Liver Phosphoenolpyruvate Carboxykinase Research Articles

Urtica dioica (Gazaneh) distillate restores glucose metabolism in diabetic rats.

Diabetes has become an important health problem in the world. Natural agents, with antidiabetic property, are potential candidates for improving diabetes. Urtica Dioica Distillate (UDD) or Araghe Gazaneh is widely used for the treatment of diabetes as per traditional medicine. Despite the tremendous use of UDD as an antidiabetic compound in folk medicine, the antidiabetic effects of UDD has been neglected by medical scientists. In this study, we aimed to evaluate the effects of UDD on the glucose metabolism in diabetic rats. A total of 24 male rats were divided equally into four groups, two treatment and two control groups, each containing normal or Streptozotocin (STZ)-induced diabetic rats. During 4 weeks, control and treatment rats received water or UDD, respectively. Fasting blood sugar (FBS), HbA1c, serum creatinine, blood urea nitrogen, and specific activities of hepatic enzymes including glucokinase (GK), hexokinase (HK), glucose-6-phosphate dehydrogenase (G6PD), and muscle glucose transporter type 4 (GLUT4) and liver phosphoenolpyruvate carboxykinase (PEPCK) mRNA levels were measured. FBS and HbA1c increased in diabetic groups. Treatment with UDD significantly lowered FBS and prevented weight loss. Decreased FBS level was associated with higher activity levels of GK and HK in UDD-treated diabetic rats. G6PD-specific activity decreased in diabetic control rats compared to nondiabetic ones, but UDD treatment improved it to the normal levels. A significant decrease in the expression level of GLUT4 was observed in diabetic control rats compared to nondiabetic ones, but UDD increased it to the normal levels. These findings suggest that UDD might exert therapeutic effects against diabetes by improving glucose metabolism and can be used as an alternative or complementary medicine for the treatment of diabetic patients.

Hepatic overexpression of protein targeting to glycogen attenuates obesity and improves hyperglycemia in db/db mice.

Increased liver glycogen content has been shown to reduce food intake, attenuate obesity, and improve glucose tolerance in a mouse model of high-fat diet (HFD)-induced obesity. Here we studied the contribution of liver glycogen to the regulation of obesity and glucose metabolism in a model of type 2 diabetes and obesity, namely the db/db mouse. To this end, we crossed db/db mice with animals overexpressing protein targeting to glycogen (PTG) in the liver to generate db/db mice with increased liver glycogen content (db/db-PTG). Hepatic PTG overexpression reduced food intake and fat weight and attenuated obesity and hyperglycemia in db/db mice. Db/db-PTG mice showed similar energy expenditure and physical activity to db/db mice. PTG overexpression reduced liver phosphoenolpyruvate carboxykinase (PEPCK) protein levels and repressed hepatic glucose production in db/db mice. Moreover, increased liver glycogen elevated hepatic ATP content in these animals. However, lipid metabolism was not modified by PTG overexpression. In conclusion, increased liver glycogen content ameliorates the diabetic and obesity phenotype in db/db mice.

251 Dietary Tryptophan Supplementation Improves Fat and Glucose Metabolism in Low Birthweight Piglets

Abstract Low birthweight (LBW) is associated with complications such as insulin resistance, obesity and metabolic disturbances of glucose and fat metabolism in early life. Dietary tryptophan (Trp) has been shown to reduce liver fat and suppress hyperglycemia in different species. The objective of this study was to assess the effect of dietary Trp on growth and glucose and fat metabolism in LBW pigs. Piglets (7-days old) weighing < 2 kg were considered as LBW while those weighting > 2 kg were considered as normal birthweight (NBW) and randomly allocated to 4 milk-replacer based treatments (n = 7–8): 1) NBW-0% Trp (NBW-T0), 2) LBW-0% Trp (LBW-T0), 3) LBW-0.4% Trp (LBW-T0.4), and 4) LBW-0.8% Trp (LBW-T0.8) for 3 weeks. Growth parameters and body weight were measured biweekly. At week 3, blood and tissue samples were collected in overnight-fasted pigs after a meal test. The mRNA and protein abundance of key glucose and lipid metabolism markers were determined using qPCR and western blot, respectively. Univariate GLM with Dunnett’s post-hoc test (SPSS®) was used to analyze the data. Growth parameters did not change among groups. Plasma triglycerides concentration was lower in LBW-T0.4 and LBW-T0.8 compared to LBW-T0. Blood glucose was lower in LBW-T0.8 than LBW-T0 at 60 min following the meal test. LBW-T0.8 had a lower transcript and protein abundance of liver glucose transporter-2 relative to LBW-T0. Compared to LBW-T0, LBW-T0.8 had a higher mRNA abundance of glucokinase and tended to have a lower transcript of phosphoenolpyruvate carboxykinase in liver. Relative to LBW-T0, LBW-T0.4 tended to have a lower protein abundance of sodium-glucose co-transporter 1 in jejunum. Compared to LBW-T0, LBW-T0.4 and LBW-T0.8 had a lower transcript of liver acetyl-CoA carboxylase and LBW-T0.4 had a higher transcript of liver 3-hydroxyacyl-CoA dehydrogenase. In conclusion, Trp supplementation reduced the lipogenesis and gluconeogenesis, but increased the glycolysis in LBW piglets.

