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Effects of acute caloric restriction on cholesterol metabolism in man.

The effects of acute caloric restriction on cholesterol balance and kinetics of plasma cholesterol specific activity were investigated in five hyperlipemic subjects with varying degrees of obesity. Caloric restriction decreased plasma triglycerides by 41 +/- 12%, plasma cholesterol by 11 +/- 9%, and the ratio of esterified to free cholesterol by 12 +/- 7+. Immediately on institution of caloric restriction there appeared to be an influx of tissue cholesterol into plasma and a reduction in endogenous synthesis of cholesterol. The cholesterol balance decreased from 1,469 +/- 441 to 1,212 +/- 349 mg/day and the rate of decay of plasma cholesterol specific activity decreased 62 +/- 3%. The effect of caloric restriction on hepatic synthesis of bile acids was also very prompt. The total fecal bile acids were reduced immediately by 36 +/- 7%. Because the effect on fecal excretion of deoxycholic acid was greater than that on fecal lithocholic acid, it was suggested that hepatic synthesis of cholic acid was reduced more than the synthesis of chenodeoxycholic acid. Caloric restriction did not cause any change in the percentage of absorption of dietary cholesterol (40 +/- 2% versus 42 +/- 3%). These observations are in accord with our model relating cholesterol metabolism with the metabolism of plasma lipoproteins in man.

Adult

Caloric restriction lowers blood pressure in the spontaneously hypertensive rat.

In the spontaneously hypertensive rat (SHR), caloric restriction without sodium restriction is associated with reduced blood pressure. Four days of fasting lowered blood pressure 19% while 4 days of eating 50% of ad lib intake reduced blood pressure 10%. Similar dietary changes had less effect on blood pressure in normotensive rats of the same strain (Wistar-Kyoto--WKY). These data are consistent with the hypothesis that caloric restriction lowers sympathetic activity.

Animals

Effect of caloric restriction and dietary composition of serum T3 and reverse T3 in man.

To evaluate the effect of caloric restriction and dietary composition on circulating T3 and rT3 obese subjects were studied after 7-18 days of total fasting and while on randomized hypocaloric diets (800 kcal) in which carbohydrate content was varied to provide from 0 to 100% calories. As anticipated, total fasting resulted in a 53% reduction in serum T3 in association with reciprocal 58% increase in rT3. Subjects receiving the no-carbohydrate hypocaloric diets for two weeks demonstrated a similar 47% decline in serum T3 but there was no significant change in rT3 with time. In contrast, the same subjects receiving isocaloric diets containing at least 50 g of carbohydrate showed no significant changes in either T3 or rT3 concentration. The decline in serum T3 during the no-carbohydrate diet correlated significantly with blood glucose and ketones but there was no correlation with insulin or glucagon. We conclude that dietary carbohydrate is an important regulatory factor in T3 production in man. In contrast, rT3 concentration is not significantly affected by changes in dietary carbohydrate. Our data suggest that the rise in serum rT3 during starvation may be related to more severe caloric restriction than that caused by the 800 kcal diet.

Adult

Effects of caloric restriction on the kinetics of indocyanine green in patients with liver diseases and in the rat.

The effect of caloric restriction on the hepatic uptake and excretion of indocyanine green (ICG) was studied in man as well as in rats. It was demonstrated that following a 72-hr caloric restriction in man, the plasma clearance rate for ICG was increased significantly at the low dose of 0.5 mg/kg, and transport maximum was increased without a significant change of storage capacity. In rats, the maximal biliary excretion was significantly increased after 48-hr fast, but neither maximal hepatic uptake (Vmax) nor hepatic ICG content was altered. The evidence is consistent with the view that fasting increases the ICG plasma clearance at low doses by enhancement of excretory steps at the bile canalicular membrane.

Adult

Glucose administration and heme catabolism after caloric restriction.

Heme catabolism was monitored through the determination of total serum bilirubin and endogenous production of carbon monoxide in 6 healthy males before and after administration of 100 g of glucose orally and intravenously, respectively. To facilitate comparison, hyperbilirubinemia was induced through a 36-hr period of subtotal caloric restriction before the study. A decrease in production of carbon monoxide was seen after glucose given orally as well as intravenously, whereas total serum bilirubin decreased significantly only after glucose orally. It is suggested that oral as well as intravenous glucose administration temporarily inhibits heme catabolism, at least when given after a period of caloric restriction. In addition, oral glucose might have--probably via a gut-related factor--a facilitating effect on liver uptake of bilirubin.

