Cinnamon improves insulin sensitivity and alters the body composition in an animal model of the metabolic syndrome.

Polyphenols from cinnamon (CN) have been described recently as insulin sensitizers and antioxidants but their effects on the glucose/insulin system in vivo have not been totally investigated. The aim of this study was to determine the effects of CN on insulin resistance and body composition, using an animal model of the metabolic syndrome, the high fat/high fructose (HF/HF) fed rat. Four groups of 22 male Wistar rats were fed for 12 weeks with: (i) (HF/HF) diet to induce insulin resistance, (ii) HF/HF diet containing 20 g cinnamon/kg of diet (HF/HF + CN), (iii) Control diet (C) and (iv) Control diet containing 20 g cinnamon/kg of diet (C + CN). Data from hyperinsulinemic euglycemic clamps showed a significant decrease of the glucose infusion rates in rats fed the HF/HF diet. Addition of cinnamon to the HF/HF diet increased the glucose infusion rates to those of the control rats. The HF/HF diet induced a reduction in pancreas weight which was prevented in HF/HF+CN group (p<0.01). Mesenteric white fat accumulation was observed in HF/HF rats vs. control rats (p<0.01). This deleterious effect was alleviated when cinnamon was added to the diet. In summary, these results suggest that in animals fed a high fat/high fructose diet to induce insulin resistance, CN alters body composition in association with improved insulin sensitivity.

Acute emotional stress and high fat/high fructose diet modulate brain oxidative damage through NrF2 and uric acid in rats.

Studies focusing on the interaction of dietary and acute emotional stress on oxidative stress in cortex frontal and in brain mitochondria are scarce. Dietary-induced insulin resistance, as observed in Western diets, has been associated with increased oxidative stress causing mitochondrial dysfunction. We hypothesized that acute emotional stress could be an aggravating factor by impacting redox status in cortex and brain mitochondria. Thus, the aim of the present study was to evaluate the combination of an insulin resistance inducing high-fat/high-fructose (HF/HFr) diet and acute emotional stress on brain oxidative stress in rats. We measured several oxidative stress parameters (carbonyls, FRAP, TBARS assays, GSH, GSSG, oxidized DNA, mRNA expression of redox proteins (Nrf2), and uric acid). The HF/HFr diet resulted in increased oxidative stress both in the brain mitochondria and in the frontal cortex and decreased expression of the Nrf2 gene. The emotional stress induced an oxidative response in plasma and in brain mitochondria of the control group. In the HF/HFr group it triggered an increase expression of the redox transcription factor Nrf2 and its downstream antioxidant genes. This suggests an improvement of the redox stress tolerance in response to an enhanced production of reactive oxygen species. Accordingly, a blunted oxidative effect on several markers was observed in plasma and brain of HF/HFr-stressed group. This was confirmed in a parallel study using lipopolysaccharide as a stress model. Beside the Nrf2 increase, the stress induced a stronger UA release in HF/HFr which could take a part in the redox stress.

Liver mitochondrial properties from the obesity-resistant Lou/C rat.

OBJECTIVE: The first objective was to evaluate the influence of caloric intake on liver mitochondrial properties. The second objective was aimed at determining the impact of increasing fat intake on these properties. DESIGN: Lou/C rats, displaying an inborn low caloric intake and resistant to diet-induced obesity, were compared to Wistar rats fed either ad libitum or pair-fed. An additional group of Lou/C rats were allowed to increase their fat intake by adjusting their diet from a standard high carbohydrate low-fat diet to a high-fat carbohydrate-free diet. MEASUREMENTS: Hydrogen peroxide (H(2)O(2)) generation, oxygen consumption rate (J(O(2))), membrane potential (DeltaPsi), activity of respiratory chain complexes, cytochrome contents, oxidative phosphorylation efficiency (OPE) and uncoupling protein 2 (UCP2) expression were determined in liver mitochondria. RESULTS: H(2)O(2) production was higher in Lou/C than Wistar rats with glutamate/malate and/or succinate, octanoyl-carnitine, as substrates. These mitochondrial features cannot be mimicked by pair-feeding Wistar rats and remained unaltered by increasing fat intake. Enhanced H(2)O(2) production by mitochondria from Lou/C rats is due to an increased reverse electron flow through the respiratory-chain complex I and a higher medium-chain acyl-CoA dehydrogenase activity. While J(O(2)) was similar over a large range of DeltaPsi in both strains, Lou/C rats were able to sustain higher membrane potential and respiratory rate. In addition, mitochondria from Lou/C rats displayed a decrease in OPE that cannot be explained by increased expression of UCP2 but rather to a slip in proton pumping by cytochrome oxidase. CONCLUSIONS: Liver mitochondria from Lou/C rats display higher reactive oxygen species (ROS) generation but to deplete upstream electron-rich intermediates responsible for ROS generation, these animals increased intrinsic uncoupling of cytochrome oxidase. It is likely that liver mitochondrial properties allowed this strain of rat to display higher insulin sensitivity and resist diet-induced obesity.