Comparative analysis of glucose metabolism responses of large yellow croaker Larimichthys crocea fed diet with fish oil and palm oil.

In order to study the effects of dietary fatty acid compositions on glucose metabolism, large yellow croaker juveniles Larimichthys crocea (initial weight, 36.80 ± 0.39g) were fed with two experiment diets for 12weeks. The two diets contained 6.5% of fish oil (FO) and palm oil (PO), respectively. Results showed that the contents of saturated fatty acids in liver and muscle, levels of glucose, triglyceride (TG), non-esterified fatty acid (NEFA), and leptin in blood were significantly higher in PO group, while the hepatic glycogen and muscle glycogen significantly decreased (P <0.05). There were no significant differences in blood insulin and adiponectin levels between the two groups (P >0.05). Compared with the FO group, the expressions of glucokinase (GK), glucose-6-phosphate dehydrogenase, glycogen synthase (GYS), glucose transporter 2 (GLUT2), insulin receptor 1 (IR1), insulin receptor substrate 1 (IRS1), insulin receptor substrate (IRS2), and protein kinase B (AKT2) were significantly decreased, and the expressions of phosphoenolpyruvate carboxykinase (PEPCK) in liver were significantly increased in the PO group. Meanwhile, the expressions of GK, phosphofructokinase, GYS, GLUT4, and insulin receptor 2 (IR2) were significantly reduced, and the expressions PEPCK, fructose-1 and 6-diphosphatase in muscle were significantly increased in the PO group. In conclusion, palm oil in diet could inhibit the utilization of glucose and promote the endogenous glucose production in large yellow croaker by reducing the sensitivity of insulin, so as to increase the blood glucose level.

Effect of reduced energy density of close-up diets on metabolites, lipolysis and gluconeogenesis in Holstein cows.

ObjectiveAn experiment was conducted to determine the effect of reduced energy density of close-up diets on metabolites, lipolysis and gluconeogenesis in cows during the transition period.MethodsThirty-nine Holstein dry cows were blocked and assigned randomly to three groups, fed a high energy density diet (HD, 1.62 Mcal of net energy for lactation [NEL]/kg dry matter [DM]), a medium energy density diet (MD, 1.47 Mcal NEL/kg DM), or a low energy density diet (LD, 1.30 Mcal NEL/kg DM) prepartum; they were fed the same lactation diet to 28 days in milk (DIM). All the cows were housed in a free-stall barn and fed ad libitum.ResultsThe reduced energy density diets decreased the blood insulin concentration and increased nonesterified fatty acids (NEFA) concentration in the prepartum period (p<0.05). They also increased the concentrations of glucose, insulin and glucagon, and decreased the concentrations of NEFA and β-hydroxybutyrate during the first 2 weeks of lactation (p<0.05). The plasma urea nitrogen concentration of both prepartum and postpartum was not affected by dietary energy density (p>0.05). The dietary energy density had no effect on mRNA abundance of insulin receptors, leptin and peroxisome proliferator-activated receptor-γ in adipose tissue, and phosphoenolpyruvate carboxykinase, carnitine palmitoyltransferase-1 and peroxisome proliferator-activated receptor-α in liver during the transition period (p>0.05). The HD cows had higher mRNA abundance of hormone-sensitive lipase at 3 DIM compared with the MD cows and LD cows (p = 0.001). The mRNA abundance of hepatic pyruvate carboxykinase at 3 DIM tended to be increased by the reduced energy density of the close-up diets (p = 0.08).ConclusionThe reduced energy density diet prepartum was effective in controlling adipose tissue mobilization and improving the capacity of hepatic gluconeogenesis postpartum.

