The Impaired Response of Non-Obese Hereditary Hypertriglyceridemic Rats to Glucose Load is Associated with Low Glucose Storage in Energy Reserves

Appl. Physiol. Nutr. Metab.

Chrastina

Hansı́ková

et al. 2015

The aim of this study was to estimate the effect of carnitine supplementation on lipid disorders and peripheral tissue insulin sensitivity in a non-obese animal model of insulin resistance, the hereditary hypertriglyceridemic (HHTg) rat. Male HHTg rats were fed a standard diet, and half of them received daily doses of carnitine (500 mg·kg(-1) body weight) for 8 weeks. Rats of the original Wistar strain were used for comparison. HHTg rats exhibited increased urinary excretion of free carnitine and reduced carnitine content in the liver and blood. Carnitine supplementation compensated for this shortage and promoted urinary excretion of acetylcarnitine without any signs of (acyl)carnitine accumulation in skeletal muscle. Compared with their untreated littermates, carnitine-treated HHTg rats exhibited lower weight gain, reduced liver steatosis, lower fasting triglyceridemia, and greater reduction of serum free fatty acid content after glucose load. Carnitine treatment was associated with increased mitochondrial biogenesis and oxidative capacity for fatty acids, amelioration of oxidative stress, and restored substrate switching in the liver. In skeletal muscle (diaphragm), carnitine supplementation was associated with significantly higher palmitate oxidation and a more favorable complete to incomplete oxidation products ratio. Carnitine supplementation further enhanced insulin sensitivity ex vivo. No effects on whole-body glucose tolerance were observed. Our data suggest that some metabolic syndrome-related disorders, particularly fatty acid oxidation, steatosis, and oxidative stress in the liver, could be attenuated by carnitine supplementation. The effect of carnitine could be explained, at least partly, by enhanced substrate oxidation and increased fatty acid transport from tissues in the form of short-chain acylcarnitines.

Section: Ex Vivo Tissue Incubation Proceduresmentioning

confidence: 99%

Carnitine supplementation alleviates lipid metabolism derangements and protects against oxidative stress in non-obese hereditary hypertriglyceridemic rats

Appl. Physiol. Nutr. Metab.

Chrastina

Hansı́ková

et al. 2015

“…This non-obese strain exhibits, apart from hypertriglyceridemia, a high serum free fatty acid (FFA) content, hyperinsulinemia and impaired glucose tolerance. 15,16 Chemicals D-[U- 14 C-] glucose was purchased from UVVVR (Prague, Czech Republic). Methoxamine, prazosin, isoproterenol (isoprenaline hydrochloride) and wortmannin were obtained from Sigma-Aldrich (St Louis, MO, USA); insulin (R-Humulin) from Eli Lilly (Indianapolis, IN, USA); and epinephrine (epinephrine hydrochloridum) from Leciva (Prague, Czech Republic).…”

Section: Animals and Experimental Protocolmentioning

confidence: 99%

Epinephrine-dependent control of glucose metabolism in white adipose tissue: the role ofα- andβ-adrenergic signalling

Páleníčková

Papáčková

et al. 2012

Exp Biol Med (Maywood)

Epinephrine controls many important and sometimes opposite processes. This pleiotropic effect is achieved via coupling to different receptor/effector systems. In epididymal white adipose tissue (EWAT) of Wistar rats, we showed that epinephrine stimulated protein kinase B (PKB) phosphorylation on Ser(473). Epinephrine further increased the glucose incorporation into glyceride-glycerol without decreasing glucose availability for other metabolic pathways (i.e. lactate production). Wortmannin (phosphatidylinositol 3-kinase inhibitor) treatment significantly decreased glucose incorporation into glyceride-glycerol and elevated the epinephrine-induced release of free fatty acids (FFA) from the adipose tissue without any change in the intensity of lipolysis measured as glycerol release. Using specific cyclic adenosine monophosphate (cAMP) analogs we demonstrated that cAMP-protein kinase A (PKA) signalling resulted in a strong PKB dephosphorylation and significantly lowered the glucose availability in EWAT. Specific activation of the Epac (exchange protein activated by cAMP)-dependent pathway had only a moderately negative effect on PKB phosphorylation and glucose metabolism. In contrast, α(1) agonist methoxamine increased PKB phosphorylation and lactate production. This effect of methoxamine was additive to the effect of insulin and it was abolished by wortmannin treatment. In EWAT of spontaneously dyslipidemic hereditary hypertriglyceridemic (HHTg) rats, we demonstrated significantly lower epinephrine-induced glucose utilization but higher sensitivity to its lipolytic effect. We conclude that in EWAT, epinephrine controls two opposite processes (FFA release and FFA retention) via two different effector systems. The impairment of α(1)-dependent, epinephrine-stimulated, glycolysis-dependent FFA esterification may contribute to the establishment of dyslipidemia in insulin resistance.