Effect of voluntary exercise on H2O2 release by subsarcolemmal and intermyofibrillar mitochondria.

Previous data have demonstrated that, to handle the oxidative stress encountered with training at high intensity, skeletal muscle relies on an increase in mitochondrial biogenesis, a reduced H(2)O(2) production, and an enhancement of antioxidant enzymes. In the present study, we evaluated the influence of voluntary running on mitochondrial O(2) consumption and H(2)O(2) production by intermyofibrillar mitochondria (IFM) and subsarcolemmal mitochondria (SSM) isolated from oxidative muscles in conjunction with the determination of antioxidant capacities. When mitochondria are incubated with succinate as substrate, both maximal (state 3) and resting (state 4) O(2) consumption were significantly lower in SSM than in IFM populations. Mitochondrial H(2)O(2) release per unit of O(2) consumed was 2-fold higher in SSM than in IFM. Inhibition of H(2)O(2) formation by rotenone suggests that complex I of the electron transport chain is likely the major physiological H(2)O(2)-generating system. In Lou/C rats (an inbred strain of rats of Wistar origin), neither O(2) consumption nor H(2)O(2) release by IFM and SSM were affected by long-term, voluntary wheel training. In contrast, glutathione peroxidase and catalase activity were significantly increased despite no change in oxidative capacities with long-term, voluntary exercise. Furthermore, chronic exercise enhanced heat shock protein 72 accumulation within skeletal muscle. It is concluded that the antioxidant status of muscle can be significantly improved by prolonged wheel exercise without necessitating an increase in mitochondrial oxidative capacities.

High dietary sucrose triggers hyperinsulinemia, increases myocardial beta-oxidation, reduces glycolytic flux and delays post-ischemic contractile recovery.

Although the causal relationship between insulin resistance (IR) and hypertension is not fully resolved, the importance of IR in cardiovascular dysfunction is recognized. As IR may follow excess sucrose or fructose diet, the aim of this study was to test whether dietary starch substitution with sucrose results in myocardial dysfunction in energy substrate utilization and contractility during normoxic and post-ischemic conditions. Forty-eight male Wistar rats were randomly allocated to three diets, differing only in their starch to sucrose (S) ratio (13, 2 and 0 for the Low S, Middle S and High S groups, respectively), for 3 weeks. Developed pressure and rate x pressure product (RPP) were determined in Langendorff mode-perfused hearts. After 30 min stabilization, hearts were subjected to 25 min of total normothermic global ischemia, followed by 45-min reperfusion. Oxygen consumption, beta-oxidation rate (using 1-13C hexanoate and Isotopic Ratio Mass Spectrometry of CO2 produced in the coronary effluent) and flux of non-oxidative glycolysis were also evaluated. Although fasting plasma glucose levels were not affected by increased dietary sucrose, high sucrose intake resulted in increased plasma insulin levels, without significant rise in plasma triglyceride and free fatty acid concentrations. Sucrose-rich diet reduced pre-ischemic baseline measures of heart rate, RPP and non-oxidative glycolysis. During reperfusion, post-ischemic recovery of RPP was impaired in the Middle S and High S groups, as compared to Low S, mainly due to delayed recovery of developed pressure, which by 45 min of reperfusion eventually resumed levels matching Low S. At the start of reperfusion, delayed post-ischemic recovery of contractile function was accompanied by: (i) reduced lactate production; (ii) decreased lactate to pyruvate ratio; (iii) increased beta-oxidation; and (iv) depressed metabolic efficiency. In conclusion, sucrose rich-diet increased plasma insulin levels, in intact rat, and increased cardiac beta-oxidation and coronary flow-rate, but reduced glycolytic flux and contractility during normoxic baseline function of isolated perfused hearts. Sucrose rich-diet impaired early post-ischemic recovery of isolated heart cardiac mechanical function and further augmented cardiac beta-oxidation but reduced glycolytic and lactate flux.

Evidence of hepatic glucagon resistance associated with hepatic steatosis: reversal effect of training.