Effect of siglidine on glucose lipid metabolism and the expression of iNOS and GLP-1 receptors in diabetic rats.

Diabetic nephropathy (DN) has become the major complication of diabetes. The progression of the disease impedes the efficacy of DN treatment. Therefore, the strategies to inhibit or reverse kidney damage in DN patients are of critical importance. We aim to investigate the effect of sitagliptin on DN within rat model and analyze the associated metabolism and expression of iNOS/GLP-1 receptor. Diabetic model was generated by using Sprague-Dawley (SD) rats, which received an intra-peritoneal injection of 30 mg/kg streptozotocin. Rats were then treated with saline or 15 mg/(kg.d) sitagliptin by gavage. After 12 weeks, fasting blood glucose and insulin resistance were measured. Rat glucose and lipid metabolism were evaluated by high triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C). Western blot was used to measure expression of glucose-6-phosphatase (G6Pase), phosphoenolpyruvate carboxykinase (PEPCK), fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC) related with glucose-lipid metabolism, and expression of iNOS and GLP-1 expression in kidney tissues. After 12 weeks of feeding, the levels of blood glucose and lipid in sitagliptin group were significantly decreased compared to those in control group (p<0.05), whilst insulin sensitivity was enhanced (p<0.05). Western blot showed that sitagliptin downregulated the expressions of glucose-lipid metabolism proteins such as G6Pase, PEPCK, ACC and FAS in rat livers, inhibited iNOS expression in kidneys and elevated GLP-1 receptor activity (p<0.05). Sitagliptin effectively stabilizes blood glucose and lipid levels in DN rats, significantly improves glucose-lipid metabolism and protects kidney and vascular endothelial cells during DN pathogenesis through inhibiting iNOS expression and elevating GLP-1 receptor activity.

Synergistic effects of dietary carbohydrate and taurine on growth performance, digestive enzyme activities and glucose metabolism in juvenile turbot Scophthalmus maximus L.

A 10-week feeding trial was conducted to evaluate the effects of taurine on growth performance, digestive enzyme activities and glucose metabolism of juvenile turbot Scophthalmus maximus (initial body weight, 3.66 ± 0.02 g) fed diets with different carbohydrate level. With a 2 × 3 two factoral experimental design, two levels of dietary carbohydrate (15% and 21%, respectively) with three levels of taurine (0.4%, 1.2%, and 2.0%, respectively) were used. In addition, the diet with 15% carbohydrate and without taurine supplementation was used as the control. The results showed that, compared with the control group, 1.2% of dietary taurine supplementation significantly increased the specific growth rate, the activities of amylase and lipase in intestine, glycogen content and the mRNA levels of glucokinase, phosphofructokinase, pyruvate kinase, glucose-6-phosphate dehydrogenase (G6PD), glycogen synthase (GS) and glucose transporter 2 in liver at 15% of dietary carbohydrate level. Meanwhile, it significantly decreased the blood glucose concentration and the mRNA levels of cytosolic phosphoenolpyruvate carboxykinase (cPEPCK) in liver. In addition, significant interaction between dietary carbohydrate and taurine were observed in blood glucose level. Compared to 15% dietary carbohydrate, 21% dietary carbohydrate significantly increased the blood glucose level at 1.2% and 2.0% dietary taurine level, whereas it had no significant effect at 0.4% dietary taurine supplementation level. At 21% of dietary carbohydrate level, although 1.2% and 2.0% of dietary taurine supplementation had no significant effects on blood glucose level, it significantly decreased the advanced glycationend products level in plasma and the fructose-1, 6-bisphosphatase mRNA level in liver. Moreover, compared to that fed diet with 15% carbohydrate, fish fed diet with 21% carbohydrate had lower activities of amylase and lipase in intestine and lower mRNA levels of G6PD, mitochondrial phosphoenolpyruvate carboxykinase and cPEPCK in liver. Furthermore, significant interactions between dietary carbohydrate and taurine were also observed in the expression of the genes involved in liver glucose metabolism above in addition to GS and cPEPCK. Overall, this study indicated that taurine had a beneficial effect on glucose homeostasis through enhancement of glycolysis, glucose transport, glycogen synthesis and the inhibition of gluconeogenesis in liver of turbot, thus decreased blood glucose level. However, the beneficial effect of taurine on glucose metabolism was affected by dietary carbohydrate level.

