Peroxisomal-mitochondrial oxidation in a rodent model of obesity-associated insulin resistance

2007 ◽  
Vol 293 (4) ◽  
pp. E986-E1001 ◽  
Author(s):  
Robert C. Noland ◽  
Tracey L. Woodlief ◽  
Brian R. Whitfield ◽  
Steven M. Manning ◽  
Jasper R. Evans ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Clinical Importance ◽  
Product Distribution ◽  
Zucker Rats ◽  
Acid Oxidation ◽  
Insulin Resistant ◽  
Malonyl Coa ◽  
Skeletal Muscle Lipid ◽  
Mitochondrial Oxidation ◽  
Cpt I

Peroxisomal oxidation yields metabolites that are more efficiently utilized by mitochondria. This is of potential clinical importance because reduced fatty acid oxidation is suspected to promote excess lipid accumulation in obesity-associated insulin resistance. Our purpose was to assess peroxisomal contributions to mitochondrial oxidation in mixed gastrocnemius (MG), liver, and left ventricle (LV) homogenates from lean and fatty ( fa/fa) Zucker rats. Results indicate that complete mitochondrial oxidation (CO2production) using various lipid substrates was increased approximately twofold in MG, unaltered in LV, and diminished ∼50% in liver of fa/fa rats. In isolated mitochondria, malonyl-CoA inhibited CO2production from palmitate 78%, whereas adding isolated peroxisomes reduced inhibition to 21%. These data demonstrate that peroxisomal products may enter mitochondria independently of CPT I, thus providing a route to maintain lipid disposal under conditions where malonyl-CoA levels are elevated, such as in insulin-resistant tissues. Peroxisomal metabolism of lignoceric acid in fa/fa rats was elevated in both liver and MG (LV unaltered), but peroxisomal product distribution varied. A threefold elevation in incomplete oxidation was solely responsible for increased hepatic peroxisomal oxidation (CO2unaltered). Alternatively, only CO2was detected in MG, indicating that peroxisomal products were exclusively partitioned to mitochondria for complete lipid disposal. These data suggest tissue-specific destinations for peroxisome-derived products and emphasize a potential role for peroxisomes in skeletal muscle lipid metabolism in the obese, insulin-resistant state.

Effects of extracellular ATP on hepatic fatty acid metabolism

1996 ◽  
Vol 270 (4) ◽  
pp. G701-G707 ◽  
Author(s):  
M. Guzman ◽  
G. Velasco ◽  
J. Castro
Keyword(s):  
Fatty Acid ◽  
De Novo ◽  
Specific Inhibitor ◽  
Rat Hepatocytes ◽  
Inhibitory Effect ◽  
Extracellular Atp ◽  
Acid Oxidation ◽  
A 23187 ◽  
Malonyl Coa ◽  
Cpt I

Incubation of rat hepatocytes with extracellular ATP inhibited acetyl-CoA carboxylase (ACC) activity and fatty acid synthesis de novo, with a concomitant decrease of intracellular malonyl-CoA concentration. However, both carnitine O-palmitoyltransferase I (CPT-I) activity and ketogenesis from palmitate were inhibited in parallel by extracellular ATP. The inhibitory effect of extracellular ATP on ACC and CPT-I activities was not evident in Ca2+ -depleted hepatocytes. Incubation of hepatocytes with thapsigargin, 2,5-di-(t-butyl)-1,4-benzohydroquinone (BHQ), or A-23187, compounds that increase cytosolic free Ca2+ concentration ([Ca2+]i), depressed ACC activity, whereas CPT-I activity was unaffected. The phorbol ester 4 beta-phorbol 12 beta-myristate 13 alpha-acetate (PMA) increased ACC activity, whereas it decreased CPT-I activity in a nonaddictive manner with respect to extracellular ATP. The inhibitory effect of extracellular ATP on ACC activity was also evident in the presence of bisindolyl-maleimide, a specific inhibitor of protein kinase C (PKC), whereas this compound abolished the extracellular ATP-mediated inhibition of CPT-I. In addition, the PMA-induced inhibition of CPT-I was not potentiated by thapsigargin, BHQ, or A-23187. Results thus show 1) that the intracellular concentration of malonyl-CoA is not the factor responsible for the inhibition of hepatic long-chain fatty acid oxidation by extracellular ATP, and 2) that the inhibition of ACC by extracellular ATP may be mediated by an elevation of [Ca2+]i, whereas CPT-I may be inhibited by extracellular ATP through a PKC-dependent mechanism.