“…Serum glucose was measured using an AccuChek glucometer (Roche, Czech Republic). Glycogen and triacylglycerol content in the liver were determined as described previously (12).…”

Section: Methodsmentioning

confidence: 99%

Metformin prevents ischemia reperfusion-induced oxidative stress in the fatty liver by attenuation of reactive oxygen species formation

American Journal of Physiology-Gastrointestinal and Liver Physi

Páleníčková

Daňková

et al. 2015

Z, Oliyarnyk O, Kazdova L. Metformin prevents ischemia reperfusion-induced oxidative stress in the fatty liver by attenuation of reactive oxygen species formation. Am J Physiol Gastrointest Liver Physiol 309: G100 -G111, 2015. First published June 4, 2015; doi:10.1152/ajpgi.00329.2014.-Nonalcoholic fatty liver disease is associated with chronic oxidative stress. In our study, we explored the antioxidant effect of antidiabetic metformin on chronic [high-fat diet (HFD)-induced] and acute oxidative stress induced by short-term warm partial ischemia-reperfusion (I/R) or on a combination of both in the liver. Wistar rats were fed a standard diet (SD) or HFD for 10 wk, half of them being administered metformin (150 mg·kg body wt Ϫ1 ·day Ϫ1 ). Metformin treatment prevented acute stress-induced necroinflammatory reaction, reduced alanine aminotransferase and aspartate aminotransferase serum activity, and diminished lipoperoxidation. The effect was more pronounced in the HFD than in the SD group. The metformin-treated groups exhibited less severe mitochondrial damage (markers: cytochrome c release, citrate synthase activity, mtDNA copy number, mitochondrial respiration) and apoptosis (caspase 9 and caspase 3 activation). Metformin-treated HFD-fed rats subjected to I/R exhibited increased antioxidant enzyme activity as well as attenuated mitochondrial respiratory capacity and ATP resynthesis. The exposure to I/R significantly increased NADH-and succinate-related reactive oxygen species (ROS) mitochondrial production in vitro. The effect of I/R was significantly alleviated by previous metformin treatment. Metformin downregulated the I/R-induced expression of proinflammatory (TNF-␣, TLR4, IL-1␤, Ccr2) and infiltrating monocyte (Ly6c) and macrophage (CD11b) markers. Our data indicate that metformin reduces mitochondrial performance but concomitantly protects the liver from I/R-induced injury. We propose that the beneficial effect of metformin action is based on a combination of three contributory mechanisms: increased antioxidant enzyme activity, lower mitochondrial ROS production, and reduction of postischemic inflammation. metformin; oxidative stress; mitochondrial respiration; liver injury; 31 P MR spectroscopy METFORMIN IS AN ORAL ANTIHYPERGLYCEMIC drug widely used in the treatment of Type 2 diabetes (T2D) (7). There is evidence that metformin also protects against oxidative stress in various tissues, although the antioxidant activity of metformin is not well understood. It has been shown that hyperglycemia is associated with increased reactive oxygen species (ROS) formation due to superoxide overproduction from the mitochondrial electron transport chain as a consequence of increased glycolysis (8). It has been hypothesized that the antioxidative effect of metformin is simply the consequence of its glucoselowering effect and subsequent decrease in superoxide anion production (3). Nevertheless, metformin has also displayed antioxidative characteristics in several models of oxidative stress without hyperglycemia (2,19,20,2...