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PubMed1991

Proteins containing peptide sequences related to Lys-Phe-Glu-Arg-Gln are selectively depleted in liver and heart, but not skeletal muscle, of fasted rats.

In response to serum withdrawal, when overall rates of proteolysis increase in cultured fibroblasts, proteins containing peptide regions similar to Lys-Phe-Gln-Arg-Gln (KFERQ) are targeted to lysosomes for degradation, and the intracellular concentrations of these proteins decline [Chiang & Dice (1988) J. Biol. Chem. 263, 6797-6805]. To test whether such proteins are also selectively depleted in mammalian tissues in vivo, we have used affinity-purified polyclonal antibodies to KFERQ to detect proteins containing such sequences in tissues of fed and fasted rats. Immunoreactive cytosolic proteins were partially depleted from liver and heart of fasted rats, but the time course differed for these two tissues. Immunoreactive proteins in liver were lost during days 2 and 3 of fasting, whereas such proteins in heart were depleted within day 1 of fasting. In the same fasted rats, levels of immunoreactive cytosolic proteins did not change in two skeletal muscles, the dark soleus and the pale extensor digitorum longus. Immunoreactive proteins in a myofibrillar fraction were also partially depleted in heart, but not in skeletal muscles, of fasted rats. The most likely explanation for these results is that the protein loss in different tissues upon fasting results from selective activation of different proteolytic pathways. The increased proteolysis in liver and heart of fasted animals includes activation of the KFERQ-selective lysosomal pathway, whereas increased proteolysis in skeletal muscle does not.

Amino Acid Sequence↗

PubMed1994

Effects of fasting on fatty acid kinetics and on the cardiovascular, thermogenic and metabolic responses to the glucose clamp.

1. The effects of fasting for 12, 36 and 72 h were examined in 19 normal subjects. Each subject was studied before and during a euglycaemic (4 mmol/l) hyperinsulinaemic (100 m-units min-1 m-2) clamp. Measurements were made of palmitate turnover and oxidation, glucose disposal, thermogenesis, intermediary metabolites and cardiovascular variables. 2. Basal respiratory exchange ratio fell from 0.78 +/- 0.01 to 0.75 +/- 0.01 to 0.72 +/- 0.01 with fasting (P < 0.001). In response to the clamp it rose to 0.91 +/- 0.02, 0.83 +/- 0.01 and 0.77 +/- 0.01 after 12, 36 and 72h respectively. Metabolic rate rose during the clamp by 0.41 +/- 0.06, 0.11 +/- 0.03 and 0.14 +/- 0.04 kJ/min respectively (P < 0.001 for 36- and 72-h values versus that at 12h). 3. Fasting reduced total insulin-mediated glucose disposal rates from 42.6 +/- 2.5, to 31.0 +/- 1.8 to 21.3 +/- 1.5 mumol min-1 kg-1 body weight after 12, 36 and 72h respectively (P < 0.001). Glucose oxidation fell from 16.9 +/- 1.1 to 8.7 +/- 1.7 to 0.2 +/- 1.3 mumol min-1 kg-1 body weight over the same period (P < 0.001). Non-oxidative glucose disposal rates did not change significantly. 4. Basal plasma palmitate turnover increased with duration of fasting, being 1.16 +/- 0.08, 1.72 +/- 0.17 and 2.30 +/- 0.35 mumol min-1 kg-1 body weight. In response to the clamp, palmitate turnover fell to 0.42 +/- 0.05, 0.69 +/- 0.08 and 1.28 +/- 0.45 mumol min-1 kg-1 body weight. Plasma palmitate oxidation was 0.58 +/- 0.04, 0.75 +/- 0.06 and 1.13 +/- 0.11 mumol min-1 kg-1 body weight basally, and fell to 0.16 +/- 0.02, 0.28 +/- 0.04 and 0.43 +/- 0.13 mumol min-1 kg-1 body weight by the end of the clamp. The proportion of total lipid oxidation represented by plasma non-essential fatty acid oxidation was not affected by fasting, but fell in response to the clamp. 5. Fasting caused a progressive resistance to the effects of insulin and glucose on oxidative glucose disposal and on forearm glucose uptake. Insulin-mediated glucose storage was unaffected by fasting, but the apparent cost of this storage was reduced by fasting.