An explanation for decreased ketogenesis in the liver of the obese Zucker rat

1989 ◽  
Vol 257 (4) ◽  
pp. R822-R828 ◽  
Author(s):  
M. J. Azain ◽  
J. A. Ontko
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Rat Liver ◽  
Intact Cell ◽  
Zucker Rats ◽  
Acid Oxidation ◽  
Palmitate Oxidation ◽  
Malonyl Coa ◽  
Obese Zucker Rats ◽  
Rat Livers

These studies were undertaken to further characterize and explain the differences in hepatic fatty acid metabolism between lean and obese Zucker rats. It was shown that the rate of palmitate or octanoate oxidation and the inhibition of palmitate oxidation by malonyl CoA in mitochondria isolated from lean and obese Zucker rats were similar. Cytochrome oxidase activity was similar in lean and obese rat livers. It was found that the addition of cytosol from the obese rat liver inhibited palmitate oxidation by 20-30% in mitochondria isolated from lean or obese rat livers and thus reproduced the conditions observed in the intact cell. Increased concentrations of metabolites such as malonyl CoA and glycerophosphate in the liver of the obese rat are likely contributors to this inhibitory effect. These results are extrapolated to the intact cell and suggest that decreased hepatic fatty acid oxidation in the obese rat can be accounted for by cytosolic influences on the mitochondria. The decreased rate of fatty acid oxidation observed in the intact hepatocyte or perfused liver cannot be explained by a defect in the capacity of mitochondria to oxidize substrate or by a decrease in mitochondrial number in the obese rat liver.

Abstract P636: Insulin Resistance in Obesity Results in Postprandial Salt and Water Loss

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Debra L Irsik ◽  
Ashley R Washington ◽  
Rabei Alaisami ◽  
Michael W Brands
Keyword(s):  
Insulin Resistance ◽  
Blood Glucose ◽  
Water Loss ◽  
Urine Volume ◽  
Zucker Rats ◽  
Sprague Dawley ◽  
Insulin Resistant ◽  
Dual Channel ◽  
Obese Rats ◽  
Postprandial Insulin

Obesity and insulin resistance contribute to the development of metabolic syndrome, a growing epidemic in our country. The obese Zucker rat is an experimental model of this disease. Previously, using Sprague Dawley rats, we have shown that the normal postprandial rise in insulin acts physiologically to prevent renal salt and water wasting after meals. This study tested whether the effects of postprandial insulin would be attenuated in insulin resistant rats and result in excess salt and water loss. Chronic artery and vein catheters were implanted in male lean and obese Zucker rats for infusion and blood sampling. Rats were housed in metabolic cages and their catheters were connected to dual-channel Instech swivels for access. Over a 24-hr period of ad libitum eating, blood glucose was not different between obese and lean rats (127±7 vs. 120±3 mg/dl) but obese rats were hyperinsulinemic (14.86 vs. 0.98 ng/ml). Obese rats had significantly greater urine volume than lean controls (22.5±1.2 vs. 14.7±0.9 ml) despite similar water intakes. Obese rats tended to excrete more Na+ than lean controls (3.46±0.15 vs. 2.97±0.35 mEq) with equal amounts of Na+ intake. To evaluate the response to a single meal while controlling for blood glucose, fasted rats were administered a glucose bolus (as 50% dextrose) that yielded peak levels of blood glucose that were not different in the two groups (589±11 vs. 596 ±3 mg/dl at t=5 min.). Plasma insulin increased from fasting in both groups to 26.35 and 9.34 ng/ml in obese and lean controls, respectively. Over the 4-hour period following the glucose administration, obese rats had significantly greater urine volume (8.6±1.3 vs. 2.2 ±0.6 ml) and Na+ excretion (0.53±0.11 vs. 0.25±0.09 mEq) than lean controls. This suggests that insulin resistance of obesity may impair the ability of postprandial insulin to participate in maintenance of Na+ and water homeostasis, but the potential role of insulin resistance specifically within the kidney requires further study.