Administration, Oral

The influence of caloric restriction on serum prolactin.

Nine obese female patients were placed on a liquid formula diet containing 320 kcal (1.34 MJ), 31 g protein, 44 g carbohydrate, 1.5 g fat, vitamins and essential minerals for a period of four weeks under metabolic-ward conditions. The diet was tolerated well in all patients and mean weight loss was 2.49 kg per week during the four-week period. Basal serum prolactin levels were normal (2.9 +/- 0.6 ng/ml) and did not show any change during this period. In six patients a TRH test was performed before and during caloric restriction. The maximal increment of PRL after TRH was significantly lowered during dietary treatment: 53.2 +/- 16.2 vs. 32.3 +/- 11.6 ng/ml; mean +/- s.e.m.; P less than 0.025). No change was observed in the serum TSH responset to TRH before and during caloric restriction. Dietary restriction suppresses prolactin synthesis and secretion as measured in response to TRH in obese female patients.

Adolescent

Caloric restriction modulates genome-wide somatic mutation in mice.

Somatic mutations accumulate throughout life in every cell, and this process constitutes one of the hallmarks of aging-genomic instability. Caloric restriction (CR) has been shown to extend lifespan across diverse species. Using high-fidelity duplex DNA sequencing of bulk liver, bulk kidney, hepatocytes, and cerebellar neurons, we found that CR in mice reduces genome-wide somatic mutation burdens across multiple tissues and cell types. CR reduced both substitution and insertion/deletion burdens, with the magnitude of these effects varying across sample types. CR also decreased the activity of the enigmatic single-base substitution (SBS) mutational process SBS5 that gives rise to most mutations in mammals. Surprisingly, the mutation burden reduction from CR was greatest in transcriptionally inactive regions. This work illuminates links between diet, aging, and genomic integrity and establishes genomic integrity as a modifiable axis of aging.

DNA

Obesity and thyroid function. 2. The effect of prolonged caloric restriction on Achilles tendon reflex values.

The results obtained are indicative of changes in thyroid function during prolonged caloric restriction. Achilles tendon reflex values were studied in obese individuals under reducing treatment. More pronounced weight loss during the first three months was associated with a shortening of Achilles tendon reflex values, or its values remained unchanged. From the sixth month on a growing percentage of obese patients in our group displayed prolongation of Achilles tendon reflex values coupled with a decrease in weight showed a statistically significant prolongation of Achilles tendon reflex values. Thyreoglobulin given at this stage normalised Achilles tendon values and reinduced weight decrease.

Achilles Tendon

Diurnal variation in endogenous production of carbon monoxide. Effect of caloric restriction.

The endogenous production of carbon monoxide (VCO) and total serum bilirubin (SB) have been followed in five healthy male volunteers during one baseline day and one day with no caloric intake. VCO in the morning studies was 11.2+/-1.7 (mean +/-1 S.E.M.) on the baseline day and 10.1+/-2.3 mumol/mmol total body heme (TBH) and day on the fasting day, respectively. In studies before noon, VCO increased significantly on both days, to values of 17.8+/-1.6 and 19.6+/-2.2 mumol/mmol TBH and day, respectively. In the first study in the afternoon, VCO differed significantly between the two days, amounting to 12.1+/-3.0 and 23.7+/-3.5 on the baseline and the fasting day, respectively. The difference was still significant in the evening, when VCO was 11.6+/-3.1 and 22.1+/-4.9 mumol/mmol TBH and day. SB followed the same pattern, with mean values of 4.0+/-0.3, 4.9+/-0.3, 4.2+/-0.9 and 3.0+/-0.3 mug/ml during the baseline day and 4.5+/-0.6, 5.4+/-1.2, 7.0+/-0.5 and 8.5+/-1.0 mug/ml, respectively, during fasting day. Only insignificant amounts of conjugated bilirubin were found. The studies confirm earlier reports on the effect of caloric restriction on VCO. Since this effect is simultaneous with an increase in SB, it is concluded that the changes are secondary to an increase in total heme catabolism. They might be due to an increase in intracellular hepatic heme turnover but it cannot be excluded that starvation affects erythropoiesis and/or red cell catabolism, thereby causing an increase in VCO and SB.

Adult

Effects of caloric restriction on lipid metabolism in man: changes of tissue lipoprotein lipase activities and of serum lipoproteins.

