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The purpose of the present study was to assess the effect of an exercise training program conducted concurrently with a high-fat (HF)-diet regimen on the induction of hepatic steatosis. Two groups of rats were fed either a standard (SD) or a HF (40% kcal) diet for 8 wk and were additionally assigned either to a sedentary (Sed) or a treadmill-trained (TR) group. Training (5 days/wk) was initiated at the same time as the HF diet and was progressively increased, reaching 60 min at 26 m/min, 10% grade, for the last 4 wk. At the end of the 8-wk period, HF-Sed rats exhibited ∼72% higher liver triacylglycerol concentration than SD-Sed rats (means ± SE: 17.15 ± 1.5 vs. 9.98 ± 1.0 mg/g; P < 0.01). Histological quantification of lipid infiltration, with the use of an image analysis computing system, revealed that, although fat was mainly stored as microvesicles (2), the HF-diet-induced hepatic steatosis occurred via the accumulation of macrovesicles (>1 μm2). Concurrent exercise training completely prevented the HF-diet-induced hepatic steatosis. The surface area of liver parenchyma infiltrated by lipid vacuoles was similar in HF-TR as in SD-Sed rats (26.4 ± 1.8 vs. 29.3 ± 5.9 × 103μm2/200,000 μm2of liver parenchyma, respectively; P> 0.05). The different states of liver lipid infiltration after the HF diet in Sed and TR rats were associated with similar changes in plasma free fatty acids and glycerol, as well as with similar changes in fat pad weights, but not with plasma triacylglycerol levels. It is concluded that, after a HF-diet regimen of 8 wk in rats, hepatic steatosis occurs primarily via the accumulation of lipid as macrovesicles. Exercise training pursued at the same time completely prevents the HF-diet-induced macrovesicular hepatic steatosis.

The purpose of the present study was to assess the effects of exogenously increasing the circulating levels of glucagon on the metabolic responses to exercise in rats. A total of six groups of rats were infused (iv) either with glucagon (20 or 50 ng x kg(-1) x min(-1)) or saline (0.9% NaCl), either in the resting state or during a bout of running exercise (45 min, 26 m x min(-1), 0% grade). Blood samples were taken at the end of the 45-min experiment. Animals infused with glucagon at 50 ng x kg(-1) x min(-1) showed significantly (P0.01) higher mean plasma glucagon concentrations than animals infused with saline or glucagon at 20 ng x kg(-1) x min(-1). In addition, exercise resulted in significantly (P0.05) higher mean plasma glucagon concentrations, compared to rest, in all groups. In spite of these differences in glucagon concentrations, there were no significant (P0.05) effects of exercise and glucagon infusion on mean hepatic glycogen, plasma glucose, insulin, C-peptide, beta-hydroxybutyrate, or catecholamine concentrations. Although exercise resulted in a significant (P0.01) increase in plasma glycerol and free fatty acid concentrations and a significant (P0.05) decrease in glycogen in the soleus muscle, these responses were not affected by the glucagon infusion. These results suggest that the liver is non-responsive to physiological hyperglucagonemia in a short-term (45 min) exercise situation.

This study was undertaken to assess the effect of 8 weeks of endurance training (treadmill, last 4 weeks: 60 min at 26 m/min, 8-10% grade) on the gluconeogenic capacity of periportal (PP-H) and perivenous (PV-H) hepatocytes of overnight fasted rats. Isolated PP-H and PV-H, obtained by selective destruction after liver perfusion with digitonin and collagenase, were incubated with saturating concentrations of a mixture of lactate and pyruvate (20:2 mM; Lac+Pyr) or alanine (20 mM; Ala) to determine the glucose production flux (J(glucose)) in the incubation medium. Endogenous J(glucose) as well as J(glucose) from substrates were significantly higher (P.05) in PP-H than PV-H in the untrained state. Following training, a selective increase (P.05) in J(glucose) from endogenous substrates and from Lac+Pyr was observed in PV-H only, resulting in the disappearance (P.05) of the difference of J(glucose) between PP-H and PV-H. It is concluded that the increase in the gluconeogenic capacity of the liver following endurance training is first observed in PV-H.

International audience; AIMS: The aims of the present study are 1) to evaluate the free fatty acid (FFA) profile and 2) to determine the relative anaerobic and aerobic contributions to total energy consumption during repeated supramaximal cycling bouts (SCE) in adolescent boys with different body weight statuses. MATERIALS AND METHODS: Normal-weight (NW), overweight (OW), and obese (OB) adolescent boys (n =15 per group) completed a SCE sessions consisted of 6 x 6s maximal sprints with 2 min of passive rest between each repetition. Plasma FFA levels were determined at rest, immediately after a 10 min warm-up, and immediately at the end of SCE. The anaerobic and aerobic contributions (%) were measured via repeated SCE bouts. Insulin resistance was calculated using the homoeostatic model assessment (HOMA-IR) index. RESULTS: The FFA concentrations measured immediately after SCE were higher in the OB group than in the OW and NW (p\textless0.01 and p\textless0.01, respectively) groups. Moreover, the anaerobic contributions to SCE were significantly lower in obese adolescents (p\textless0.01) and decreased significantly during the 2nd, 3rd and 4th repetitions. The FFA levels were significantly associated with the HOMA-IR index and aerobic contribution among adolescent boys (r=0.83 and r=0.91, respectively, p\textless0.01). CONCLUSION: In contrast to the NW and OW groups, there is an increase in lipid mobilization and sift to aerobic energy metabolism during SCE in the OB group

The crucial role of the liver as the only organ to produce glucose used by skeletal muscle during exercise is well known. Since hepatic glucose production is central to blood glucose homeostasis during exercise, it has been postulated that the liver may inform the central nervous system and other organs of its diminishing capacity to produce glucose from glycogen, before blood glucose falls. The sensory role of the liver during exercise would be similar to its role in the control of food intake. As a consequence, the experimental approaches used to test the hypothesis that afferent signals from the liver contribute to metabolic regulation during exercise are inspired by those used to test the same hypothesis in the regulation of food intake. In the present review, two questions are addressed. The existing evidence for the liver's sensory influence on metabolic adjustments to exercise is first reviewed; the nature of the initiating stimuli for the afferent contribution of the liver to physical exercise is discussed thereafter. The hypothetical construct upon which rests the contribution of the liver's afferent signals to metabolic regulation during exercise is that a decrease in liver glycogen or a related metabolic intermediate is sensed by the liver, and the signal is transduced to the central nervous system, most likely through the afferent activity of the hepatic vagus nerve, where it contributes to the orchestration of the metabolic and hormonal responses to exercise. Support in favour of this construct comes mainly from the demonstration that sectioning of the hepatic vagus nerve attenuates the normal hormonal response to exercise. It seems that the liver–glucagon axis is particularly responsive to this reflex activation. In other respects, the hepatic mechanism responsible for linking the metabolic activity in the liver to an afferent signal capable of regulating the metabolic response to exercise remains speculative. Substrates or derivatives of substrate oxidation, energy-related compounds (ATP and Pi), or changes in cell volume may all be related to changes in transmembrane potential in the liver cell, which according to the "potentiostatic" theory would determine the afferent vagal activity. Key words: hepatic vagotomy, insulin, glucagon, portal infusion, metabolic regulation.