The present study was undertaken to test the hypothesis that a high-fat diet-induced hepatic steatosis is associated with a reduction in hepatic glucose output (HGO) in response to a hyperglucagonemic infusion, and that this postulated state of hepatic glucagon resistance in high-fat fed rats is attenuated by concurrent exercise training. In four groups of anesthetized rats, glucagon (2 ug/kg/min iv) was infused over a period of 60 min to measure HGO. Two groups of rats were either fed a standard (SD) or a high-fat (HF; 42 % kcal) diet for eight weeks and were assigned either to a Sedentary (Sed) or a treadmill-trained (TR) group. Training was initiated two weeks after the beginning of the diet protocol and was progressively increased over a period of 6 weeks reaching 60 min at 26 m/min, 10 % grade, for the last 3 weeks. The HF compared to the SD diet resulted in approximately 28 % higher (p < 0.01) liver triglyceride levels in Sed rats. This increase was completely prevented by the exercise training program in the HF-TR group. Plasma glucagon ( approximately 90,000 pg/ml) and insulin ( approximately 500 pmol/l) levels were increased to a similar extent in all four groups, with the exception of higher (p<0.05) insulin levels in SD-Sed group. Glucagon induced-hyperglycemia ( approximately 300 mg/dl) was higher (p<0.05) in the SD-Sed than in HF-Sed and SD-TR groups. Glucagon infusion resulted in a significantly (p<0.05) lower increase ( approximately 35 %) in HGO in HF-Sed compared to SD-Sed group. The lower level of HGO in HF-Sed compared to SD-Sed rats was observed whether HGO was measured after 25, 40, or 60 min of glucagon infusion. Exercise training in HF fed rats resulted in a significant (p<0.05) attenuation (50 %) of the state of HF-induced glucagon resistance. Comparisons of all individual liver triglyceride and 60-min HGO values revealed that liver triglyceride values were highly (p<0.001) predictive of the decreased glucagon action on HGO (R= -0.849). The present results indicate that the feeding of a high-fat diet induces a state of hepatic glucagon resistance, which is partially attenuated by concurrent exercise training. It is suggested that liver lipid infiltration may interfere with the action of glucagon, thus inducing glucagon resistance in liver.

Effects of supranormal liver glycogen content on hyperglucagonemia-induced liver glycogen breakdown.

The purpose of the present study was to test the hypothesis that a higher hepatic glycogen level is associated with higher glucagon-induced hepatic glycogen depletion. Four groups of anesthetized rats received three injections (at times 0, 30, and 60 min) of glucagon (intravenously, 20 [microg/kg). Among these groups, hepatic glycogen levels had previously been manipulated either by an overloading diet (Fast-refed), a reduction in food intake (1/2-fast), or exercise (75 min of running, 26 m/ min, 0% grade). A fourth group had normal hepatic glycogen levels. A fifth group of rats was injected only with saline (0.9% NaCl). Liver glycogen concentrations were measured every 30 min during the course of the 90-min experiment, using liver samples obtained from the open liver biopsy technique. Plasma glucagon concentrations were significantly higher (P < 0.05) in the glucagon-injected groups than in the saline-injected group. As expected, liver glycogen levels were significantly higher (P < 0.01; 1.6-fold) in the Fast-refed group than in all other groups. Glucagon-induced decreases in liver glycogen concentrations were similar in Fast-refed than in normally fed and exercised rats when the overall 90-min period was considered. However, during the course of the last 30-min period, liver glycogen was significantly (P < 0.01) decreased only in the Fast-refed group. The Fast-refed, normally fed, and exercised groups had a similar glucagon-induced hyperglycemia that was significantly more elevated (P < 0.01) than glucose levels measured in the saline-injected group. Glucagon-induced reactive hyperinsulinemia was observed only in the Fast-refed and normally fed rats, and not in the exercised and 1/2-fast rats. It is concluded that supranormal levels of liver glycogen may be associated with a larger hyperglucagonemia-induced liver glycogen breakdown.

Evidence that a decrease in liver glycogen content stimulates FFA mobilization during exercise.

This study evaluated a liver glycogen content decrease before exercise on the metabolic responses during exercise. Rats injected with glucagon (20 microg x kg(-1)) were compared to rats with a 50% food restriction (1/2-fast) and normally fed rats. All were studied at rest and during exercise (26 m/min, 0% grade). Resting liver glycogen concentrations were twice as high (P<.01) in normally fed rats, with no significant differences between 1/2-fast and glucagon-injected rats. During exercise, liver glycogen content was significantly reduced in normally fed rats. After exercise, plasma insulin levels were decreased (P<.01) in all groups, and beta-hydroxybutyrate concentrations were similar in normally fed and glucagon-injected rats and significantly (P<.01) lower in 1/2-fast rats. Exercise caused a significant increase in FFA concentrations in all groups (P<.01). No significant differences in FFA concentrations were found between 1/2-fast and glucagon-injected groups (P>0.05).