Adult↗

PubMed1996

Fasting increases the extent of muscle necrosis in the mdx mouse.

1. The effects of fasting for 48 h were investigated in C57BL/10 (wild type) and age-matched C57BL/10 dystrophin-deficient (mdx) mice. 2. Fasting resulted in an increased percentage of necrotic fibres in muscles from the hindlimb and lumbar regions of mdx mice. The percentage of necrotic fibres of forelimb and chest muscles of mdx mice was unaltered by fasting. In wild-type mice, very few necrotic fibres were observed after fasting. 3. The necrotic changes in fasted mdx muscle were not accompanied by altered energy status as evaluated by muscle ATP and phosphocreatine concentrations. 4. A significantly decreased rectal temperature was observed in mdx but not in wild-type mice after fasting. 5. Fasting would normally be expected to cause a reduction in muscle fibre size. The high prevalence of necrosis in fasted mdx mice is therefore an unusual response that may be related to disturbance of the mechanisms which, in the fed state, compensate for the dystrophin deficiency in these animals.

Animals↗

PubMed1997

Effects of silicon, citrate and the fasting state on the intestinal absorption of aluminium in rats.

1. The effect of silicon (Si) contained in drinking water and solid food on the intestinal absorption of aluminium (Al) remains a matter of debate. The present study was designed to readdress this issue in the experimental animal, and to examine concomitantly the effects of citrate and the fasting state, respectively. 2. Three groups of young, non-fasted rats (n = 8 per group) were gavaged by solutions containing 3.8 ng of 26Al, 63 ng of 27Al, and either distilled water (< 0.1 mg/l Si) or commercial mineral water with a medium (6 mg/l) or high (14 mg/l) Si concentration. 3. Two other groups of eight non-fasted rats each received the same distilled water or high-Si gavage solution, respectively, together with a high citrate concentration (62 g/l). In each case the animals had free access to drinking water for 5 days before and 2 days after the gavage, containing the same Si concentration as in the gavage solution. A sixth group of eight rats was gavaged by low-Si, Al and distilled water in the fasted state. 4. The animals were killed 48 h after gavage, and blood, tissue and urine samples were collected for 26Al measurements by accelerator mass spectrometry. 5. We found that the fraction of absorbed 26Al retained in the skeleton (0.025-0.030%) was of the same order of magnitude as the fraction excreted in the 48 h urine (0.035-0.037%). High Si concentrations in the drinking water failed to depress the 26Al fraction absorbed, as estimated on the basis of skeletal accumulation and urinary excretion. 6. The administration of citrate-containing fluid enhanced 26Al absorption 5- to 10-fold (P < 0.005), but again the Si content of drinking water did not interfere. Finally, the intestinal absorption of 26Al was approximately 15 times higher in the fasted than in the non-fasted state. 7. In conclusion, the provision of large amounts of Si in the drinking water failed to modify physiological intestinal Al absorption under basal conditions or after its stimulation by citrate. However, a prolonged fast greatly enhanced Al absorption, compared with the non-fasted state.

Aluminum↗

PubMed1998

Hypotensive and regional haemodynamic effects of exercise, fasted and after food, in human sympathetic denervation.

1. In human sympathetic denervation due to primary autonomic failure, food and exercise in combination may produce a cumulative blood pressure lowering effect due to simultaneous splanchnic and skeletal muscle dilatation unopposed by corrective cardiovascular reflexes. We studied 12 patients with autonomic failure during and after 9 min of supine exercise, when fasted and after a liquid meal. Standing blood pressure was also measured before and after exercise. 2. When fasted, blood pressure fell during exercise from 162 +/- 7/92 +/- 4 to 129 +/- 9/70 +/- 5 mmHg (mean arterial pressure by 22 +/- 5%), P < 0.0005. After the meal, blood pressure fell from 159 +/- 8/88 +/- 6 to 129 +/- 6/70 +/- 4 mmHg (mean arterial pressure by 22 +/- 3%), P < 0.0001, and further during exercise to 123 +/- 6/61 +/- 3 mmHg (mean arterial pressure by 9 +/- 3%), P < 0.01. The stroke distance-heart rate product, an index of cardiac output, did not change after the meal. During exercise, changes in the stroke distance-heart rate product were greater when fasted. 3. Resting forearm and calf vascular resistance were higher when fasted. Calf vascular resistance fell further after exercise when fasted. Resting superior mesenteric artery vascular resistance was lower when fed; 0.19 +/- 0.02 compared with 0.32 +/- 0.06, P < 0.05. After exercise, superior mesenteric artery vascular resistance had risen by 82%, to 0.53 +/- 0.12, P < 0.05 (fasted) and by 47%, to 0.29 +/- 0.05, P < 0.05 (fed). 4. On standing, absolute levels of blood pressure were higher when fasted [83 +/- 7/52 +/- 7 compared with 71 +/- 2/41 +/- 3 (fed), each P < 0.05]. Subjects were more symptomatic on standing post-exercise when fed. 5. In human sympathetic denervation, exercise in the fed state lowered blood pressure further than when fasted and worsened symptoms of postural hypotension.