scholarly journals Are marine n-3 fatty acids protective towards insulin resistance? From cell to human

2020 ◽  
Vol 79 (4) ◽  
pp. 417-427 ◽  
Author(s):  
Jacques Delarue
Keyword(s):  
Insulin Resistance ◽  
Fatty Acids ◽  
Protective Effect ◽  
Specific Effect ◽  
Experimental Models ◽  
Zucker Rats ◽  
Diabetic Patients ◽  
High Dose ◽  
Biochemical Alterations ◽  
Insulin Resistant

Marine n-3 fatty acids improve most of the biochemical alterations associated with insulin resistance (IR). Experimental models of dietary-induced IR in rodents have shown their ability (often at a very high dose) to prevent IR, but with sometimes a tissue specific effect. However, in a high sucrose diet-induced IR rat model, they are unable to reverse IR once installed; in other rodent models (dexamethasone, Zucker rats), they are inefficacious perhaps because of the severity of IR. The very low incidence of type-2 diabetes (T2D) in Inuits in the 1960s, which largely increased over the following decades in parallel to the replacement of their traditional marine food for a western diet strongly suggests a protective effect of marine n-3 towards the risk of T2D; this was confirmed by reversal of its incidence in intervention studies reintroducing their traditional food. In healthy subjects and insulin-resistant non-diabetic patients, most trials and meta-analyses conclude to an insulin-sensitising effect and to a very probable preventive or alleviating effect towards IR. Concerning the risk of T2D, concordant data allow us to conclude the protective effect of marine n-3 in Asians while suspicion exists of an aggravation of risk in Westerners, but with the possibility that it could be explained by a high heterogeneity of studies performed in this population. Some longitudinal cohorts in US/European people showed no association or a decreased risk. Further studies using more homogeneous doses, sources of n-3 and assessment of insulin sensitivity methods are required to better delineate their effects in Westerners.

Obesity augments vasoconstrictor reactivity to angiotensin II in the renal circulation of the Zucker rat

2007 ◽  
Vol 293 (4) ◽  
pp. H2537-H2542 ◽  
Author(s):  
David W. Stepp ◽  
Erika I. Boesen ◽  
Jennifer C. Sullivan ◽  
James D. Mintz ◽  
Clark D. Hair ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Angiotensin Ii ◽  
Vascular Reactivity ◽  
Sodium Intake ◽  
Renin Angiotensin System ◽  
Plasma Renin ◽  
Zucker Rats ◽  
Ang Ii ◽  
Renal Vasoconstriction ◽  
Insulin Resistant