The purpose of the present study was to test the hypothesis that the exercise-induced increase in insulin-like growth factor binding protein (IGFBP)-1 is not always linked to a decrease in blood glucose level and to examine whether the decreasing levels of liver glycogen during exercise may be associated with the increase in IGFBP-1. Three groups of rats were submitted to a 70-min treadmill exercise. One group of rats was fed normally, and the two other groups had their food intake restricted by 50% (50% fast) the night before the experiment. One of these two 50% fasted groups of rats was infused (intravenously) with glucose throughout exercise to maintain euglycemia. Exercise in noninfused 50% fasted rats, compared with the normally fed rats, resulted in significantly lower blood glucose ( minute 70) and insulin levels, significantly lower liver glycogen content, no change in IGF-I, and significantly higher increases in free fatty acid, glycerol, β-hydroxybutyrate, and IGFBP-1. Maintenance of euglycemia during exercise in glucose-infused 50% fasted rats reduced to a large extent the decrease in insulin levels but only slightly attenuated the lipid response and the IGFBP-1 response seen in noninfused 50% fasted rats. Comparisons of all individual liver glycogen and IGFBP-1 values revealed that liver glycogen values were highly ( P < 0.001) predictive of the IGFBP-1 response during exercise ( R = 0.564). The present results indicate that the IGFBP-1 response during exercise is not always linked to a decrease in plasma glucose and suggest that the increase in IGFBP-1 during exercise may be related to the decrease in liver glycogen content.

OBJECTIVE: To investigate whether regular endurance-type exercise can benefit rats submitted to a model of ovariectomy (OVX)-induced obesity with or without estrogen replacement. SUBJECTS: OVX Sprague-Dawley rats were compared to an ovariectomized-estradiol-treated group (OVXE2) and a Sham-operated (Sham) group. Each of these groups were subdivided into a sedentary and a treadmill-trained (8 wk) group. DESIGN AND MEASUREMENTS: An experimental study in which various parameters, including fat depots, blood lipids and several organ weights were measured. RESULTS: Plasma levels of 17β-estradiol and uterus weights were significantly (P

The purpose of the present study was to test the hypothesis that a prior period of exercise is associated with an increase in hepatic glucagon sensitivity. Hepatic glucose production (HGP) was measured in four groups of anesthetized rats infused with glucagon (2 μg · kg−1 · min−1 iv) over a period of 60 min. Among these groups, two were normally fed and, therefore, had a normal level of liver glycogen (NG). One of these two groups was killed at rest (NG-Re) and the other after a period of exercise (NG-Ex; 60 min of running, 15–26 m/min, 0% grade). The two other groups of rats had a high hepatic glycogen level (HG), which had been increased by a fast-refed diet, and were also killed either at rest (HG-Re) or after exercise (HG-Ex). Plasma glucagon and insulin levels were increased similarly in all four conditions. Glucagon-induced hyperglycemia was higher ( P < 0.01) in the HG-Re group than in all other groups. HGP in the HG-Re group was not, however, on the whole more elevated than in the NG-Re group. Exercised rats (NG-Ex and HG-Ex) had higher hyperglycemia, HGP, and glucose utilization than rested rats in the first 10 min of the glucagon infusion. HG-Ex group had the highest HGP throughout the 60-min experiment. It is concluded that hyperglucagonemia-induced HGP is stimulated by a prior period of exercise, suggesting an increased sensitivity of the liver to glucagon during exercise.

The aim of this study was to determine the effects of ovariectomy in rats on hepatic gene expression of key molecules involved in cholesterol metabolism and to verify if exercise training may play a role in preventing hypercholesterolemia in Ovx rats. Sprague-Dawley rats were ovariectomized (Ovx) or sham-operated (Sham) and were either trained (Tr) on treadmill or kept sedentary (Sed) for 8 weeks. Rats were divided into 5 groups: Sham-Sed, Sham-Tr, Ovx-Sed, Ovx-Tr and Ovx with 17β-estradiol supplementation (Ovx-E2). Ovx animals had significantly (p

This study was undertaken to evaluate the effects of regular endurance-type exercise on glucose tolerance and glucose-stimulated insulin response (GSIR) in ovariectomized (OVX) rats with and without estrogen replacement. To do that, OVX Sprague-Dawley rats were compared with an OVX estradiol-treated group (OVXE2) and a sham-operated (Sham) group. Each of these groups was subdivided into a sedentary and a treadmill-trained (8 wk) group. Intravenous glucose tolerance tests (0.5 g/kg) were conducted in all rats 48 h after the last training session. Plasma levels of 17β-estradiol and the uterus weight were significantly ( P < 0.05) lower in OVX compared with results in Sham and significantly ( P< 0.01) higher in OVXE2 (hyperestrogenic) compared with results in Sham. Body weights were significantly ( P < 0.01) different among groups, in the following decreasing order: OVX, Sham, and OVXE2. The average daily food intake was significantly ( P < 0.01) increased in OVX rats compared with Sham, whereas estradiol treatment diminished this effect ( P< 0.01). Exercise training was found to alter none of the above-mentioned variables in all three experimental conditions. Although the mean integrated area under the glucose and insulin curves was not affected by OVX, training induced a significant ( P < 0.01) reduction in the mean integrated area under the insulin curve in all three experimental conditions. It is concluded that the positive effects of physical training on improving GSIR in OVX and hyperestrogenic animals are similar to what has been found in Sham.

This study evaluated a liver glycogen content decrease before exercise on the metabolic responses during exercise. Rats injected with glucagon (20 μg•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 0.05). Key words: glucagon injection, fasting, insulin, hepatic receptors

The purpose of the present study was to investigate the effects of exercise (30 min, 23 m/min, 0% grade) on the hepatic levels of ATP in fasted adrenodemedullated rats, with an intraperitoneal injection of sodium phosphate (Na (2) PO (4 ), 0.91 mM) or saline (NaCl). Sodium phosphate was injected to determine if the postulated decrease in liver ATP during exercise may be changed by providing an excess of phosphate. At the end of exercise, a piece of liver was rapidly freeze clamped and used for the enzymatic determination of ATP levels. Liver ATP, in saline-injected rats, was significantly (P0.05) decreased by fasting, compared to fed rats (Xscr; +/- SE: 3. 21 +/- 0.2 vs 2.86+/- 0.2 micromol/g). Exercise in fasted rats decreased even more the ATP response in liver (2.58 +/- 0.14 micromol/g). Injection of Na (2) PO (4) did not significantly (P0. 05) alter the pattern of ATP response following these 3 conditions (3.35 +/- 0.14 vs 3.0 +/-0.12 vs 2.57 +/- 0.1 micromol/g), ATP levels being significantly (P0.05) decreased by the fast and the exercise in the fasted state. Fasting and exercise resulted in a significant (P0.05) decrease in liver glycogen and plasma glucose concentrations and an increase in free fatty acid levels in both NaCl- and Na (2 )PO (4) -injected groups. In both injection conditions, beta-hydroxybutyrate and peripheral insulin concentrations were respectively, increased and decreased (P0.05) by fasting, while norepinephrine and portal glucagon were decreased (P0.05) following exercise. The main effect of the injection of Na ( 2) PO (4) was a stimulation (P0.05) of peripheral glucagon response following exercise. It is concluded that exercise results in a decrease in liver ATP levels even in fasted rats and that this decrease is not corrected by Na (2 )PO( 4) administration. The decreased liver ATP levels might be involved in the metabolic adaptations to exercise.

The fructose analogue 2,5-anhydro-D-mannitol (2,5-AM) has been shown to act specifically in liver by decreasing liver ATP and by blocking glycogenolysis and gluconeogenesis. The present investigation was designed to determine the effects of the administration of 2,5-AM on pancreatic hormone responses during a situation of increased energy demand such as physical exercise, and by comparison to the resting response, to test the possibility that the hormonal effects of 2,5-AM during exercise may be dissociated from a decrease in blood glucose levels. Adrenodemedullated rats were injected intraportally with a dose of 200 mg/kg of 2,5-AM (50 mg/ml) or by an equivalent volume of saline (0.9% NaCl) before being submitted to a 30-min treadmill run (26 m/min, 0% grade). Administration of 2,5-AM at rest resulted in a significant (P < 0.05) decrease of plasma glucose and insulin levels and an increase in beta-hydroxybutyrate concentrations. During exercise, administration of 2,5-AM, as compared to resting values, resulted in a larger decrease in glucose, a similar decrease in insulin, and a much larger increase in glucagon, glucagon/insulin molar ratio, and beta-hydroxybutyrate concentrations. It is concluded that exercise amplifies some of the metabolic and hormonal effects of 2,5-AM, and that these effects cannot all be explained by the decrease in blood glucose levels.

