Deficiency of carbohydrate-activated transcription factor ChREBP prevents obesity and improves plasma glucose control in leptin-deficient (ob/ob) mice

2006 ◽  
Vol 291 (2) ◽  
pp. E358-E364 ◽  
Author(s):  
Katsumi Iizuka ◽  
Bonnie Miller ◽  
Kosaku Uyeda
Keyword(s):  
Transcription Factor ◽  
Fatty Acid ◽  
Mrna Expression ◽  
Plasma Glucose ◽  
Plasma Free Fatty Acid ◽  
Acid Synthesis ◽  
Appetite Control ◽  
Glucose Levels ◽  
Long Term Storage ◽  
Deficient Mice

The transcription factor carbohydrate response element-binding protein (ChREBP) mediates insulin-independent, glucose-stimulated gene expression of multiple liver enzymes responsible for converting excess carbohydrate to fatty acids for long-term storage. To investigate ChREBP's role in the development of obesity and obesity-associated metabolic dysregulation, ChREBP-deficient mice were intercrossed with ob/ob mice. As a result of deficient leptin expression, ob/ob mice overeat, become obese and resistant to insulin, and display marked elevations in hepatic lipogenesis, gluconeogenesis, and plasma glucose and triglycerides. mRNA expression of all hepatic lipogenic enzymes was significantly lower in ob/ob-ChREBP−/− than in ob/ob mice, resulting in decreased hepatic fatty acid synthesis and normalization of plasma free fatty acid and triglyceride levels. Overall weight gain in addition to adiposity was reduced in the doubly deficient mice. The former was largely attributable to decreased food intake and may result from decreased hypothalamic expression of the appetite-stimulating neuropeptide agouti-related protein. mRNA expression and activity of gluconeogenic enzymes also was lower in the doubly deficient mice, contributing to significantly lower blood glucose levels. The results of this study suggest that inactivation of ChREBP expression not only reduces fat synthesis and obesity in ob/ob mice but also results in improved glucose tolerance and appetite control.

scholarly journals High glucose levels reduce fatty acid oxidation and increase triglyceride accumulation in human placenta

2013 ◽  
Vol 305 (2) ◽  
pp. E205-E212 ◽  
Author(s):  
Francisco Visiedo ◽  
Fernando Bugatto ◽  
Viviana Sánchez ◽  
Irene Cózar-Castellano ◽  
Jose L. Bartha ◽  
...  
Keyword(s):  
Fatty Acid ◽  
High Glucose ◽  
De Novo ◽  
Acid Synthesis ◽  
Acid Oxidation ◽  
Glucose Levels ◽  
Triglyceride Accumulation ◽  
Triglyceride Content ◽  
Low Glucose ◽  
Cpt I

Placentas of women with gestational diabetes mellitus (GDM) exhibit an altered lipid metabolism. The mechanism by which GDM is linked to alterations in placental lipid metabolism remains obscure. We hypothesized that high glucose levels reduce mitochondrial fatty acid oxidation (FAO) and increase triglyceride accumulation in human placenta. To test this hypothesis, we measured FAO, fatty acid esterification, de novo fatty acid synthesis, triglyceride levels, and carnitine palmitoyltransferase activities (CPT) in placental explants of women with GDM or no pregnancy complication. In women with GDM, FAO was reduced by ∼30% without change in mitochondrial content, and triglyceride content was threefold higher than in the control group. Likewise, in placental explants of women with no complications, high glucose levels reduced FAO by ∼20%, and esterification increased linearly with increasing fatty acid concentrations. However, de novo fatty acid synthesis remained unchanged between high and low glucose levels. In addition, high glucose levels increased triglyceride content approximately twofold compared with low glucose levels. Furthermore, etomoxir-mediated inhibition of FAO enhanced esterification capacity by ∼40% and elevated triglyceride content 1.5-fold in placental explants of women, with no complications. Finally, high glucose levels reduced CPT I activity by ∼70% and phosphorylation levels of acetyl-CoA carboxylase by ∼25% in placental explants of women, with no complications. We reveal an unrecognized regulatory mechanism on placental fatty acid metabolism by which high glucose levels reduce mitochondrial FAO through inhibition of CPT I, shifting flux of fatty acids away from oxidation toward the esterification pathway, leading to accumulation of placental triglycerides.