Obesity is an emerging risk factor for renal dysfunction, but the mechanisms are poorly understood. Obese patients show heightened renal vasodilation to blockade of the renin-angiotensin system, suggesting deficits in vascular responses to angiotensin II (ANG II). This study tested the hypothesis that obesity augments renal vasoconstriction to ANG II. Lean (LZR), prediabetic obese (OZR), and nonobese fructose-fed Zucker rats (FF-LZR) were studied to determine the effects of obesity and insulin resistance on reactivity of blood pressure and renal blood flow to vasoconstrictors. OZR showed enlargement of the kidneys, elevated urine output, increased sodium intake, and decreased plasma renin activity (PRA) vs. LZR, and renal vasoconstriction to ANG II was augmented in OZR. Renal reactivity to norepinephrine and mesenteric vascular reactivity to ANG II were similar between LZR and OZR. Insulin-resistant FF-LZR had normal reactivity to ANG II, indicating the insulin resistance was an unlikely explanation for the changes observed in OZR. Four weeks on a low-sodium diet (0.08%) to raise PRA reduced reactivity to ANG II in OZR back to normal levels without effect on LZR. From these data, we conclude that in the prediabetic stages of obesity, a decrease in PRA is observed in Zucker rats that may lead to increased renal vascular reactivity to ANG II. This increased reactivity to ANG II may explain the elevated renal vasodilator effects observed in obese humans and provide insight into early changes in renal function that predispose to nephropathy in later stages of the disease.

scholarly journals The role of changes in the sensitivity of hepatic mitochondrial overt carnitine palmitoyltransferase in determining the onset of the ketosis of starvation in the rat

1996 ◽  
Vol 318 (3) ◽  
pp. 767-770 ◽  
Author(s):  
Lesley DRYNAN ◽  
Patti A. QUANT ◽  
Victor A. ZAMMIT
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Time Course ◽  
Ketone Body ◽  
Serum Insulin ◽  
Carnitine Palmitoyltransferase ◽  
Acid Oxidation ◽  
Malonyl Coa ◽  
Cpt I ◽  
Body Concentration

The relationships between the increase in blood ketone-body concentrations and several parameters that can potentially influence the rate of hepatic fatty acid oxidation were studied during progressive starvation (up to 24 h) in the rat in order to discover whether the sensitivity of mitochondrial overt carnitine palmitoyltransferase (CPT I) to malonyl-CoA plays an important part in determining the intrahepatic potential for fatty acid oxidation during the onset of ketogenic conditions. A rapid increase in blood ketone-body concentration occurred between 12 and 16 h of starvation, several hours after the marked fall in hepatic malonyl-CoA and in serum insulin concentrations and doubling of plasma non-esterfied fatty acid (NEFA) concentration. Consequently, both the changes in hepatic malonyl-CoA and serum NEFA preceded the increase in blood ketone-body concentration by several hours. The maximal activity of CPT I increased gradually throughout the 24 h period of starvation, but the increases did not become significant before 18 h of starvation. By contrast, the sensitivity of CPT I to malonyl-CoA and the increase in blood ketone-body concentration followed an identical time course, demonstrating the central importance of this parameter in determining the ketogenic response of the liver to the onset of the starved state.

scholarly journals Hepatic ketogenesis in newborn pigs is limited by low mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase activity

1994 ◽  
Vol 298 (1) ◽  
pp. 207-212 ◽  
Author(s):  
P H Duée ◽  
J P Pégorier ◽  
P A Quant ◽  
C Herbin ◽  
C Kohl ◽  
...  
Keyword(s):  
Rat Liver ◽  
Liver Mitochondria ◽  
Oxidation Products ◽  
Rat Liver Mitochondria ◽  
Acid Oxidation ◽  
Acetyl Coa ◽  
Pig Liver ◽  
Adult Rat ◽  
Malonyl Coa ◽  
Cpt I