The present study was conducted to investigate the in vivo effects of an intrahepatic infusion of deionized water during exercise in rats. Adrenodemedullated male Sprague-Dawley rats were continuously infused for 30 min either at rest or during treadmill exercise (26 m/min, 0% grade). Rats were randomly assigned to one of three infusion conditions (52 μl/min) with either deionized water (PW) or saline (PS; NaCl; 0.9%) via the hepatic portal vein or deionized water through the jugular vein (JW). The exercise period caused a significant ( P < 0.05) decrease in liver glycogen and relative liver water content and peripheral and portal blood glucose and insulin while increasing peripheral and portal glucagon and K+ plasma concentrations. These responses, with the exception of K+, were not influenced by the different types of infusions. The increase in K+ during exercise was significantly ( P < 0.05) higher in JW rats than in the PW and PS groups. Both the infusion and exercise protocols did not significantly alter the liver weight-to-body weight ratio, plasma osmolality, free fatty acids, β-hydroxybutyrate, Na+, Cl−, vasopressin, and catecholamine concentrations. It is concluded that an hepatic portal infusion of deionized water does not specifically alter the metabolic and hormonal responses to exercise in rats.

Tadjoré, Maurice, Raynald Bergeron, Martin Latour, François Désy, Claude Warren, and Jean-Marc Lavoie.Effects of dietary manipulations and glucose infusion on glucagon response during exercise in rats. J. Appl. Physiol. 83(1): 148–152, 1997.—The purpose of the present investigation was to test the hypothesis that blood glucose concentration is not always related to glucagon response during exercise. Three groups of rats were submitted to a prolonged (3-h) swimming exercise. Two groups of rats had their normal food intake restricted by 50% the night before the experiment. One of these two groups of rats was intravenously infused with glucose throughout exercise to maintain euglycemia. The third group of rats swam while under normal dietary conditions. Plasma glucose, sampled in arterial blood, was reduced ( P < 0.05) at 75, 105, 150, and 170 min of exercise (from ∼130 to 110 mg/dl) in the food-restricted animals without glucose infusion, whereas a significant ( P < 0.05) increase was measured in the two other groups during exercise. A significant ( P < 0.01) difference in the mean integrated areas under the glucose-concentration curve was found only between the fed and the two food-restricted groups. Plasma insulin concentrations decreased ( P < 0.05) similarly in all groups during exercise, whereas plasma epinephrine and norepinephrine concentrations increased significantly ( P < 0.01) in all groups. Despite differences between groups in plasma glucose response during exercise, and despite the absence of any decrease in exercising blood glucose levels in at least two of the three groups, plasma glucagon responses were increased ( P < 0.05) similarly in all groups (from ∼250 to 550 pg/ml) at the end of the exercise period. The increase in glucagon was significant after 90 min of exercise in the food-restricted groups, with or without glucose infusion, but only after 140 min in the fed group. These results indicate that the glucagon response during exercise is not always linked to the decrease in plasma glucose.

The purpose of the present study was to determine the effects of an acute hepatic vagotomy on plasma insulin and catecholamines levels in fasted and fed rats with and without adrenodemedullation. Rats were first divided into two groups: adrenodemedullated (ADM) and non-adrenodemedullated rats, each group being subdivided into a normally fed and a fasted (14 hrs) group. Anesthetized rats were first ADM or sham operated, and a jugular catheter was inserted. The first blood sample was taken 30 min later (time 0). Rats were then hepatic vagotomized (HV) or sham operated, and the second blood sample was taken 30 min after the HV. Results (0 vs 30 min) indicate an increase in plasma glucose, epinephrine, and norepinephrine concentrations in rats non-adrenodemedullated. This effect was independent of the nutritional state and the integrity of the vagus nerve. A weakly significant (P < 0.07) effect of the HV on insulin response was found in ADM rats, independently of the fed or fast state (different levels of hepatic glycogen content). These results indicate the necessity of using ADM animals to study the effects of an acute HV. They also suggest that the hepato-pancreatic axis is not influenced by the level of hepatic glycogen.

The present investigation was designed to evaluate the effect of a selective hepatic vagotomy (HV) on the insulin response in rats fasted for 24 h when blood glucose levels were or were not maintained by a constant glucose infusion. Rats were divided into three dietary groups: one group of normally fed rats, one group of 24-h fasted rats, and one group of 24-h fasted rats infused with glucose throughout the fasting period. Each of these groups was subdivided into HV and sham-operated (SHM) rats. Fasting without glucose infusion resulted in a significant (p0.05) decrease in plasma glucose, liver glycogen, and insulin concentrations and in a significant (p0.01) increase in beta-hydroxybutyrate and FFA concentration. Despite the maintenance of plasma glucose concentrations in the glucose-infused groups, the concentrations of liver glycogen and insulin were still decreased (p0.01) and the concentrations of beta-hydroxybutyrate were still increased (p0.05) at the end of the fasting period. However, no significant differences in insulin or in beta-hydroxybutyrate concentration were found between HV and SHM rats. It is concluded that the decline in plasma glucose concentration during fasting does not totally explain the insulinopenic response to fasting, and that the liver, through the mediation of the hepatic vagus nerve, does not seem to contribute to insulinopenia in 24-h fasted rats.

The purpose of the present study was to submit disabled swimmers to two maximal swimming tests, and by comparing the physiological and performance responses of disabled and normal swimmers to determine if these adapted tests can be used to design training programmes for this particular class of swimmer. Two groups of disabled (n = 8 and 6) and two groups of normal competitive swimmers (n = 9 and 13) were respectively submitted to a functional maximal aerobic power test (FMAPT) and a maximal anaerobic lactic test (MANLT). For the disabled, the FMAPT included a slower initial speed and a slower increase in swimming speeds. In the maximal aerobic test, exercise duration, peak heart rate, and the maximal speed relative to the respective best time of a 100-m race [55.5 (SD 3.9) compared to 56.5 (SD 2.8)%] were not significantly different between the disabled and normal swimmers. Peak lactate concentration was, however, higher in the disabled swimmers [10.8 (SD 3.5) compared to 6.8 (SD 1.6)mmol.l-1]. In the MNALT, peak lactate concentration [14.3 (SD 4) compared to 16.8 (SD 1.9)mmol.l-1], and the maximal speed relative to the respective best time in a 100-m race [99.1 (SD 3.2) compared to 98.3 (SD 2.5)%] were not significantly different between the disabled and normal swimmers. These results would seem to indicate that functional maximal aerobic and anaerobic field tests could be used to evaluate and design training programmes for disabled competitive swimmers.

It is well known that several amino acids, such as arginine, are potent stimuli for insulin and glucagon secretion from the pancreas. Recently, vagal arginine sensors, which modulate arginine-induced pancreatic hormone secretion, have been reported to exist in the liver. The present investigation was designed to evaluate the role played by gluconeogenesis in this hepatic influence. To this end, we studied the effects of an intraperitoneal injection of 3-mercaptopicolinic acid (3-MPA), a gluconeogenic inhibitor, on the pancreatic hormonal response induced by intraperitoneal administration of arginine (1 g/kg body mass) to hepatic vagotomized and sham vagotomized rats. Fifteen min following the injection of arginine, the increases in glucose and insulin concentrations were significantly lower in rats with an inhibited gluconeogenesis than in rats with an intact capacity for gluconeogenesis. There were no effects of the hepatic vagotomy on the arginine-induced hormonal responses either with or without the 3-MPA injection. The results suggest that gluconeogenesis is implicated in the hepatic modulation of arginine-induced pancreatic hormone secretion.