Reduced running endurance in gluconeogenesis-inhibited rats

1986 ◽  
Vol 251 (1) ◽  
pp. R137-R142 ◽  
Author(s):  
H. B. John-Alder ◽  
R. M. McAllister ◽  
R. L. Terjung
Keyword(s):  
Fatty Acid ◽  
Blood Glucose ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Plasma Free Fatty Acid ◽  
Hepatic Glycogen ◽  
Endurance Time ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Lactate Levels ◽  
Blood Lactate Levels

The functional significance of gluconeogenesis in prolonging endurance during submaximal activity was assessed in untrained and endurance-trained rats. Gluconeogenesis was inhibited at the phosphoenolpyruvate carboxykinase reaction by 3-mercaptopicolinic acid (3-MPA). Endurance was significantly reduced by 3-MPA in untrained (-32%; P less than 0.005) and in trained rats (-26%; P less than 0.001). Metabolic correlates of fatigue were examined in trained rats. At exhaustion, 3-MPA-treated rats had only 3% of resting hepatic glycogen, 46% of resting white quadriceps glycogen, and 37% of resting blood glucose. All of these substrates were at higher levels in sham-injected controls after the same duration of running (130 min). Glycogen levels in red quadriceps, blood lactate levels, and blood glycerol levels were not different between groups. Plasma free fatty acid levels were elevated to the same extent in both groups after 90 min of activity, remained high at 130 min in controls, but had returned to resting levels in the severely hypoglycemic 3-MPA-treated rats at exhaustion. The results indicate that gluconeogenesis is important for maintaining blood glucose levels and for prolonging endurance time during submaximal activity.

scholarly journals Detecting Glucose Levels in Blood Plasma and Artificial Tear by Au(I) Complex on the Carbopol Polymer: A Microfluidic Paper-Based Method

Polymers ◽  
2018 ◽  
Vol 10 (9) ◽  
pp. 1001 ◽  
Author(s):  
Jong-Jheng Luo ◽  
Sheng-Wei Pan ◽  
Jia-Hui Yang ◽  
Tian-Lin Chang ◽  
Peng-Yi Lin ◽  
...  
Keyword(s):  
Plasma Glucose ◽  
Limit Of Detection ◽  
Microfluidic Channel ◽  
Glucose Sensing ◽  
Single Type ◽  
Dual Emission ◽  
Glucose Levels ◽  
Long Term Storage ◽  
Tear Glucose ◽  
Response Region

We report on a selective paper-based method and a microfluidic paper-based analytical device (μPAD) for the detection of human plasma glucose and tear glucose using carbopol polymer-encapsulated Au(I) complex (AuC2C6H4OMe)2(Ph2P(C6H4)3PPh2), (B5). To the best of our knowledge, this demonstrates for the first time the glucose sensing based on dual emission, i.e., fluorescence and phosphorescence, of a single type molecule on the carbopol polymer. Upon addition of human blood treated with anticoagulants to μPADs, plasma is separated from the blood and flows into the response region of the μPADs to react with carbopol polymer-encapsulated B5, in which the ratiometric luminescence is analyzed. The plasma glucose concentration can be quantitively detected at 1.0–50.0 mM on paper, and tear glucose can be detected at 0.1–4.0 mM on μPADs. Owing to the structural design, this device has superior ratiometric changes of dual emission over other Au(I) complexes for signal transduction. The encapsulation of carbopol polymer also offers long-term storage stability. In tear measurement, carbopol polymer is not only used to encapsulate enzyme to remain the enzyme’s activity, but also played as a glue (or media) to connect microfluidic channel and response region. This further improves the sensitivity and limit of detection for glucose. Moreover, this sensor provides a faster response time, a wider range for glucose sensing than reported previously, and no statistical difference of the data from a commercial glucometer, allowing for practical diagnosis of diabetes and healthy individuals.

Plasma free fatty acid turnover during insulin-induced hypoglycemia

1961 ◽  
Vol 201 (3) ◽  
pp. 535-539 ◽  
Author(s):  
D. T. Armstrong ◽  
R. Steele ◽  
N. Altszuler ◽  
A. Dunn ◽  
J. S. Bishop ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Free Fatty Acid ◽  
Glucose Uptake ◽  
Plasma Glucose ◽  
Glucose Concentration ◽  
Insulin Infusion ◽  
Plasma Free Fatty Acid ◽  
Plasma Glucose Concentration ◽  
Free Insulin ◽  
Adrenal Response

Plasma free fatty acid (FFA) concentration falls when an infusion of glucagon-free insulin is initiated in the normal unanesthetized dog in the postabsorptive state. Using C14 palmitate it was shown that the lowered FFA concentration is caused by decreased FFA production. This decreased FFA production accompanies increased glucose uptake by the tissues as demonstrated using C14 glucose. During slow insulin infusion, when plasma glucose concentration remains above 75 mg%, FFA production and concentration remain low. However, during more rapid insulin infusion, when plasma glucose concentration falls below 50 mg%, the initially lowered FFA production rebounds and FFA production and concentration exceed the preinsulin level. Glucose uptake always remains elevated during insulin infusion. Dibenzyline or guanethidine pretreatment blocks the rebound in FFA production. Thus decreased FFA production, due presumably to decreased FFA release by adipose tissue because of insulin-stimulated glucose uptake, can be overpowered by a sympatho-adrenal response to hypoglycemia during a continued infusion of insulin and a resulting continued increased glucose uptake.