In newborn-pig hepatocytes, the rate of oleate oxidation is extremely low, despite a very low malonyl-CoA concentration. By contrast, the sensitivity of carnitine palmitoyltransferase (CPT) I to malonyl-CoA inhibition is high, as suggested by the very low concentration of malonyl-CoA required for 50% inhibition of CPT I (IC50). The rates of oleate oxidation and ketogenesis are respectively 70 and 80% lower in mitochondria isolated from newborn-pig liver than from starved-adult-rat liver mitochondria. Using polarographic measurements, we showed that the oxidation of oleoyl-CoA and palmitoyl-L-carnitine is very low when the acetyl-CoA produced is channelled into the hydroxymethylglutaryl-CoA (HMG-CoA) pathway by addition of malonate. In contrast, the oxidation of the same substrates is high when the acetyl-CoA produced is directed towards the citric acid cycle by addition of malate. We demonstrate that the limitation of ketogenesis in newborn-pig liver is due to a very low amount and activity of mitochondrial HMG-CoA synthase as compared with rat liver mitochondria, and suggest that this could promote the accumulation of acetyl-CoA and/or beta-oxidation products that in turn would decrease the overall rate of fatty acid oxidation in newborn- and adult-pig livers.

Altered hepatic mitochondrial fatty acid oxidation and ketogenesis in endotoxic rats

1990 ◽  
Vol 259 (4) ◽  
pp. E498-E505 ◽  
Author(s):  
N. Takeyama ◽  
Y. Itoh ◽  
Y. Kitazawa ◽  
T. Tanaka
Keyword(s):  
Oxygen Consumption ◽  
Fatty Acid ◽  
Maximum Velocity ◽  
Oxidative Capacity ◽  
Acid Oxidation ◽  
Acetyl Coa ◽  
Mitochondrial Fatty Acid Oxidation ◽  
Malonyl Coa ◽  
Mitochondrial Fatty Acid ◽  
Cpt I

Rat hepatic mitochondrial function, including oxidative phosphorylation, fatty acid oxidative capacity, kinetic parameters of carnitine palmitoyltransferase I (CPT I), and sensitivity of CPT I to malonyl-CoA inhibition were studied in vitro in isolated mitochondria following Escherichia coli lipopolysaccharide (LPS). The hepatic mitochondrial CPT I in LPS-treated rats showed a lower apparent maximum velocity (Vmax) for palmitoyl-CoA and Ki for malonyl-CoA without changes in apparent Km for palmitoyl-CoA. The rate of oxygen consumption or end-product formation of palmitoyl-L-carnitine and octanoate was not altered, but the rate of CPT I-dependent palmitoyl-CoA (plus L-carnitine) oxidation was reduced by LPS, when acetyl-CoA produced via beta-oxidation was directed toward citrate. When acetyl-CoA was directed to acetoacetate, the oxygen consumption rates of palmitoyl-L-carnitine and palmitoyl-CoA (plus L-carnitine) were decreased by LPS, although mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase activity was not altered. These results indicate that hepatic mitochondria isolated from LPS-treated rats show lower ketogenic and long-chain acyl-CoA oxidative capacity than those of fasted controls, and inhibition of ketogenesis is elicited at a site distal to CPT I in addition to reduction in CPT I activity.

Carnitine palmitoyltransferase I control of acetogenesis, the major pathway of fatty acid β-oxidation in liver of neonatal swine

2010 ◽  
Vol 298 (5) ◽  
pp. R1435-R1443 ◽  
Author(s):  
Xi Lin ◽  
Kwanseob Shim ◽  
Jack Odle
Keyword(s):  
Fatty Acid ◽  
Ketone Bodies ◽  
Carnitine Palmitoyltransferase ◽  
Acid Oxidation ◽  
Major Pathway ◽  
Malonyl Coa ◽  
Suckling Piglets ◽  
Carnitine Palmitoyltransferase I ◽  
Newborn Pigs ◽  
Cpt I