Long-term effect of dietary overload lithium on the glucose metabolism in broiler chickens

Lithium, like insulin, activates glycogen synthase and stimulates glucose transport in rat adipocytes. To investigate the effect of dietary overload lithium on glucose metabolism in broiler chickens, one-day-old chicks were fed a basal diet supplemented with 0 (control) or 100mg lithium/kg (overload lithium) for 35days. Compared to controls, glucose disappearance rates were lower (p=0.035) 15–120min after glucose gavage, and blood glucose concentrations were lower (p=0.038) 30min after insulin injection in overload lithium broilers. Overload lithium decreased (p<0.05) glycogen and glucose-6-phosphate concentrations in liver, but increased (p<0.05) their concentrations in pectoralis major. Overload lithium increased (p<0.05) mRNA expression of glucose transporter (GLUT) 3 and GLUT9 in liver, and GLUT1, GLUT3, GLUT8, and GLUT9 in pectoralis major, but decreased (p<0.05) cytosolic phosphoenolpyruvate carboxykinase (PEPCK) in liver and mitochondrial PEPCK in pectoralis major. These results suggest that dietary overload lithium decreases glucose tolerance and gluconeogenesis, but increases insulin sensitivity and glucose transport in broiler chickens.

Proteomics Analysis Reveals an Important Role for the PPAR Signaling Pathway in DBDCT-Induced Hepatotoxicity Mechanisms.

A patented organotin di-n-butyl-di-(4-chlorobenzohydroxamato)tin (DBDCT) with high a antitumor activity was designed, however, its antitumor and toxic mechanisms have not yet been clearly illustrated. Hepatic proteins of DBDCT-treated rats were identified and analyzed using LC-MS/MS with label-free quantitative technology. In total, 149 differentially expressed proteins were successfully identified. Five protein and mRNA expressions were involved in the peroxisome proliferator-activated receptor (PPAR) signaling pathway, including a scavenger receptor (CD36), adipocyte fatty acid binding protein 4 (FABP4), enoyl-CoA hydratase (EHHADH), acetyl-CoA acyltransferase 1 (ACAA1), and phosphoenolpyruvate carboxykinase (PEPCK) in DBDCT-treated Rat Liver (BRL) cells. PPAR-α and PPAR-λ were also significantly decreased at both protein and mRNA levels. Furthermore, compared with the DBDCT treatment group, a special blocking agent of PPAR-λ T0070907 was used to evaluate the relationship between PPAR-λ and its downstream genes. Our studies indicated that DBDCT may serve as a modulator of PPAR-λ, further up-regulating CD36, FABP4 and EHHADH on the PPAR signal pathway.

Effects of nutritional history on stress response in gibel carp (Carassius auratus gibelio) and largemouth bass (Micropterus salmoides).

The stress response of omnivorous gibel carp (Carassius auratus gibelio) and carnivorous largemouth bass (Micropterus salmoides) with different nutritional history were evaluated. A 2×2 layout, including two fish species (gibel carp or largemouth bass) and two nutritional history (fasted or fed to satiation for four weeks), was used. After feeding or fasting, the fishes were subjected to an acute handling. Fasting resulted in decrease of plasma glucose level and liver glycogen content of gibel carp and largemouth bass. After handling stress, plasma levels of cortisol, glucose and lactate of gibel carp and largemouth bass increased, regardless the fasted fish or fed fish. During the period from 0h to 24h post-stress, the fasted gibel carp exhibited lower plasma cortisol and glucose levels, brain and liver glycogen contents, and liver phosphoenolpyruvate carboxykinase (PEPCK) activity compared with the fed counterpart. The plasma glucose level, brain glucose level, brain and liver glycogen contents were lower, while the liver PEPCK and hexokinase (HK) activities were higher, in the faster largemouth bass than the fed counterpart. This study indicates that nutritional history can influence stress response of gibel carp and largemouth bass, and the stress response is less severe in the fasted fish relative to the fed counterpart. This study also reveals that gibel carp and largemouth bass may have different strategies in response to fasting and acute handling stress.