This study was designed to determine how estrogens withdrawal during a high-fat (HF) diet regimen affects liver triacylglycerol (TAG) and cholesterol accumulation. Female Sprague-Dawley rats were submitted to a HF (42% energy as fat) or a standard (SD) diet for 6 weeks before being either ovariectomized (Ovx) or sham operated (Sham). Thereafter, Ovx and Sham rats were kept on the same diet for another 6 weeks leading to euthanasia. Liver TAG content was increased (p

We examined the capacity of high-intensity intermittent training (HI-IT) to facilitate the delivery of lipids to enzymes responsible for oxidation, a task performed by the carnitine palmitoyl transferase (CPT) system in the rat gastrocnemius muscle. Male adult Wistar rats (160-250 g) were randomly distributed into 3 groups: sedentary (Sed, N = 5), HI-IT (N = 10), and moderate-intensity continuous training (MI-CT, N = 10). The trained groups were exercised for 8 weeks with a 10% (HI-IT) and a 5% (MI-CT) overload. The HI-IT group presented 11.8% decreased weight gain compared to the Sed group. The maximal activities of CPT-I, CPT-II, and citrate synthase were all increased in the HI-IT group compared to the Sed group (P < 0.01), as also was gene expression, measured by RT-PCR, of fatty acid binding protein (FABP; P < 0.01) and lipoprotein lipase (LPL; P < 0.05). Lactate dehydrogenase also presented a higher maximal activity (nmol·min -1 ·mg protein ) in HI-IT (around 83%). We suggest that 8 weeks of HI-IT enhance mitochondrial lipid transport capacity thus facilitating the oxidation process in the gastrocnemius muscle. This adaptation may also be associated with the decrease in weight gain observed in the animals and was concomitant to a higher gene expression of both FABP and LPL in HI-IT, suggesting that intermittent exercise is a “time-efficient” strategy inducing metabolic adaptation. Key words: High-intensity intermittent training; Lipid metabolism; Carnitine palmitoyl transferase

The purpose of the present investigation was to evaluate the effects of a small infusion of pyruvate into the hepatic portal vein on the pancreatic hormone response during exercise (30-min treadmill run; 26 m/min, 0% grade) in adrenodemedullated rats. Resting and exercising rats were infused with either pyruvate (5% solution; 0.016 ml/min) into the portal vein, pyruvate into the jugular vein, or saline into the portal vein. Peripheral and portal blood glucose concentrations were decreased (P < 0.01) similarly in all groups after the exercise period. Peripheral insulin, glucagon, and norepinephrine levels, either at rest or after exercise, were not significantly affected by the infusions. The response of portal pancreatic hormone concentrations to exercise was, however, reduced by the pyruvate infused into the portal and jugular veins for insulin and into the portal vein only for glucagon. The normal increase in peripheral glucagon-insulin molar ratio during exercise was shut down by the infusion of pyruvate into the portal vein but not by the infusion of pyruvate into the jugular vein or by the infusion of saline. These results indicate that a small blood infusion of pyruvate, even in the presence of a decreasing blood glucose level, can attenuate substantially the pancreatic hormone response during exercise in adrenodemedullated rats.

Lipid metabolism in the liver is complex and involves the synthesis and secretion of very low density lipoproteins (VLDL), ketone bodies, and high rates of fatty acid oxidation, synthesis, and esterification. Exercise training induces several changes in lipid metabolism in the liver and affects VLDL secretion and fatty acid oxidation. These alterations are even more conspicuous in disease, as in obesity, and cancer cachexia. Our understanding of the mechanisms leading to metabolic adaptations in the liver as induced by exercise training has advanced considerably in the recent years, but much remains to be addressed. More recently, the adoption of high intensity exercise training has been put forward as a means of modulating hepatic metabolism. The purpose of the present paper is to summarise and discuss the merit of such new knowledge.

One segment of the population that is particularly inclined to liver fat accumulation is postmenopausal women. Although nonalcoholic hepatic steatosis is more common in men than in women, after menopause there is a reversal in gender distribution. At the present time, weight loss and exercise are regarded as first line treatments for NAFLD in postmenopausal women, as it is the case for the management of metabolic syndrome. In recent years, there has been substantial evidence coming mostly from the use of the animal model, that indeed estrogens withdrawal is associated with modifications of molecular markers favouring the activity of metabolic pathways ultimately leading to liver fat accumulation. In addition, the use of the animal model has provided physiological and molecular evidence that exercise training provides estrogens-like protective effects on liver fat accumulation and its consequences. The purpose of the present paper is to present information relative to the development of a state of NAFLD resulting from the absence of estrogens and the role of exercise training, emphasizing on the contribution of the animal model on these issues.

In recent years, we came to realize that obesity, broadly defined as increased body mass index or increased total body fat, is not necessarily associated with metabolic dysfunction and greater risk for cardiometabolic disease. In fact, there are several obese persons who are “metabolically healthy,” as there are nonobese persons who are “metabolically abnormal.” Although the reason(s) underlying this phenomenon are still not entirely clear, a number of studies conducted over the past several years indicate that the anatomical location of excess fat is more important than total body adiposity in determining metabolic outcomes. Ectopic fat accumulation, particularly in the liver, is frequently observed in obese persons and is strongly associated with metabolic dysfunction, including multiorgan insulin resistance and dyslipidemia. Intrahepatic fat, possibly more than visceral or intramyocellular fat, may thus be a prominent factor modifying the metabolic risk associated with increasing whole-body adiposity. However, cause-and-effect relationships have not yet been established, and it is also possible that intrahepatic triglyceride content is not a determinant but merely a marker of metabolic health. Understanding the regulation of fat accumulation in the liver will thus have important implications in both research and clinical practice. Little is known regarding the specific effects of lifestyle factors such as diet and exercise in regulating the accumulation of fat in the liver and its depletion thereof. In this special issue, we have invited a few papers in an attempt to partly fill this gap in our knowledge. In the first paper of this issue, “Putative factors that may modulate the effect of exercise on liver fat: insights from animal studies,” several studies in animals are reviewed in order to highlight putative factors that may modulate the effect of exercise on liver fat. This includes the fat content of the diet (exercise appears to be more effective under high-fat feeding), the role of concurrent exercise-induced loss of body weight or visceral fat, sex (males versus females), prandial status (fasted versus fed), and the duration of training, as well as the time elapsed from the last bout of exercise. The potential importance of these factors in modifying the exercise-induced changes in liver fat has not yet been formally tested in man, thereby providing a wide array of opportunities for future research. The second paper of this issue, “Nafld, estrogens, and physical exercise: the animal model,” focuses on the effects of exercise on liver fat in relation to estrogen availability. Estrogen deficiency, such as that occurring naturally after menopause in women, is strongly associated with fatty liver in animals. Exercise training exerts an estrogenic-like effect on the expression of genes involved in hepatic lipid metabolism and is a powerful means for preventing liver fat accumulation in estrogen-deficient animals. The third paper of this special issue, “Dietary conjugated linoleic acid and hepatic steatosis: species specific effects on liver and adipose lipid metabolism and gene expression,” reviews the effects of dietary conjugated linoleic acid on liver fat content and hepatic and adipose tissue fatty acid metabolism in animals. Conjugated linoleic acids, particularly the trans-10, cis-12, lead to hepatic steatosis owing to increased de novo lipogenesis and increased hepatic fatty acid uptake, at rates far exceeding the rates of disposal of intrahepatic fatty acids towards oxidation, esterification, and triglyceride export. The fourth paper of this issue, “Effects of exercise training on molecular markers of lipogenesis and lipid partitioning in fructose-induced liver fat accumulation,” examines the effects of exercise training on liver fat in starved and subsequently fructose-refed animals. Fructose, a simple sugar, is a potent dietary trigger for liver fat accretion. Exercise training in this model is not able to reverse the fructose-induced changes in lipogenic enzymes and does not reduce intrahepatic fat content. Thus, contrary to the large body of evidence demonstrating that exercise is effective in alleviating hepatic steatosis induced by high-fat feeding, exercise is not able to reverse the changes induced by fructose feeding. The final paper of this special issue, “Exercise and omega-3 polyunsaturated fatty acid supplementation for the treatment of hepatic steatosis in hyperphagic OLETF rats,” evaluates the effects of exercise on a hyperphagic model of obesity, with or without concurrent omega-3 polyunsaturated fatty acid supplementation. Exercise training in this animal model alleviates hepatic steatosis even under low-fat feeding conditions, predominantly by increasing hepatic fatty acid oxidation, whereas supplementation with omega-3 fatty acids slightly increases liver-fat content and attenuates the liver-fat-depleting effect of exercise. It is noteworthy that omega-3 fatty acid supplementation in this study accounted for only 3% of total dietary energy, whereas in several previous studies showing that omega-3 fatty acids reduce liver fat the supplement was administered at much greater doses. Research presented and reviewed in this special issue not only highlights the independent effects of exercise and diet on liver fat accumulation but also, more importantly, raises the intriguing possibility of interactive effects between exercise and diet on the mechanisms regulating liver fat accretion and depletion. It seems that several dietary factors are able to either augment or attenuate the intrahepatic triglyceride-depleting effect of exercise. Faidon Magkos Jean-Marc Lavoie Konstantinos Kantartzis Amalia Gastaldelli

