of carbohydrates and free fatty acids is a well‐known phenomenon during cold stress. Nevertheless, sources of the fuels used have not been fully clarified as yet. Thus, the aim of our study was to evaluate the effect of acute cold exposure on lipid and carbohydrate metabolism in human subcutaneous adipose tissue and to identify the possible regulatory mechanisms involved. Ten volunteers were exposed for 30 min to an ambient temperature of 4°C. Interstitial metabolism was assessed with the aid of the microdialysis technique. Lipolysis intensity was evaluated from changes of glycerol concentration in plasma and in dialysate. Cold exposure induced a significant increase of glycerol concentration both in plasma (by 199 ± 16%, p < 0.01) and in dialysate (by 308 ± 58%, p < 0.001). No changes in glucose concentration were found whether in plasma or in the dialysate. Ethanol concentration in dialysate increased (148 ± 15%, p < 0.01), indicating a slower blood flow in the subcutaneous region. Plasma concentrations of various gluco‐ and/or lipid‐regulatory hormones remained unaffected by the cold exposure, except for norepinephrine, which rose about threefold (309 ± 41%, p < 0.001). The data indicate an important role for subcutaneous adipose tissue in mobilization of free fatty acids during cold exposure. This process seems to be regulated by the sympathetic nervous system, whereas hormones involved in the regulation of lipid metabolism, such as epinephrine, insulin, cortisol, and growth hormone, may play a less significant role—at least under the conditions studied.

Regulation of gene expression for lipogenic enzymes in the liver and adipose tissue of hereditary hypertriglyceridemic, insulin-resistant rats: effect of dietary sucrose and marine fish oil

Hypertriglyceridemia is closely linked to insulin resistance. Increased dietary intake of n-3 polyunsaturated fatty acids reverses both hypertriglyceridemia and insulin resistance. To evaluate molecular mechanisms responsible for the hypotriglyceridemic effects of n-3 polyunsaturated fatty acids, the expression of genes for lipogenic enzymes in liver and white and brown adipose tissue was estimated in hereditary hypertriglyceridemic rats which underwent an euglycemic hyperinsulinemic clamp. Before the clamp, animals were fed a basal or a high (63%) sucrose diet with or without fish oil for two weeks. Results were compared to data obtained from control animals subjected to the identical protocol. In hereditary hypertriglyceridemic rats, gene expression for malic enzyme was increased in liver and in brown adipose tissue but not in white adipose tissue. The high sucrose diet raised malic enzyme mRNA levels in liver of both hereditary hypertriglyceridemic and control rats, and this effect was more pronounced in brown adipose tissue. Supplementing the high sucrose diet with fish oil led to a suppression of malic enzyme gene expression in liver and brown adipose tissue of control rats. However, this inhibitory effect was not as pronounced in the hereditary hypertriglyceridemic rats. Raised levels of fatty acid synthase mRNA in liver and brown adipose tissue of control rats fed high sucrose diet were suppressed by consumption of diet high in n-3 fatty acids. On the other hand, in hereditary hypertriglyceridemic rats fed high sucrose diet, fish oil supplementation failed to suppress increased levels of fatty acid synthase mRNA in liver and in brown adipose tissue. It appears that hereditary hypertriglyceridemic rats have elevated levels of mRNA for lipogenic enzymes in liver and brown adipose tissue and dietary control leading to an alteration of hypertriglyceridemia influences gene expression of lipogenic enzymes only under special dietary circumstances.

The Effect of Hyperlipidemia on Serum Fatty Acid Composition in Type 2 Diabeticsa

Fatty acid (FA) profiles of total serum lipids were determined by capillary gas chromatography in Type 2 diabetic patients (NIDDM) with diverse types of hyperlipidemia. In patients with hypertriglyceridemia (DM-HTG) and combined hypertriglyceridemia and hypercholesterolemia (DM-HLP), a significantly different total FA composition was found compared with healthy controls or diabetics with normal serum lipids. In particular, the proportions of saturated and monounsaturated FA were increased and the proportions of n-6 polyunsaturated FA were decreased. In DM-HLP patients, PUFA n-6 metabolites and C20-C22 PUFA were also decreased. Thus, hyperlipidemia shifts significantly the serum FA composition in NIDDM patients into an atherogenic profile. More study is needed, however, to understand if serum FA changes may contribute to the increased atherogenesis commonly found in these patients.