Effects of introducing physical training in the course of a 16-week high-fat diet regimen on hepatic steatosis, adipose tissue fat accumulation, and plasma lipid profile.

OBJECTIVE: We recently reported that an 8-week high-fat diet-induced hepatic steatosis was completely prevented if an exercise training programme was introduced and pursued concurrently with the diet. The purpose of the present study was to determine the extent to which introducing exercise training at mid-point in the course of a 16-week high-fat diet regimen contributes to the reversal of liver lipid infiltration and the reduction of blood lipid profile deterioration and body fat accumulation. DESIGN AND SUBJECTS: Two groups of rats were fed a high-fat diet (42% kcal) for 16 weeks, one remaining sedentary during this entire period (HF-Sed) and the other being exercise trained for the last 8 weeks (HF-Tr). A third group was fed a standard diet and remained sedentary for all 16 weeks (SD-Sed). Training (5 days/week for 8 weeks) began 8 weeks after introducing the high-fat diet and consisted of treadmill running that was progressively increased to reach 60 min at 26 m/min, 10% grade, for the last 4 weeks. MEASUREMENTS: Various parameters including liver lipid infiltration, fat depots and blood lipids. RESULTS: Unexpectedly, liver lipid infiltration was not significantly higher in HF-Sed than in SD-Sed rats (means+/-s.e.: 14.9+/-1.7 vs 12.3+/-0.4 mg/g; P>0.05). High-fat compared to age-matched standard fed rats also showed an absence of difference (P>0.05) in the weight of total visceral fat pads (13%), plasma nonesterified fatty acids (NEFA), and leptin concentrations, but depicted significantly (P<0.01) higher values for subcutaneous fat pad weight and plasma triacyglycerol. Exercise training largely decreased visceral and subcutaneous fat accumulation by 30 and 26%, respectively (P<0.01) as well as NEFA, triacylglycerol, and leptin concentrations (P<0.01). CONCLUSION: Liver lipid infiltration does not seem to progress linearly over 16 weeks of high-fat feeding in light of what has previously been observed after 8 weeks of high-fat feeding. Introducing a training programme in the course of a 16-week high-fat diet protocol reduced adiposity, plasma NEFA, and leptin concentrations below the levels observed in standard fed rats. These data indicate that, exercise training, whether conducted concurrently or introduced during the course of a high-fat diet, is an asset to reduce the deleterious effects of a high-fat diet.

Metabolic and hormonal responses to exercise in the anti-obese Lou/C rats.

OBJECTIVE: Lou/C rats are a substrain of Wistar rats that exhibit a spontaneous low caloric intake and no development of obesity with age. Recently, we reported that Lou/C rats, compared to equally food-restricted Wistar counterparts, show lower resting levels of plasma glucose, epinephrine and liver glycogen. To further explore this metabolic particularity, we used exercise (swimming 60 min) as a situation of high-energy demand, to test the ability of Lou/C rats to maintain euglycemia. DESIGN: Male Lou/C rats (14-week-old) were compared to age-matched male Wistar rats fed either ad libitum (WAL) or Wistar rats whose food was chronically restricted (WFR) to the same caloric intake as the Lou/C rats. RESULTS: In spite of low liver glycogen stores ( approximately 50% of normal values), Lou/C rats were able to maintain euglycemia during exercise even though liver glycogen breakdown was blunted. The decreased use of glycogen during exercise in Lou/C rats was associated with a reduced epinephrine response compared to WFR animals. By contrast, WFR were also able to maintain euglycemia during exercise but at the expense of a significant (P<0.01) decrease in liver and muscle glycogen content. Plasma free fatty acid and glycerol concentrations were increased (P<0.01) similarly in all three groups during exercise. In a separate experiment conducted in isolated hepatocytes from 24 h fasted Lou/C and Wistar rats, it was found that gluconeogenic flux from glycerol was found to be significantly (P<0.01) higher in Lou/C than in Wistar rats (5.4+/-0.2 vs 3.7+/-0.1 micromol/min/g dry cells). Resting and exercising plasma leptin levels were also significantly (P<0.05) lower in Lou/C than in the two other groups. CONCLUSION: It is concluded that Lou/C rats have the particularity to rely spontaneously less on their liver glycogen stores to meet their energy demands during exercise while maintaining euglycemia.