Amarogentin ameliorates diabetic disorders in animal models.

Amarogentin is a bitter-tasting secoiridoid glycoside isolated from an herb. Inhibition of aldose reductase by amarogentin has been documented as an antidiabetic action. However, the mechanisms of action of amarogentin in diabetic disorders remain unknown. The present study employed streptozotocin-induced type 1 diabetic (T1DM) rats to investigate the antihyperglycemic action of amarogentin. Changes in the protein expression of glucose transporter 4 (GLUT4) and phosphoenolpyruvate carboxykinase (PEPCK) in skeletal muscle and liver, respectively, were also detected by Western blotting. Additionally, a type 2 diabetes (T2DM) animal model induced using a fructose-rich diet was also applied to assess the effect of amarogentin on insulin resistance according to the homeostasis model assessment-insulin resistance (HOMA-IR). Amarogentin dose-dependently attenuated hyperglycemia in the T1DM rats lacking insulin. The action of amarogentin was further supported in rats administered the oral glucose tolerance test. Western blotting showed that amarogentin reversed the decreased GLUT4 level in skeletal muscle and reduced the elevated PEPCK expression in livers isolated from the T1DM rats. Moreover, amarogentin decreased the HOMA-IR and increased insulin sensitivity in the T2DM rats. These data show that amarogentin may ameliorate glucose homeostasis in diabetic rats, indicating its potential for future development as an antidiabetic drug.

Effect of silymarin on gluconeogenesis and lactate production in exercising rats.

In this study, we investigated the effects of silymarin (SM) on gluconeogenesis during exercise in rats. After 4 weeks of exercise, blood samples, liver, and skeletal muscle tissues were collected, and the levels of triglycerides (TG), lactate, peroxisome proliferator activated receptor gamma (PPARγ), phosphoenol pyruvate carboxykinase (PEPCK), pyruvate dehydrogenase kinase 4 (PDK4), and phosphorylated 5-AMP activated protein kinase (AMPK) were measured. The TG and lactate level of the serum were reduced. In addition, the expression of Akt, PEPCK, and PPARγ in liver was decreased as well as the expression of AMPK in muscle. On the contrary, the level of PDK4 in muscle was increased. These results showed that that administration of SM ameliorated exerciseinduced gluconeogenesis and β-oxidation through the regulation of PPARγ, PEPCK, and PDK4. Thus, intake of SM during exercise may improve endurance by modulating of the metabolism of glucose, lipids, and lactate.

Modulation of aquaporins expressions and its impact on alleviating diabetic complications in rats: role of Citrullus colocynthis

Background: Aquaporins (AQPs) belong to a class of small, integral membrane proteins that enable water transfer across the plasma membranes of cells as a reaction to osmotic gradients. There are 13 known types of AQPs in humans (AQP0 to AQP12), which are expressed in various organs such as the kidney, brain, liver, lungs, and salivary glands. In patient with diabetes mellitus, a reduction in salivary secretion is noted in concurrence with low salivary AQP5 levels. The Citrullus colocynthis (CC) extracts were reported to have beneficial effects on glucose homeostasis and body weight maintenance, in either alloxan- or streptozotocin (STZ)-induced diabetic rats through exerting insulinotropic effect. Aims and Objective: To check the changes in AQPs expression and to understand the antidiabetic effect of CC as a medicinal herb in STZ-induced diabetic rats. Materials and Methods: Forty-two male Wistar rats were assigned equally into six groups. The first and second groups were kept as control groups: the first remained without treatment, but the second received CC orally. Diabetes was induced by a single intraperitoneal (i.p) injection of STZ (60 mg/kg b.w.) in the remaining four groups. Three diabetic groups were treated with insulin or CC or both together for 4 weeks. The remaining diabetic group was left untreated as control diabetic group. Blood and organs were taken for biochemical, gene expression, and immunohistochemistry examinations. Result: Diabetic rats displayed increases in blood glucose, lipid profile, liver, and kidney parameters, which were restored significantly to normal with insulin or CC or both. At molecular level, diabetic rats showed significant downregulation in mRNA expressions of antioxidant enzymes, insulin receptor substrate 1 and 2, pyruvate kinase, GLUT-2 in liver and of AQP1, AQP5, AQP7, and AQP8 expressions in kidney, salivary gland, and pancreas, respectively, and normalized significantly by insulin or CC or in combination administrations. Expressions of phosphoenol pyruvate carboxykinase in liver and of AQP2 and AQP3 in kidney were upregulated in diabetic rats and returned to normal completely by insulin alone or CC or their combination. Values were statistically significant at p < 0.05. Immunohistochemical examinations revealed a downregulation of insulin and GLUT-2 in pancreas and upregulation of AQP2 in kidney of diabetic rats, but treatments with CC augmented insulin effect and restored their expression to normal levels. Conclusion: Current results concluded that AQPs could be a promising target for drug development. Moreover, Citrullus colocynthis extract acts as antidiabetic medicinal herb, which has been confirmed by its molecular and immunohistochemical effects.