The present study was designed to investigate the effects of estrogen withdrawal and exercise training on hepatic very low density lipoprotein-triglyceride (VLDL-TG) production and on expression of genes involved in hepatic VLDL synthesis in response to lipid infusion. Female Sprague-Dawley rats underwent ovariectomy (Ovx), sham surgery (Sham), and Ovx with 17β-estradiol supplementation (OvxE2) before being subdivided into sedentary (Sed) and trained (Tr) groups for 8 weeks. Exercise training consisted of continuous running on a rodent treadmill 5 times/wk. At the end of the 8-week period, all rats in the fasted state were intravenously infused with a 20% solution of Intralipid for 3-h followed by an injection of Triton WR-1339 to block lipoprotein lipase activity. Plasma TG accumulation was subsequently measured during 90 min to estimate VLDL-TG production. An additional control group consisting of Sham-Sed rats was infused with saline (0.9% NaCl). Estrogen withdrawal resulted in higher (p

The purpose of the study was: (1) to determine the effects of microsomal triglyceride transfer protein (MTP) inhibition on endoplasmic reticulum (ER) stress in liver, and (2) to determine if this response is altered in exercise-trained rats. Female Sprague-Dawley rats (6 weeks) fed either a standard (SD) or a high-saturated fat (HF; 43% as energy) diet were trained (Tr) or kept sedentary (Sed) for 6 week. Exercise training consisted of continuous running on a motor-driven rodent treadmill 5 times/week. Ten days before the end of these interventions, rats were administrated (ip) daily a MTP inhibitor (MTPX) or a placebo (P). MTPX injection resulted in a large (p < 0.01) liver triacylglycerol (TAG) accumulation in SD and HF-fed rats (approximately 200 mg g(-1)), irrespective of the training status, while plasma TAG levels were largely (approximately 80%) decreased (p < 0.01). MTPX injection in HF but not in SD-fed animals resulted in an increase in BiP/GRP78, ATF6, PERK, and XBP-1 mRNA levels, (p < 0.01) indicating an increase in the unfolding protein response (UPR) to ER stress. Interestingly, exercise training in rats fed the HF diet resulted in a further increase in BiP/GRP78 and XBP-1 mRNA levels in MTPX animals (p < 0.01). It is concluded that: (1) ER stress induced by MTPX occurs only in HF-fed rats despite the fact that liver TAG levels were largely increased in both dietary models; (2) the increase in gene expression of UPR markers with training may constitute a protective mechanism against ER stress in liver.

We hypothesized that the reduction in liver fat accumulation known to occur with exercise training in ovariectomized (Ovx) rats is associated with reduced expression of genes involved in lipogenesis while favoring the expression of transcription factors regulating lipid oxidation. We also tested the hypothesis that liver fat accumulation in Ovx rats is associated with an increased gene expression of several inflammatory biomarkers and that exercise training would attenuate this response. Sprague-Dawley female rats (14 weeks of age) were randomly divided into 4 groups of sedentary sham-operated (Sham), Ovx, Ovx with 17β-estradiol (E2) supplementation using a pellet (0.72 mg; 0.012 mg/d) with a biodegradable carrier binder, and Ovx trained with endurance exercise. Endurance exercise training consisted of continuous running on a motor-driven rodent treadmill 5 times per week for 5 weeks. Fat accumulation in liver as well as in adipose fat depots was higher (P < .01) in Ovx than in Sham rats. This response was prevented in Ovx animals with 17β-estradiol supplementation and with endurance exercise training. Liver gene expressions of sterol regulatory element-binding protein 1-c, stearoyl coenzyme A desaturase 1 (and its protein content), carbohydrate response element binding protein, and acetyl-coenzyme A carboxylase were increased with estrogen withdrawal (P < .01). These responses were corrected with E2 supplementation alone as well as with training alone. Conversely, hepatic peroxisome proliferator-activated receptor α messenger RNA levels were lower (P < .01) after estrogen removal compared with Sham rats. The lower hepatic peroxisome proliferator-activated receptor α messenger RNA levels in Ovx rats were reincreased by E2 replacement or by exercise training. Gene expression of proinflammatory cytokines including inhibitor-κB kinase β and interleukin-6, as well as protein content of nuclear factor-κB, was higher (P < .01) in Ovx than in Sham animals. E2 supplementation or exercise training prevented the expression of the proinflammatory markers. It is concluded that exercise training reduces fat accumulation in liver of Ovx rats possibly through regulation of key molecules involved in lipogenesis and lipid oxidation. Exercise training also acts as estrogens in properly regulating the expression of inflammatory biomarkers in liver of Ovx rats.

This study was undertaken to evaluate the effects of regular endurance-type exercise (i.e., swimming) on glucose tolerance and glucose-stimulated insulin response (GSIR) in 55- and 90-day-old peripubertal male rats. Intravenous glucose tolerance tests (0.5 g/kg) were done in four groups of male Sprague-Dawley rats: two groups of trained (TR; 55- and 90-day-old) and two groups of age- and weight-matched untrained (UNTR) rats. The UNTR rats were subjected to a continuous food restriction to maintain body weights equal to those of the TR rats. Rats were received in our laboratory after weaning at 21 days of age and were evaluated 48 h after the last exercise bout. No significant differences in body weights were found between TR and UNTR rats, at the age of either 55 or 90 days. A significant (P < 0.01) decrease in the mean integrated area under the glucose and insulin curves was observed in TR compared with UNTR groups in 55- as well as 90-day-old rats. These results indicate that exercise training in male rats improves the glucose tolerance and GSIR before and during puberty (21–90 days) independently of a reduction in body weight gain.