Cardiac Output↗

PubMed2000

Metabolism of prostaglandin F2alpha during fasting in prepubertal gilts.

The study was conducted to investigate a possible mechanism behind earlier observations of fasting-induced increases of blood concentrations of prostaglandin (PG) F2alpha metabolite (P-PG) in gilts. Six animals were fasted for 28 h, then administered i.v. PGF2alpha (500 ng/kg body weight). Blood samples were withdrawn at 1, 3, 5, 7, 10, 15, 20, 30, 40, 60 min, 2 and 3 h after the injection. A control group followed an identical protocol, except that they were fed during the corresponding 28 h-period. P-PG increased as previously observed during the 28 h of fasting. The P-PG increase in terms of area under the concentration time curve (AUC) following injection was significantly larger in the fasted than in the non-fasted gilts. In the fasted animals, the mean P-PG maximum concentration (Cmax) was 7145 pmol/L, the corresponding value for the non-fasted animals was 4566 pmol/L. PGs are metabolised through beta-oxidation in the liver. The results of this study imply that reduced 15-ketodihydro-PGF2alpha breakdown in the liver might contribute to the fasting-induced increases in P-PG.

Animals↗

PubMed2003

A postnatal fasting plasma glucose is useful in determining which women with gestational diabetes should undergo a postnatal oral glucose tolerance test.

AIMS: It is recommended that women with gestational diabetes (GDM) should have a 6-week postnatal oral glucose tolerance test (OGTT). As this test may be unpleasant, time-consuming and has resource implications, we evaluated whether the 6-week postnatal fasting glucose could be used to determine which women should undergo an OGTT. METHODS: All women with GDM, diagnosed according to the World Health Organization criteria, who were delivered at the Princess Anne Hospital, Southampton between May 2000 and May 2002, were recommended to have an OGTT. The results of the fasting plasma glucose concentration were assessed in relation to the 2-h glucose value. RESULTS: One-hundred and fifty-two women with GDM were delivered. Thirty (19.7%) women refused an OGTT or failed to attend. In the 122 OGTTs, three (2.4%; 95% confidence interval 0.8, 7) women had diabetes, three had impaired glucose tolerance and four had impaired fasting glycaemia. No woman with a normal test had fasting glucose of > or =6.0 mmol/l. Fasting glucose was correlated with the 2-h glucose (r=0.62, P<0.0001). Only 10 (8.1%) of the OGTTs would have been performed if only women with fasting glucose of > or =6.0 mmol/l underwent the test. The sensitivity and specificity of this approach for the diagnosis of postnatal diabetes is 100% and 94%, respectively. Linear regression methods indicate that it would miss fewer than three in 10 000 cases. CONCLUSIONS: In our population, a 6-week postnatal fasting plasma glucose is useful in determining which women with gestational diabetes should undergo an OGTT. Consequently we now perform OGTT only in women whose postnatal fasting plasma glucose is > or =6.0 mmol/l.

Blood Glucose↗

PubMed2000

Effects of fasting, feeding, and bisphosphonate administration on serum calcitriol levels in phosphate-deprived rats.