In Pursuit of Genes of Glucose Metabolism

If you don't know where you're going, you might wind up someplace else—Yogi Berra My professional journey, once I accepted the fact that I would not play first base for the Chicago Cubs, was not accomplished in a straight line. I entered medical school intending to become a family physician but soon became interested in research. I took an internal medicine residency at the University of California, San Francisco (UCSF), then a long research fellowship in the nascent field of molecular biology at the National Institutes of Health (NIH), and followed that with training in clinical endocrinology at the University of Wisconsin. I spent the next fifteen years dividing my time between the clinic and laboratory at the University of Iowa. Finally, I decided to concentrate on research and spent the next twenty-three years at Vanderbilt University. For the past eleven years, I have been at the University of Iowa, where I helped establish a new diabetes research center. My research journey also had several different directions. Upon reflection, I guess I ended up “someplace else” by choice, and it certainly has been an interesting trip. It is one I unreservedly recommend.

Arsenic Exposure and Glucose Intolerance/Insulin Resistance in Estrogen-Deficient Female Mice.

BackgroundEpidemiological studies have reported that the prevalence of diabetes in women > 40 years of age, especially those in the postmenopausal phase, was higher than in men in areas with high levels of arsenic in drinking water. The detailed effect of arsenic on glucose metabolism/homeostasis in the postmenopausal condition is still unclear.ObjectivesWe investigated the effects of arsenic at doses relevant to human exposure from drinking water on blood glucose regulation in estrogen-deficient female mice.MethodsAdult female mice who underwent ovariectomy or sham surgery were exposed to drinking water contaminated with arsenic trioxide (0.05 or 0.5 ppm) in the presence or absence of 17β-estradiol supplementation for 2–6 weeks. Assays related to glucose metabolism were performed.ResultsExposure of sham mice to arsenic significantly increased blood glucose, decreased plasma insulin, and impaired glucose tolerance, but did not induce insulin resistance. Blood glucose and insulin were higher, and glucose intolerance, insulin intolerance, and insulin resistance were increased in arsenic-treated ovariectomized mice compared with arsenic-treated sham mice. Furthermore, liver phosphoenolpyruvate carboxykinase (PEPCK) mRNA expression was increased and liver glycogen content was decreased in arsenic-treated ovariectomized mice compared with arsenic-treated sham mice. Glucose-stimulated insulin secretion in islets isolated from arsenic-treated ovariectomized mice was also significantly decreased. Arsenic treatment significantly decreased plasma adiponectin levels in sham and ovariectomized mice. Altered glucose metabolism/homeostasis in arsenic-treated ovariectomized mice was reversed by 17β-estradiol supplementation.ConclusionsOur findings suggest that estrogen deficiency plays an important role in arsenic-altered glucose metabolism/homeostasis in females.CitationHuang CF, Yang CY, Chan DC, Wang CC, Huang KH, Wu CC, Tsai KS, Yang RS, Liu SH. 2015. Arsenic exposure and glucose intolerance/insulin resistance in estrogen-deficient female mice. Environ Health Perspect 123:1138–1144; http://dx.doi.org/10.1289/ehp.1408663

Potassium diformate influences gene expression of GH/IGF-I axis and glucose homeostasis in weaning piglets