Effects of essential fatty acid deficiency on enterohepatic circulation of bile salts in mice

2009 ◽  
Vol 297 (3) ◽  
pp. G520-G531 ◽  
Author(s):  
S. Lukovac ◽  
E. L. Los ◽  
F. Stellaard ◽  
E. H. H. M. Rings ◽  
H. J. Verkade
Keyword(s):  
Fatty Acid ◽  
Bile Salt ◽  
Mrna Expression ◽  
Essential Fatty Acid ◽  
Bile Flow ◽  
Bile Salts ◽  
Enterohepatic Circulation ◽  
Synthesis Rate ◽  
Bile Production ◽  
Deficient Mice

Essential fatty acid (EFA) deficiency in mice has been associated with increased bile production, which is mainly determined by the enterohepatic circulation (EHC) of bile salts. To establish the mechanism underlying the increased bile production, we characterized in detail the EHC of bile salts in EFA-deficient mice using stable isotope technique, without interrupting the normal EHC. Farnesoid X receptor (FXR) has been proposed as an important regulator of bile salt synthesis and homeostasis. In Fxr −/− mice we additionally investigated to what extent alterations in bile production during EFA deficiency were FXR dependent. Furthermore, we tested in differentiating Caco-2 cells the effects of EFA deficiency on expression of FXR-target genes relevant for feedback regulation of bile salt synthesis. EFA deficiency-enhanced bile flow and biliary bile salt secretion were associated with elevated bile salt pool size and synthesis rate (+146 and +42%, respectively, P < 0.05), despite increased ileal bile salt reabsorption (+228%, P < 0.05). Cyp7a1 mRNA expression was unaffected in EFA-deficient mice. However, ileal mRNA expression of Fgf15 (inhibitor of bile salt synthesis) was significantly reduced, in agreement with absent inhibition of the hepatic bile salt synthesis. Bile flow and biliary secretion were enhanced to the same extent in EFA-deficient wild-type and Fxr −/− mice, indicating contribution of other factors besides FXR in regulation of EHC during EFA deficiency. In vitro experiments show reduced induction of mRNA expression of relevant genes upon chenodeoxycholic acid and a selective FXR agonist GW4064 stimulation in EFA-deficient Caco-2 cells. In conclusion, our data indicate that EFA deficiency is associated with interrupted negative feedback of bile salt synthesis, possibly because of reduced ileal Fgf15 expression.

PLASMA GLUCOSE, LACTATE AND FREE FATTY ACID RESPONSES TO ADRENALINE IN CHRONICALLY WARM- AND COLD-EXPOSED SHEEP

1981 ◽  
Vol 61 (4) ◽  
pp. 919-924 ◽  
Author(s):  
A. D. GRAHAM ◽  
G. D. PHILLIPS
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Free Fatty Acid ◽  
Free Fatty Acids ◽  
Cold Exposure ◽  
Plasma Glucose ◽  
Plasma Free Fatty Acid ◽  
Temperature Treatment ◽  
Glucose Response ◽  
Adrenaline Infusion

The effects of chronic cold exposure, fasting, or both on the plasma metabolite responses to jugular infusions of adrenaline were studied in eight five-mo-old wether lambs. Following maintenance at 20–22 °C or −4 to 10 °C for 2–3 wk the sheep received adrenaline infusions (0.15 μg∙kg−1∙min−1) for 75 min prior to and following a 72-h fast. Plasma samples collected at intervals of 10–15 min before and during adrenaline infusion were analyzed for glucose, lactate and total free fatty acids. Chronic cold exposure had no effect on the pre-infusion plasma glucose, lactate or free fatty acid concentrations. Fasting decreased plasma glucose and lactate and increased plasma free fatty acid concentrations. The plasma glucose response to adrenaline was greater (P < 0.01) in cold- than warm-exposed sheep and fasting depressed this response to a greater extent in the cold-exposed sheep. The plasma lactate response to adrenaline was not influenced by temperature treatment or fasting. Both groups of fasted sheep showed a large increase in plasma free fatty acids during adrenaline infusion but when fed the response was minimal.

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