BACKGROUND: In a recent study, we showed in phosphate-deprived rats that morning feeding decreased serum phosphate and increased serum calcium values as compared with similar rats fasted overnight, and high doses of bisphosphonates did not reduce the magnitude of hypercalcemia. In the present study, we evaluated in phosphate-deprived rats whether serum calcitriol values were: (1) affected by the differences in serum phosphate induced by morning feeding and overnight fasting, (2) correlated with changes in serum phosphate levels, and (3) influenced by bisphosphonate administration. METHODS: Four groups of rats were studied: (1) low-phosphate diet (LPD; P < 0.05%), (2) LPD + the bisphosphonate pamidronate (APD), (3) normal diet (ND; P 0.6%), and (4) ND + APD. Both diets contained 0.6% calcium. In rats receiving APD, high doses (0.8 mg/kg) were given subcutaneously four times during the study. On day 11, rats were sacrificed after an overnight fast or two to four hours after morning feeding. RESULTS: In the fed phosphate-deprived rats (LPD and LPD + APD), serum phosphate levels were less (P < 0.05) and serum calcium levels were greater (P < 0.05) than in similar rats fasted overnight. In rats on the ND (ND and ND + APD), no differences were observed between fed and fasted rats. In phosphate-deprived rats, serum calcitriol levels were greater (LPD, P < 0.05) or tended to be greater (LPD + APD, P = 0.10) in the fed than in the fasted groups. In APD-treated rats, serum calcitriol values were greater than in rats not given APD whether rats were (1) fed or fasted, or (2) on an LPD or ND. An inverse correlation was present between serum phosphate and serum calcitriol (r = -0.58, P = 0.001). In a stepwise regression model in which serum calcitriol was the dependent variable and independent variables were APD administration and serum calcium, phosphate, and PTH, serum phosphate (P = 0.003) had an inverse and APD (P < 0.001) administration a direct effect on serum calcitriol (r2 = 0.59). CONCLUSION: Calcitriol synthesis is rapidly inducible in rats during chronic phosphate deprivation, and the increase in serum calcitriol values is best attributed to feeding-induced decreases in serum phosphate. APD administration independently increases serum calcitriol levels in rats on normal and phosphate-deprived diets. Finally, whether our results in the rat are applicable to the clinical setting should be evaluated because in previous human studies of dietary phosphate restriction, serum calcitriol measurements were performed the morning after an overnight fast.

Animals↗

PubMed1981

Influence of diet and prolonged fasting on blood lipids, ketone bodies, glucose and insulin in adult sheep.

In order to study changes in blood composition during feeding and prolonged fasting, six adult Suffolk ewes received three different diets during three periods of four weeks. Two intake levels (one and three times maintenance) and two roughage/concentrate ratios (100 and 14 p. 100 roughage) were compared according to a twofold latin square. Afterwards the animals were fasted for an 11-day period. The concentration of free fatty acids in the blood decreased when concentrate was added to the diet and when energy intake level, insufficient to meet maintenance requirements, was increased to just sufficient and then to excessive. Blood lipid and lipoprotein composition was not influenced by a change in diet. Supplying concentrate instead of roughage produced increases in the proportions of stearic acid in the triglycerides and free fatty acids and of linoleic acid in the phospholipids and cholesteryl esters and decreases in the proportions of oleic acid in the free fatty acids and of oleic and palmitic acids in the triglycerides and cholesteryl esters. When increasing intake level, the proportion of linoleic acid in the phospholipids and cholesteryl esters was further increased. Increased insulinemia was also observed with concentrate intake, particularly when the concentrate was fed ad libitum. Differences in blood composition resulting from the dietary treatments rapidly disappeared with fasting. After an initial decrease, blood ketone bodies increased and the beta-hydroxybutyrate/acetoacetate (BHB/AA) ratio decreased. Glycemia decreased initially and then stabilized; the concentration of free fatty acids increased from the first day onwards and the proportion of free fatty acids in total blood lipids also increased. An increased proportion of oleic acid in the free fatty acids and triglycerides was compensated for by a decrease of saturated acids. A decrease in the level of polyunsaturated fatty acids in the phospholipids and cholesteryl esters was balanced by increased levels of saturated and oleic acids. The high density lipoprotein/low density lipoprotein ratio (HDL/LDL) decreased and insulinemia showed a strong decrease during the first day. Blood composition seemed to stabilize after-5-6 days of fasting, except for the ketone bodies which increased again after 10 days of the fast and for glycemia which increased after 5-6 days of the fast. The influence of previous dietary treatment on changes in blood composition during fasting clearly depended on the body conformation of the animal. When animals showed similar body conformation, no differences in the blood changes were observed during fasting. But when lean and fat animals were compared, extensive differences were found in the blood composition after the food was removed.