The objective of this study was to determine the effects of potassium diformate (KDF) on growth performance of weaning piglets and genes expression related with growth axis and hepatic gluconeogenesis. A total of 180 piglets weaned at 28d of age were allocated randomly into two groups, with 6 pens in each group and 15 piglets in each pen. Piglets in the control group were fed basal diet, whereas the KDF-treated group was fed basal diet supplemented with 10g/kg KDF. After 5 weeks feeding, KDF-treated piglets showed higher average daily feed intake (ADFI) and average daily bodyweight gain (ADG) than those of the control (P<0.05), whereas the feed conversion ratio (FCR) was lower than that of the control (P=0.02). The apparent digestibility of dry matter and crude protein of the KDF-treated group were higher than those of the control group (P<0.01). KDF treatment did not change the blood indices level of insulin-like growth factor-I (IGF-I), high density lipoprotein (HDL), low density lipoprotein (LDL), total cholesterol (TC), triglyceride (TG) and blood glucose (BG) in plasma. KDF treatment did not influence the mRNA expression of growth hormone releasing hormone (GHRH) and somatostatin (SS) in hypothalamus, and the levels of growth hormone receptor (GHR) and IGF-I receptor (IGF-IR) mRNA in pituitary. Whereas, it increased the abundance of GH mRNA in pituitary, and the mRNA of GHR, IGF-I, IGF-IR, glucose-6-phosphatase (G6PC), fructose-1,6-bisphosphatase (FBP) and phosphoenolpyruvate carboxykinase (PCK) in liver (P<0.05). Furthermore, KDF treatment increased the concentration of IGF-I peptide in liver (P=0.000). These results suggest that, the beneficial effect of KDF on the growth performance may relate to the regulation of the GH axis and glucose homeostasis in piglets.

Carotid body denervation prevents fasting hyperglycemia during chronic intermittent hypoxia.

Obstructive sleep apnea causes chronic intermittent hypoxia (IH) and is associated with impaired glucose metabolism, but mechanisms are unknown. Carotid bodies orchestrate physiological responses to hypoxemia by activating the sympathetic nervous system. Therefore, we hypothesized that carotid body denervation would abolish glucose intolerance and insulin resistance induced by chronic IH. Male C57BL/6J mice underwent carotid sinus nerve dissection (CSND) or sham surgery and then were exposed to IH or intermittent air (IA) for 4 or 6 wk. Hypoxia was administered by decreasing a fraction of inspired oxygen from 20.9% to 6.5% once per minute, during the 12-h light phase (9 a.m.-9 p.m.). As expected, denervated mice exhibited blunted hypoxic ventilatory responses. In sham-operated mice, IH increased fasting blood glucose, baseline hepatic glucose output (HGO), and expression of a rate-liming hepatic enzyme of gluconeogenesis phosphoenolpyruvate carboxykinase (PEPCK), whereas the whole body glucose flux during hyperinsulinemic euglycemic clamp was not changed. IH did not affect glucose tolerance after adjustment for fasting hyperglycemia in the intraperitoneal glucose tolerance test. CSND prevented IH-induced fasting hyperglycemia and increases in baseline HGO and liver PEPCK expression. CSND trended to augment the insulin-stimulated glucose flux and enhanced liver Akt phosphorylation at both hypoxic and normoxic conditions. IH increased serum epinephrine levels and liver sympathetic innervation, and both increases were abolished by CSND. We conclude that chronic IH induces fasting hyperglycemia increasing baseline HGO via the CSN sympathetic output from carotid body chemoreceptors, but does not significantly impair whole body insulin sensitivity.

Programming of phosphoenolpyruvate carboxykinase by maternal high fat diet may contribute to hepatic fat accumulation in female offspring rats (942.6)

Phosphoenolpyruvate carboxykinase (PEPCK) produces phosphoenolpyruvate during glyceroneogenesis. We previously demonstrated that high fat diet during pregnancy induced PEPCK mRNA expression in neonatal pups, which is characterized by histone modifications in specific regions of the gene. In the present study, we investigated persistency of the alterations in adult offspring. Dams were fed either control or high fat diet throughout gestation and lactation. Offspring were placed on control diet after weaning, generating C/C and HF/C groups. Liver was collected at 12 wks of age. Hepatic NADH level was increased in both genders but fat accumulation occurred only in female liver (HF/C). This was accompanied by a significant increase of PEPCK and Fatty Acid Synthase (FASN) mRNA expression in female liver. The induction of PEPCK gene expression was associated with an increased dimethylated histone H3 lysine 4 level in multiple regions of the gene. Meanwhile, trimethylated histone H3 lysine 4 was induced at a specific coding region in HF/C, accompanied by a decreased trimethylated histone H3 lysine 9 level at the promoter. In conclusion, maternal high fat diet programs PEPCK expression through histone modifications in adult offspring. Persistent PEPCK induction contributes to triglyceride synthesis. Combined with induced FASN and NADH, this leads to increased fat deposition in a gender‐specific manner.