It was been reported that insulin concentration is altered by a hepatic vagotomy following intraperitoneal glucose injection (0.3 g/kg) resulting in supraphysiological blood glucose concentrations. On the other hand, neural activity of the hepatic vagus nerve has been shown to be substantially reduced by lower doses (0.05 g/kg intraportal; 0.1 g/kg intravenous). The present study was conducted in order to examine the role of the hepatic vagus nerve in insulin response after intraperitoneal injections of 0.1 and 0.3 g/kg of glucose. Measurements were made 5 days after section of this branch. In a first experiment, arterial glucose and insulin concentrations were not affected by the hepatic vagotomy following injections of either 0.1 or 0.3 g/kg of glucose. The same finding was also found in a second experiment in which portal glucose and insulin levels were measured after injection of 0.1 g/kg of glucose. These results suggest that large changes in neural activity are needed for the hepatic vagus nerve to influence the insulin response.

2-Deoxy-D-glucose (2-DG) is a nonmetabolizable analogue of glucose that, by competitive inhibition of glucose utilization, produces a central neuroglucopenia and a peripheral hyperglycemia. This glucopenic agent was used to gain more insight into the combined effects of central glucopenia and exercise on plasma catecholamine response. This was carried out by comparing one group of exercising (26 m/min, 0% grade) rats injected with 2-DG (2-DG-EX; 250 mg/kg iv) with two control groups: one group of exercising rats injected with a saline solution (SAL-EX) and one group of resting rats injected with 2-DG (2-DG-RE). Significant (P less than 0.05) increases in blood glucose levels were observed 10 min after administration of 2-DG (7.2–13.8 and 7.3–12.4 mmol/l in 2-DG-EX and 2-DG-RE groups, respectively). These elevated blood glucose levels were maintained throughout the experiment in the 2-DG-RE condition but decreased in 2-DG-EX rats to levels observed in the SAL-EX group after 45 min of running (13.8–8.0 mmol/l). The combination of 2-DG-induced neuroglucopenia and exercise resulted in an additive response of norepinephrine (0.59 vs. 0.34 and 0.34 ng/ml; t = 12 min) and an amplified epinephrine response (1.4 vs. 0.37 and 0.31 ng/ml; t = 12 min) compared with the responses to each stimulus alone (2-DG-EX vs. 2-DG-RE and SAL-EX, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

The aim of this study was to examine the effects of the addition of a resistance training programme to a caloric restriction weight loss intervention on psychosocial profile. The study sample consisted of 137 overweight and obese post-menopausal women. Participants were randomized to a caloric restriction group and caloric restriction + resistance training group. Psychosocial, anthropometric, and metabolic variables were measured before and after the 6-month weight loss intervention. Both groups presented similar weight loss and there were no significant differences between the caloric restriction group and caloric restriction + resistance training group for changes in psychosocial profile. Thereafter, all participants were classified into quintiles based on the amount of weight loss. In all quintiles, women markedly improved body esteem and self-esteem, and decreased hunger and perceived risk for diabetes mellitus (P0.05). However, significant increases in dietary restraint were observed in quintiles 2-5 (or =2.4 % body weight loss), decreases in disinhibition in quintiles 3-5 (or =4.9 %), increases in self-efficacy in quintiles 3-5 (or =4.9 %), and increases in health perceptions in quintile 5 (or =11.1%). The results of this study do not support the hypothesis that the addition of a resistance training programme to a caloric restriction weight loss intervention has additional benefits on psychosocial profile. Overall, the significant improvements in the psychosocial profile observed were mostly accounted for by the degree of weight loss.

Regular physical activity is beneficial in preventing the risk of cardiovascular complications of diabetes. Recent studies showed a cardioprotective role of oxytocin (OT) to induce natriuretic peptides (NPs) and nitric oxide (NO) release. It is not known if the diabetic state is associated with a reduced OT–NPs–NO system and if exercise training improves this system. To address this, we investigated the effects of treadmill running using the db/db mouse model of type 2 diabetes. Eight-week-old db/db mice were subjected to running 5 days per week for a period of 8 weeks. The lean db/+ littermates were used as controls. Sedentary db/db mice were obese and hyperglycaemic, and exercise training was not effective in reducing body weight and the hyperglycaemic state. Compared to control mice, db/db mice had lower heart weight and heart-to-body weight ratios. In these mice, this was associated with augmented cardiac apoptosis, cardiomyocyte enlargement and collagen deposits. In addition, db/db mice displayed significant downregulation in gene expression of OT (76%), OT receptors (65%), atrial NP (ANP; 43%), brain NP (BNP; 87%) and endothelial nitric oxide synthase (eNOS) (54%) in the heart (P < 0.05). Exercise training had no effect on expression of these genes which were stimulated in control mice. In response to exercise training, the significant increment of anti-apoptotic Bcl-2 gene expression was observed only in control mice (P < 0.05). In conclusion, downregulation of the OT–NPs–NO system occurs in the heart of the young db/db mouse. Exercise training was not effective in reversing the defect, suggesting impairment of this cardiac protective system in diabetes.

To determine whether a training state protects against the metabolically deleterious effects of ovariectomy on liver and adipocyte fat accumulation in rats.Female rats were randomly assigned to each group (n = 8 rats/group). The animals were first either exercise-trained (Tr) for 6 weeks or kept sedentary (Sed) before being sham-operated (Sham), ovariectomized (Ovx), or ovariectomized with 17beta-estradiol supplementation (OvxE2). Following surgery, sedentary rats either remained sedentary (Sed-Sed) or undertook exercise training for 6 weeks (Sed-Tr) while exercise-trained rats either became sedentary (Tr-Sed) or resumed exercise training (Tr-Tr).Body weight and energy intake along with intra-abdominal and subcutaneous fat pad weights and homeostasis model assessment of insulin resistance (HOMA-IR) were significantly (p0.01) increased in the Ovx group compared to the Sham and OvxE2 groups. Rats kept in a sedentary state after surgery showed the higher (p0.05) values for all of these variables whether they were trained or not before surgery (Sed-Sed and Tr-Sed), indicating no protective effect of a previous exercise-trained state. On the other hand, training conducted after surgery resulted in a lowering of fat mass and HOMA-IR whether rats had been trained or not before surgery (Sed-Tr and Tr-Tr), indicating the effectiveness of exercise training even initiated after surgery. These responses were independent of surgery. Interestingly, liver triacylglycerol concentrations followed a pattern of responses identical to fat mass with the exception that all of the responses were observed only in the Ovx group (p0.05).There is no protective effect of a previous exercise-training state on ovariectomy-induced liver and adipocyte fat accumulation if rats remain sedentary after ovariectomy. However, training conducted concurrently with estrogen withdrawal has protective effects, especially on liver fat accumulation, whether or not rats were previously trained.

Limited data are available regarding the impact of caloric restriction (CR) in combination with resistance training (RT) on the metabolic profile of postmenopausal women.The objective of the study was to determine whether RT adds to CR in improving body composition and the metabolic profile.This was a 6-month, randomized, clinical trial.Patients included 107 postmenopausal women (body mass index27 kg/m(2)).The intervention was a 6-month CR alone or in combination with a RT program.Fat mass (FM), lean body mass (LBM), abdominal sc fat and visceral fat, fasting lipids, insulin sensitivity, resting blood pressure, and inflammation markers were measured.Both groups were similar at baseline and significantly decreased body weight, body mass index, FM, percent FM, abdominal sc fat, and visceral fat after the study (P0.001), with greater losses of percent FM and trunk FM in the CR + RT group (P0.05). LMB significantly decreased in the CR (-0.9 +/- 2.4 kg) and the CR+RT (-0.4 +/- 2.2 kg) groups (P0.005), with no difference between them. Both groups significantly improved plasma triglycerides, fasting insulin level, glucose disposal, and markers of the inflammation profile after weight loss (P0.05), with no difference between groups. No improvements were observed for the other variables of interest in both groups.CR+RT was associated with greater losses in percent FM and trunk FM compared with CR alone. However, CR+RT was not associated with additional improvements in the metabolic profile compared with CR alone.