Animal Feed↗

PubMed1985

Effects of dietary lipid level on ketonemia and other plasma parameters related to glucose and fatty acid metabolism in the rabbit during fasting.

The effects of a high-fat diet on ketonemia and other plasma parameters of gluconeogenesis and ketogenesis were studied in rabbits during feeding, during a 4-day fast, and again during refeeding. Arterial plasma glucose, lactate, total aminoacids, ketone bodies, insulin and glucagon were measured daily. In the fed state, the high-fat diet induced an increase in plasma NEFA and ketone bodies and a decrease in alaninemia. The most striking effect of the high-fat diet, compared with the normal low-fat diet was the twofold increase of ketonemia during fasting, even though the difference in NEFA level after both diets was only 19%. This effect was maintained throughout the fasting period. The high-fat diet also induced higher glycemia and lower alaninemia during further fasting. Insulinemia sharply decreased to a very low value from the beginning of fasting, but the high-fat diet did not have any particular effect. Glucagonemia was not different in the fed state than in fasting, whatever preceding diet was given. Therefore, lipid content of the diet prior to fasting introduced important and persistent modifications in the triglycerides and glucose metabolism during fasting.

Alanine↗

PubMed2003

Induction of hepatic ABC transporter expression is part of the PPARalpha-mediated fasting response in the mouse.

BACKGROUND & AIMS: Fatty acids are natural ligands of the peroxisome proliferator-activated receptor alpha (PPARalpha). Synthetic ligands of this nuclear receptor, i.e., fibrates, induce the hepatic expression of the multidrug resistance 2 gene (Mdr2), encoding the canalicular phospholipid translocator, and affect hepatobiliary lipid transport. We tested whether fasting-associated fatty acid release from adipose tissues alters hepatic transporter expression and bile formation in a PPARalpha-dependent manner. METHODS: A 24-hour fasting/48-hour refeeding schedule was used in wild-type and Pparalpha((-/-)) mice. Expression of genes involved in the control of bile formation was determined and related to secretion rates of biliary components. RESULTS: Expression of Pparalpha, farnesoid X receptor, and liver X receptor alpha genes encoding nuclear receptors that control hepatic bile salt and sterol metabolism was induced on fasting in wild-type mice only. The expression of Mdr2 was 5-fold increased in fasted wild-type mice and increased only marginally in Pparalpha((-/-)) mice, and it normalized on refeeding. Mdr2 protein levels and maximal biliary phospholipid secretion rates were clearly increased in fasted wild-type mice. Hepatic expression of the liver X receptor target genes ATP binding cassette transporter a1 (Abca1), Abcg5, and Abcg8, implicated in hepatobiliary cholesterol transport, was induced in fasted wild-type mice only. However, the maximal biliary cholesterol secretion rate was reduced by approximately 50%. CONCLUSIONS: Induction of Mdr2 expression and function is part of the PPARalpha-mediated fasting response in mice. Fasting also induces expression of the putative hepatobiliary cholesterol transport genes Abca1, Abcg5, and Abcg8, but, nonetheless, maximal biliary cholesterol excretion is decreased after fasting.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed2001

The effects of fasting and refeeding on serum parathormone and calcitonin concentrations in young and old male rats.