The constitutive androstane receptor activator 4‐[(4R,6R)‐4,6‐diphenyl‐1,3‐dioxan‐2‐yl]‐N,N‐dimethylaniline inhibits the gluconeogenic genes PEPCK and G6Pase through the suppression of HNF4α and FOXO1 transcriptional activity

The dual role of the constitutive androstane receptor (CAR) as both a xenosensor and a regulator of endogenous energy metabolism (lipogenesis and gluconeogenesis) has recently gained acceptance. Here, we investigated the effects of 4-[(4R,6R)-4,6-diphenyl-1,3-dioxan-2-yl]-N,N-dimethylaniline (transpDMA), an effective CAR activator, on the gluconeogenic genes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) in rat livers. The effects of transpDMA were investigated in normal and high-fat diet-fed Wistar rats using real-time PCR, Western blotting, chromatin immunoprecipitation assays (ChIP), glucose tolerance test and insulin tolerance test. The expression of the gluconeogenic enzymes PEPCK and G6Pase was repressed by transpDMA treatment under fasting conditions. Long-term CAR activation by transpDMA significantly reduced fasting blood glucose levels and improved glucose homeostasis and insulin sensitivity in high-fat diet-fed rats. The metabolic benefits of CAR activation by transpDMA may have resulted from the inhibition of hepatic gluconeogenic genes. ChIP assays demonstrated that transpDMA prevented the binding of forkhead box O1 (FOXO1) to insulin response sequences in the PEPCK and G6Pase gene promoters in rat livers. Moreover, transpDMA-activated CAR inhibited hepatocyte nuclear factor-4α (HNF4α) transactivation by competing with HNF4α for binding to the specific binding element (DR1-site) in the gluconeogenic gene promoters. Our results provide evidence to support the conclusion that transpDMA inhibits the gluconeogenic genes PEPCK and G6Pase through suppression of HNF4α and FOXO1 transcriptional activity.

Impact of Cadmium Exposure during Pregnancy on Hepatic Glucocorticoid Receptor Methylation and Expression in Rat Fetus

Adverse fetal environment due to maternal undernutrition or exposure to environmental chemicals alters glucocorticoid (GC) metabolism increasing the risk of metabolic disorders in adulthood. In this study, we investigated the effects of maternal exposure to cadmium (Cd, 50 ppm) during pregnancy in the methylation of fetal hepatic glucocorticoid receptor promoter (GR) and the correlation with its expression and that of the DNA methyltransferases (DNMT1a and 3a). We also studied the expression of liver phosphoenolpyruvate carboxykinase (PEPCK) and acyl-CoA oxidase (AOX), two enzymes involved in the metabolism of carbohydrates and lipids respectively. The methylation of the rat GR gene exon 110 (GR110) in nucleotides -2536 to -2361 was analyzed by pyrosequencing. Quantitative real time PCR was used to assess hepatic GR, PEPCK and AOX mRNA, and their protein levels using Western blotting analysis. Differential methylation was noted across groups at all CpG sites in the GR exon 110 in a sex-dependent manner. In males, CpG were more methylated than the controls (185±21%, p<0.001) but only CpG sites 1,6,7 and 9 showed a significantly different extent of methylation. In addition, a lower expression of GR (mRNA and protein) was found. On the contrary, in females, CpG were less methylated than the controls (62±11%, p<0.05) and overexpressed, affecting PEPCK and AOX expression, which did not change in males. The GR methylation profile correlates with DNMT3a expression which may explain epigenetic sex-dependent changes on GR110 promoter induced by Cd treatment. In conclusion, Cd exposure during pregnancy affects fetal liver DNMT3a resulting in sex-dependent changes in methylation and expression of GR110. Although these effects do not seem to be directly involved in the low birth weight and height, they may have relevant implications for long-term health.