To examine the regulation of hepatic acetogenesis in neonatal swine, carnitine palmitoyltransferase I (CPT I) activity was measured in the presence of varying palmitoyl-CoA (substrate) and malonyl-CoA (inhibitor) concentrations, and [1-14C]-palmitate oxidation was simultaneously measured. Accumulation rates of 14C-labeled acetate, ketone bodies, and citric acid cycle intermediates within the acid-soluble products were determined using radio-HPLC. Measurements were conducted in mitochondria isolated from newborn, 24-h (fed or fasted), and 5-mo-old pigs. Acetate rather than ketone bodies was the predominant radiolabeled product, and its production increased twofold with increasing fatty acid oxidation during the first 24-h suckling period. The rate of acetogenesis was directly proportional to CPT I activity. The high activity of CPT I in 24-h-suckling piglets was not attributable to an increase in CPT I gene expression, but rather to a large decrease in the sensitivity of CPT I to malonyl-CoA inhibition, which offset a developmental decrease in affinity of CPT I for palmitoyl-CoA. Specifically, the IC50 for malonyl-CoA inhibition and Km value for palmitoyl-CoA measured in 24-h-suckling pigs were 1.8- and 2.7-fold higher than measured in newborn pigs. The addition of anaplerotic carbon from malate (10 mM) significantly reduced 14C accumulation in acetate ( P < 0.003); moreover, the reduction was much greater in newborn (80%) than in 24-h-fed (72%) and 5-mo-old pigs (55%). The results demonstrate that acetate is the primary product of hepatic mitochondrial β-oxidation in Sus scrofa and that regulation during early development is mediated primarily via kinetic modulation of CPT I.

scholarly journals Evidence that the sensitivity of carnitine palmitoyltransferase I to inhibition by malonyl-CoA is an important site of regulation of hepatic fatty acid oxidation in the fetal and newborn rabbit. Perinatal development and effects of pancreatic hormones in cultured rabbit hepatocytes

1990 ◽  
Vol 269 (2) ◽  
pp. 409-415 ◽  
Author(s):  
C Prip-Buus ◽  
J P Pegorier ◽  
P H Duee ◽  
C Kohl ◽  
J Girard
Keyword(s):  
Fatty Acid ◽  
Cyclic Amp ◽  
Fatty Acid Oxidation ◽  
Carnitine Palmitoyltransferase ◽  
Acid Oxidation ◽  
Fetal Hepatocytes ◽  
Malonyl Coa ◽  
Carnitine Palmitoyltransferase I ◽  
Cpt I ◽  
Hepatic Fatty Acid Oxidation

The temporal changes in oleate oxidation, lipogenesis, malonyl-CoA concentration and sensitivity of carnitine palmitoyltransferase I (CPT 1) to malonyl-CoA inhibition were studied in isolated rabbit hepatocytes and mitochondria as a function of time after birth of the animal or time in culture after exposure to glucagon, cyclic AMP or insulin. (1) Oleate oxidation was very low during the first 6 h after birth, whereas lipogenesis rate and malonyl-CoA concentration decreased rapidly during this period to reach levels as low as those found in 24-h-old newborns that show active oleate oxidation. (2) The changes in the activity of CPT I and the IC50 (concn. causing 50% inhibition) for malonyl-CoA paralleled those of oleate oxidation. (3) In cultured fetal hepatocytes, the addition of glucagon or cyclic AMP reproduced the changes that occur spontaneously after birth. A 12 h exposure to glucagon or cyclic AMP was sufficient to inhibit lipogenesis totally and to cause a decrease in malonyl-CoA concentration, but a 24 h exposure was required to induce oleate oxidation. (4) The induction of oleate oxidation by glucagon or cyclic AMP is triggered by the fall in the malonyl-CoA sensitivity of CPT I. (5) In cultured hepatocytes from 24 h-old newborns, the addition of insulin inhibits no more than 30% of the high oleate oxidation, whereas it stimulates lipogenesis and increases malonyl-CoA concentration by 4-fold more than in fetal cells (no oleate oxidation). This poor effect of insulin on oleate oxidation seems to be due to the inability of the hormone to increase the sensitivity of CPT I sufficiently. Altogether, these results suggest that the malonyl-CoA sensitivity of CPT I is the major site of regulation during the induction of fatty acid oxidation in the fetal rabbit liver.

Sign in / Sign up

Export Citation Format

Share Document