Although fasting and refeeding reveal the existence of age-related changes in carbohydrate and lipid metabolism, the effects of aging on mineral metabolism in refed animals are unknown. We therefore investigated hormonal regulation of calcium metabolism in young (4 months) and old (26 months) male rats fasted for 48 hours and then refed for 4 or 24 hours. Serum concentrations of total and ionized calcium and parathormone were similar in control young and old rats. Serum calcitonin level was higher, and the concentrations of albumin and inorganic phosphate and alkaline phosphatase activity were lower in fed old rats. In young fasted rats, the serum ionized and total calcium was decreased, and phosphate concentration was increased. In old rats, fasting resulted in the increase of serum parathormone level. Fasting reduced serum alkaline phosphatase activity to a similar extent in both age groups. In young rats, refeeding for 24h normalized serum calcium and phosphate levels and alkaline phosphatase activity, and decreased serum concentrations of PTH and calcitonin. In old refed rats, serum calcitonin concentration was raised by 77% compared to fed or fasted animals, whereas parathormone levels were normalized. Our results indicate that old fasted or refed rats maintain normal serum calcium concentration in a different way than young animals, possibly through the increase in serum levels of parathormone and/or calcitonin. Thus, dietary manipulations such as fasting and refeeding constitute an interesting model for the investigation of the effects of aging on the hormonal regulation of serum calcium level.

Aging↗

PubMed1988

Effect of exposure to diabetic and fasted plasma on glucose oxidation in rat aorta.

Glucose metabolism is depressed in aortic intima-media of fasted and diabetic rats. The aim of this study was to elucidate the influence of diabetic and fasted plasma on glucose oxidation in rat aorta. Male Sprague-Dawley rats weighing about 200 g were used. Diabetes was induced by streptozotocin (65 mg/kg) and the rats were used after a diabetes duration of two weeks. Fasted rats were used after food deprivation for 3 days. Aortic intima-media was preincubated in plasma for 120 or 240 min. During a further incubation for 2 hours in Krebs-Henseleit bicarbonate buffer the oxidation of 14C-glucose to 14CO2 was measured. Preincubation of normal aorta in diabetic or fasted rat plasma and diabetic human plasma significantly depressed the subsequently determined glucose oxidation in comparison to aorta preincubated in normal plasma. Preincubation of aorta from diabetic or fasted rats in normal rat plasma enhanced the glucose oxidation compared with the glucose oxidation in aorta of diabetic or fasted rats after preincubation in the corresponding plasma. These results suggest that diabetic and fasted plasma contains factor(s) which in vitro depress glucose oxidation in vascular smooth muscle and, thus, may be of importance for the lowered glucose oxidation found in vascular smooth muscle preparations obtained from diabetic or fasted animals.

Adult↗

PubMed1984

Metabolic and hormonal response to short term fasting after endurance training in the rat.

The metabolic and hormonal response to short term fasting was studied after endurance exercise training. Rats were kept running on a motor driven rodent treadmill 5 days/wk for periods up to 1 h/day for 6 wk. Trained and untrained rats were then fasted for 24 h and 48 h. Liver and muscle glycogen, blood glucose, lactate, beta OH butyrate, glycerol, plasma insulin, testosterone and corticosterone were measured in fed and fasted trained and untrained rats. 48 h fasted trained rats show a lower level of blood lactate (1.08 +/- 0.05 vs 1.33 +/- 0.08 mmol/l-1 of blood glycerol (1 +/- 0.11 vs 0.84 +/- 0.08 mmol/l-1), and of muscle glycogen. There is a significant increase in plasma corticosterone in 48 h fasted trained rats from fed values. Plasma testosterone decreases during fasting, the values are higher in trained rats. Plasma insulin decreases during fasting without any difference between the two groups. These results show higher lipolysis, and decreased glycogenolysis in trained animals during 48 h fasting. The difference between the groups in steroid hormone response could reduce neoglucogenesis and muscle proteolysis in trained animals.

Animals↗

PubMed1995

Correlations between lipid peroxide and glutathione levels in vitamin C supplemented fasting guinea pigs.

The object of this study was to investigate correlations between lipid peroxide (MDA) and glutathione (GSH) levels in liver, kidney, heart and brain of guinea pigs during fasting (24 h, 48 h, 120 h) and respectively by supplementation (A single dose, 500 mg/kg bw, ip) of vitamin C (AA, Ascorbic acid) on fasting (24 h, 48 h, 120 h). MDA and GSH levels of various tissues by fasting and AA supplemented fasting were dependent on the function of each tissue during the fasting period. Lipid peroxide (LP) levels of kidney, heart and brain decreased for the AA supplemented fasting period. However, LP levels of liver increased in the AA supplemented 48 h and 120 h fasting groups. GSH levels of all tissues were affected differently in all of the AA supplemented fasting periods.