Stearoyl-CoA desaturase-1 (SCD-1) is the rate limiting enzyme in the biosynthesis of saturated-derived monounsaturated fats that are the major constituents of very-low-density-lipoproteins-triacylglycerol (VLDL-TAG) and are involved in regulating cellular metabolism. The purpose of this study was to evaluate the effects of an 8-week exercise training program on the hepatic gene expression of this crucial enzyme. Female rats either trained (TR) or kept sedentary (Sed) for 8 weeks were submitted either to standard (SD) diet for 8 or for 6 weeks followed by high-fat (HF; 42% kcal) diet for 2 weeks. The 2-week-high fat feeding resulted in an increase in liver triacylgycerol (TAG), plasma free-fatty-acids (FFA), abdominal fat mass, sterol-regulatory-element-binding protein-1c (SREBP-1c), and carbohydrate-response-element-binding protein (ChREBP) gene expression in liver along with a decrease in SCD-1 gene expression and plasma and liver SCD-1 desaturation index (C16:1/C16:0). Liver TAG, plasma FFA, SREBP-1c mRNA, and SCD-1 desaturation indexes (C16:1/C16:0; C18:1/C18:0) were not changed in liver or in plasma by the training program. Nevertheless, training resulted in an important decrease in fat mass (P < 0.01), hepatic SCD-1 mRNA levels (P < 0.01), and protein content (P < 0.05) in both SD and HF fed rats. It is concluded that despite an absence of decreased liver TAG, exercise training contributes to the proper regulation of fat metabolism by down-regulating hepatic SCD-1 gene expression and protein content.

The purpose of this study was to investigate the level of plasma hepatic enzymes in obese women displaying the metabolically healthy but obese (MHO) phenotype. We studied 104 obese, sedentary, postmenopausal women. Subjects were classified as MHO or at risk based on insulin sensitivity as assessed with the oral glucose tolerance test-derived Matsuda index. Subjects were divided into quartiles according to insulin sensitivity values. Subjects in the upper quartile were categorized as MHO, whereas subjects in the lower 3 quartiles represented at-risk subjects. Outcome measures were hepatic enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase, and gamma-glutamyltransferase [GGT]], high-density lipoprotein cholesterol, triglycerides, triglycerides to high-density lipoprotein cholesterol ratio, apolipoprotein B, fatty liver index, body composition (dual-energy x-ray absorptiometry), and visceral adipose tissue (computed tomography). The MHO individuals had significantly lower concentrations of ALT, AST, and GGT as well as a lower fatty liver index compared with at-risk subjects (P < .05). In addition, lean body mass index and visceral adipose tissue were significantly lower in MHO individuals (P < .05). Moreover, stepwise regression analysis showed that ALT explained 17.9% of the variation in insulin sensitivity in our cohort, which accounted for the greatest source of unique variance. Results of the present study indicate that postmenopausal women displaying the MHO phenotype present favorable levels of ALT, AST, and GGT. Lower concentrations of hepatic enzymes, in particular, lower circulating ALT levels, in MHO individuals may reflect lower hepatic insulin resistance and lower liver fat content; and this could be involved, at least in part, in the protective profile of MHO individuals.

Estrogen-deficient states are associated with hepatic steatosis. Based on previous findings obtained at the molecular and enzymatic levels, it has been suggested that estradiol exerts its lipid-lowering effects in liver through partitioning of triacylglycerols into oxidative pathways. However, information on relevant physiological response was lacking. Therefore, the purpose of the present study was to assess fatty acid oxidation rate in the liver of intact and ovariectomized rats. Tritiated water released from liver slices incubated with 9,10-[ (3)H]palmitate was measured as a reflection of in vivo fatty acid metabolism. Fatty acid oxidation rate was lowered by 34% (p

The liver, through the afferent pathway of the hepatic vagus nerve, has been reported to influence the hormonal response to exercise in adrenodemedullated rats. The present investigation was designed to evaluate the role played by gluconeogenesis in this hepatic influence. To this end, we studied the effects of a selective hepatic vagotomy on the hormonal response to a 30-min treadmill run (26 m/min, 0% grade) in adrenodemedullated rats injected with 3-mercaptopicolinic acid, a gluconeogenic inhibitor. Hepatic vagotomy was associated with small but significant higher (P less than 0.05) elevations of peripheral blood glucose levels at rest and after exercise. No significant differences were observed between hepatic-vagotomized and sham-operated rats in either resting or exercising levels of liver glycogen, portal glucose, portal and peripheral insulin and glucagon, and peripheral epinephrine and norepinephrine. All hormonal responses, with the exception of epinephrine, were either decreased or increased similarly in the two experimental conditions after exercise. These data indicate that contrary to what has been reported in rats with an intact capacity for gluconeogenesis, hepatic-vagotomized and sham-operated rats with an inhibited gluconeogenesis had similar hormonal responses to exercise. It is concluded that gluconeogenesis plays a role in the afferent neural influence exerted by the liver via the hepatic vagus nerve in the regulation of hormonal response to exercise.

Microsomal triglyceride transfer protein (MTP) is a protein that exerts a central regulatory role in very-low-density lipoprotein (VLDL) assembly and secretion. The purpose of the study was to investigate the effects of an exercise-training program on hepatic content of MTP and its relation to hepatic VLDL-triglyceride (VLDL-TG) production in response to lipid infusion. Female rats either fed a standard (SD) or an obesity-induced high-fat (HF; 43% as energy) diet for 8 weeks were subdivided into sedentary (Sed) and trained (Tr) groups. Exercise training consisted of continuous running on a motor-driven rodent treadmill 5 times/week for 8 weeks. At the end of this period, all rats in the fasted state were intravenously infused with a 20% solution of Intralipid for 3 h followed by an injection of Triton WR1339 to block lipoprotein lipase. An additional control group consisting of Sed rats fed the SD diet was infused with saline (0.9% NaCl). Plasma TG accumulation was thereafter measured during 90 min to estimate VLDL-TG production. Under HF diet, hepatic MTP content and plasma TG accumulation after Triton blockade (thus reflecting VLDL-TG synthesis and secretion) were not changed in Sed rats, whereas liver TG content was highly increased (approximately 90%; p

In addition to acting in the central nervous system, leptin also acts on peripheral tissues such as liver to provide a protection against lipid accretion. Previous evidence from human and animal model indicates that exercise training reduces circulating leptin levels beyond the changes in adiposity levels. Because liver is one of the main peripheral organs for leptin action, this present study was designed to determine whether leptin receptors expression in liver is changed by exercise training. Female rats trained (TR) or kept sedentary (Sed) for 8 weeks were submitted either to a standard (SD) diet for 8 weeks or for 6 weeks followed by 2 weeks of high-fat (HF) or high-carbohydrate (HC) feeding. Food intake, adiposity levels, circulating plasma leptin and insulin concentrations along with the hepatic expression of leptin receptors (ObR-a, -b, and -e) and peroxisome proliferator-activated receptor alpha (PPARalpha) and peroxisome proliferator-activated receptor-gamma co-activator-1alpha (PGC-1alpha), were measured in all the animals. Intra-abdominal fat depots were increased under the HF but not under the HC diet. As expected, exercise training decreases intra-abdominal adiposity in animals fed with the SD and the HF diet, and to a lesser extent in HC-fed rats. Plasma leptin levels either expressed in absolute values or in values relative to adiposity levels were significantly (P0.05) increased with the HF diet and significantly decreased in TR animals, independently of the diet. Moreover, a significant (P0.01) reduction in hepatic gene expression of ObR-a, -b and -e was found in TR animals in all the three diet conditions. PPARalpha and PGC-1alpha mRNAs were also decreased (P0.05) in TR animals in two out of three diet conditions. The present findings indicate that exercise training-induced decrease in plasma leptin levels is accompanied by a reduction in gene expression of three different isoforms of leptin receptors in liver.