Animals↗

PubMed2000

Characterization of the fasting-induced adipose factor FIAF, a novel peroxisome proliferator-activated receptor target gene.

Fasting is associated with significant changes in nutrient metabolism, many of which are governed by transcription factors that regulate the expression of rate-limiting enzymes. One factor that plays an important role in the metabolic response to fasting is the peroxisome proliferator-activated receptor alpha (PPARalpha). To gain more insight into the role of PPARalpha during fasting, and into the regulation of metabolism during fasting in general, a search for unknown PPARalpha target genes was performed. Using subtractive hybridization (SABRE) comparing liver mRNA from wild-type and PPARalpha null mice, we isolated a novel PPARalpha target gene, encoding the secreted protein FIAF (for fasting induced adipose factor), that belongs to the family of fibrinogen/angiopoietin-like proteins. FIAF is predominantly expressed in adipose tissue and is strongly up-regulated by fasting in white adipose tissue and liver. Moreover, FIAF mRNA is decreased in white adipose tissue of PPARgamma +/- mice. FIAF protein can be detected in various tissues and in blood plasma, suggesting that FIAF has an endocrine function. Its plasma abundance is increased by fasting and decreased by chronic high fat feeding. The data suggest that FIAF represents a novel endocrine signal involved in the regulation of metabolism, especially under fasting conditions.

Adipose Tissue↗

PubMed2000

Defect in peroxisome proliferator-activated receptor alpha-inducible fatty acid oxidation determines the severity of hepatic steatosis in response to fasting.

Fasting causes lipolysis in adipose tissue leading to the release of large quantities of free fatty acids into circulation that reach the liver where they are metabolized to generate ketone bodies to serve as fuels for other tissues. Since fatty acid-metabolizing enzymes in the liver are transcriptionally regulated by peroxisome proliferator-activated receptor alpha (PPARalpha), we investigated the role of PPARalpha in the induction of these enzymes in response to fasting and their relationship to the development of hepatic steatosis in mice deficient in PPARalpha (PPARalpha(-/-)), peroxisomal fatty acyl-CoA oxidase (AOX(-/-)), and in both PPARalpha and AOX (double knock-out (DKO)). Fasting for 48-72 h caused profound impairment of fatty acid oxidation in both PPARalpha(-/-) and DKO mice, and DKO mice revealed a greater degree of hepatic steatosis when compared with PPARalpha(-/-) mice. The absence of PPARalpha in both PPARalpha(-/-) and DKO mice impairs the induction of mitochondrial beta-oxidation in liver following fasting which contributes to hypoketonemia and hepatic steatosis. Pronounced steatosis in DKO mouse livers is due to the added deficiency of peroxisomal beta-oxidation system in these animals due to the absence of AOX. In mice deficient in AOX alone, the sustained hyperactivation of PPARalpha and up-regulation of mitochondrial beta-oxidation and microsomal omega-oxidation systems as well as the regenerative nature of a majority of hepatocytes containing numerous spontaneously proliferated peroxisomes, which appear refractory to store triglycerides, blunt the steatotic response to fasting. Starvation for 72 h caused a decrease in PPARalpha hepatic mRNA levels in wild type mice, with no perceptible compensatory increases in PPARgamma and PPARdelta mRNA levels. PPARgamma and PPARdelta hepatic mRNA levels were lower in fed PPARalpha(-/-) and DKO mice when compared with wild type mice, and fasting caused a slight increase only in PPARgamma levels and a decrease in PPARdelta levels. Fasting did not change the PPAR isoform levels in AOX(-/-) mouse liver. These observations point to the critical importance of PPARalpha in the transcriptional regulatory responses to fasting and in determining the severity of hepatic steatosis.

Animals↗

PubMed1999

Effects of physical exercise on liver ATP levels in fasted and phosphate-injected rats.

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 (P < 0.05) 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 (P > 0. 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 (P <0.05) decreased by the fast and the exercise in the fasted state. Fasting and exercise resulted in a significant (P < 0.05) 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 (P < 0.05) by fasting, while norepinephrine and portal glucagon were decreased (P > 0.05) following exercise. The main effect of the injection of Na ( 2) PO (4) was a stimulation (P < 0.05) 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.

Adenosine Triphosphate↗