The purpose of the present study was to determine the effects of an exercise training programme in high-fat-fed rats on in vitro lipolysis in a visceral (mesenteric) and a non-visceral fat depot (retroperitoneal) and its relationship to perilipin content. Two groups of female rats were fed a high-fat diet (42 % as energy) for 8 weeks, one remaining sedentary (Sed) and the other being exercise trained (Tr) for this entire period. Rats were killed after 2 and 8 weeks of their respective treatment. The significantly (P < 0.01) higher levels in mesenteric and retroperitoneal fat pad weights, plasma leptin, NEFA and glucose observed with time in Sed high-fat-fed rats were significantly (P < 0.05) attenuated in Tr animals. Isoproterenol-stimulated (10- 5-10- 4 m) lipolysis in the mesenteric, but not in the retroperitoneal tissue, was significantly (P < 0.05) lower (about 57 %) in Tr than in Sed rats after 8 weeks of high-fat feeding. The isoproterenol-stimulated lipolysis in the mesenteric tissue of 8-week Tr high-fat-fed rats was lowered to the level measured in 2-week fat-fed rats although mesenteric fat accumulation was still significantly (P < 0.01) higher in 8- than in 2-week Tr rats. Perilipin content (Western blot) was not affected by the exercise training programme. These results indicate that exercise training resulted in a reduction in the high-fat diet-induced elevated levels of lipolysis in the mesenteric tissue. This response appears to be independent of the perilipin content.

Ovarian hormones have been shown to regulate liver lipid accumulation in rats. The present study was designed to evaluate liver lipid resorption in ovariectomized (Ovx) rats. Ovx and sham-operated (Sham) rats were submitted to a high-fat (HF; 43% kcal fat as energy) diet for 5 weeks and then either maintained on this diet or switched to a standard (SD; 12.5% kcal fat as energy) diet till weeks 8 and 13 (n=8 rats/group). Body weight, energy intake, liver and intra-abdominal fat accumulation and plasma metabolic profile were determined. Body weight was significantly (P

Plasma cholesterol level is determined by a complex dynamics that involves transport lipoproteins which levels are tightly dependent on how the liver and the intestine regulate cholesterol and biliary acid metabolism. Regulation of cholesterol and biliary acids by the liver and the intestine is in turn coupled to a large array of enzymes and transporters that largely influence the inflow and the outflow of cholesterol and biliary acids through these organs. The activity of the key regulators of cholesterol and biliary acids may be influenced by several external factors such as pharmacological drugs and the nutritional status. In recent years, more information has been gathered about the impact of estrogens on regulation of cholesterol in the body. Exposure to high levels of estrogens has been reported to promote cholesterol gallstone formation and women are twice as likely as men to develop cholesterol gallstones. The impact of estrogen withdrawal, such as experienced by menopausal women, is therefore of importance and more information on how the absence of estrogens influence cholesterol regulation is started to come out, especially through the use of animal models. An interesting alternative to metabolic deterioration due to estrogen deficiency is exercise training. The present review is intended to summarize the present information that links key regulators of cholesterol and biliary acid pathways in liver and intestine to the absence of estrogens in an animal model and to discuss the potential role of exercise training as an alternative.

Background: Menopause is associated with increased lipid deposition in the liver and fat accumulation in the abdomen. Objective: The purpose of the present study was to determine the effects of adding a resistance training program (RT) to a restrictive diet (RD) on liver lipid accumulation and abdominal fat depots in ovariectomized (Ovx) rats. Methods: One group of sham-operated and three groups of Ovx rats were compared. Five weeks after surgery, Ovx rats were either submitted to an ∼25% RD with or without RT for 3 or 8 weeks, while a third group of Ovx rats were fed ad libitum and remained sedentary. The RT program consisted of climbing a 6 m vertical metal grill five times a week with an increasing load up to 75% of body weight attached to the tail. The number of repetitions increased from two to four sets of 10 repetitions. Results: Ovariectomy resulted in significantly higher (P < 0.01) body weight, energy intake, intra-abdominal fat depots, plasma leptin levels (P < 0.05), and liver triacylglycerol concentrations. All of these responses were (P < 0.01) reduced in Ovx rats following the RD with the exception of liver lipid infiltration. The addition of RT to the RD treatment synergistically reduced abdominal fat deposition and plasma-free fatty acid levels. Moreover, liver lipid infiltration was completely prevented by the addition of the RT program. Muscle mass relative to body weight was significantly increased in Ovx-RD-RT compared to all other groups. Conclusion: It is concluded that RT is an asset to minimize the deleterious effects of ovarian hormone withdrawal on liver lipid accumulation and abdominal fat accumulation in Ovx rats. © 2008 Elsevier Ireland Ltd. All rights reserved.

Estrogens exert their biological roles mainly through estrogen receptors (ER) that function as ligand-activated transcription factors. ER content in a cell is regulated by many factors and is decisive for estrogen action. The purpose of the present study was to investigate the influence of an 8-wk endurance training program on ER expression in the liver, right atrium (RA), and left ventricle (LV) of intact and ovariectomized (Ovx) rats. We measured ERalpha and ERbeta mRNA content by reverse transcription-polymerase chain reaction (RT-PCR). We found an important increase in ERalpha mRNA levels in the liver (300%; P0.01) and in ERbeta mRNA levels in the RA (200%; P0.05), and a marked decrease in ERalpha (80%; P0.01) and ERbeta (40%; P0.05) transcripts content in the LV of intact rats after endurance training. On the other hand, ERalpha mRNA levels were depressed by 50% (P0.01) in the liver, and increased by 60% (P0.01) in LV of Ovx rats after exercise training. These results first indicate that endurance training is associated with modifications of ER transcripts levels in the liver, LV, and RA of female rats. More specifically, these effects are tissue and isoform-specific and the direction of the response (increase or decrease) is different in intact and Ovx rats. It is suggested that some of the adaptations to endurance training in liver and heart may be mediated by an ER-dependent mechanism.

Studies have revealed that high-fat (HF) diets promote hyperglycaemia, whole-body insulin resistance and non-alcoholic fatty liver disease (NAFLD). Recently, hepatic glucagon resistance has been shown to occur in rats fed a HF diet. More precisely, diet-induced obesity (DIO) reduces the number of hepatic plasma membrane glucagon receptors (GR), which results in a diminished response to glucagon during a hyperglucagonaemic clamp. The present study was undertaken to test the hypothesis that a HF-DIO is associated with a desensitization and destruction of the hepatic GR. We also hypothesized that a single bout of endurance exercise would modify the GR cellular distribution under our DIO model. Male rats were either fed a standard (SD) or a HF diet for two weeks. Each group was subdivided into a non-exercised (Rest) and an acute exercised (EX) group. The HF diet resulted in a reduction of total hepatic GR (55%) and hepatic plasma membrane GR protein content (20%). These changes were accompanied by a significant increase in endosomal and lysosomal GR content with the feeding of a HF diet. The reduction of GR plasma membrane as well as the increase in endosomal GR was strongly correlated with an increase of PKC-alpha, suggesting a role of PKC-alpha in GR desensitization. EX increased significantly PKC-alpha protein content in both diets, suggesting a role of PKC-alpha in EX-induced GR desensitization. The present results suggest that liver lipid infiltration plays a role in reducing glucagon action in the liver through a reduction in total cellular and plasma membrane GR content. Furthermore, the GR desensitization observed in our in vivo model of HF diet-induced hepatic steatosis and in EX individuals may be regulated by PKC-alpha.