Heparin-releasable lipoprotein lipase (LPL) activity was measured in biopsy samples of adipose tissue and skeletal muscle of 8 normal healthy females, first during an isocaloric diet and then after 2 and 7 days on a 400-kcal diet. In adipose tissue the LPL activity expressed per tissue weight fell to 38% and to 22% of the initial level after 2 and 7 days' caloric restriction, respectively. In skeletal muscle the LPL activity rose slightly after two days (+24%) but decreased to 49% of the initial value after seven days on diet. The estimated total body LPL activity decreased to 50% and to 20% of the baseline value after 2 and 7 days, respectively, but the relative contribution of skeletal muscle to the total LPL increased from 10 to 30%. The triglyceride and VLDL triglyceride concentrations were not significantly changed during the low calorie diet but the LDL triglyceride increased and the HDL cholesterol decreased significantly (P less than 0.01). It is concluded that substantial restriction of calorie intake results in a decrease of over-all triglyceride removal capacity but in an increase of the fraction removed by skeletal muscle. The decrease of HDL cholesterol is probably a consequence of the low turnover of exogenous and endogenous triglyceride-rich lipoproteins.

Adipose Tissue

Dynamics of gut bacteriophage in diversity outbred mice studied over lifespan and during extreme caloric restriction.

BACKGROUND: The majority of bacteria in the vertebrate gut harbor integrated bacterial viruses ("bacteriophages" or "phages"; integrated phage are termed "prophages"). To probe phage replication strategies in the mammalian gut microbiome, we investigated phage activity in a large longitudinal study of diversity outbred mice (913 animals) undergoing extreme dietary restriction with detailed phenotypic characterization across lifespan. RESULTS: We assembled 54,119 candidate DNA viral genomes from 2997 longitudinal metagenomes, forming 6462 viral operational taxonomic units (vOTUs). Over 85% of vOTUs annotated as novel. Viruses annotated predominantly as prophages in the Caudoviricetes class. We detected no eukaryotic DNA viruses, and none of the strictly lytic Crassvirales order that is abundant in human gut. The most prevalent phages had the widest predicted host ranges. The relative abundance of most phages was highly correlated to that of their inferred host bacteria, suggesting quiescent prophages dominate viral metagenomes, consistent with "piggyback-the-winner" dynamics. After accounting for close phage-bacterial covariation, we did identify a subset of phages changing in relative abundance and prevalence relative to their hosts in response to dietary restriction and aging. In particular, phages with larger genomes become less common in diets with restricted calories, potentially reflecting a higher fitness cost to their host. Generalist phages were enriched for a gene encoding a single-strand DNA binding protein which is reportedly involved in DNA repair and protection from nucleases encoded by host cells. Lytic phages became more common with aging, and we observed a reduction in phage richness with age, both findings previously observed in human cohorts. CONCLUSION: These studies enrich our understanding of DNA phage dynamics in gut while emphasizing the predominance of "piggyback-the-winner" strategies.

Animals

Effects of alcohol and caloric restrictions on blood pressure and serum lipids in overweight men.

We have examined the independent and combined effects on blood pressure and blood lipids of alcohol restriction and weight loss in overweight male drinkers with a view to assessing overall effects on cardiovascular risk of two widely promoted nonpharmacological approaches for hypertension. Eighty-six men with a mean age of 44.3 years, a mean regular alcohol intake of 440 ml/wk (five or six standard drinks per day), a mean blood pressure of 137.4 mm Hg systolic and 84.8 mm Hg diastolic, and a mean body mass of 92.5 kg entered a controlled two-way factorial study. The subjects were randomly assigned to four groups for an 18-week intervention in which members of two groups drank only low-alcohol beer, thereby reducing their alcohol intake by 374 ml/wk, while those of the other two groups continued their normal alcohol intake. Within the low and normal alcohol intake groups subjects either continued their usual diet or reduced their caloric intake by 4,200-6,300 kJ/day (1,000-1,500 kcal/day) (with protein, fat, and carbohydrate provided as 15%, 30%, and 55% of total calories, respectively). Calorie reduction and alcohol restriction caused weight losses of 7.5 (p less than 0.001) and 2.1 (p less than 0.01) kg, respectively. Calorie reduction and alcohol restriction were associated with decreases in systolic blood pressure of 5.4 (p less than 0.001) and 4.8 (p less than 0.01) mm Hg, respectively, and in diastolic blood pressure of 4.2 (p less than 0.001) and 3.3 (p less than 0.01) mm Hg, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult

Effect of caloric restriction on basal insulin levels and the in vivo lipogenesis and glycogen synthesis from glucose in the Koletsky obese rat.

Fasting plasma immunoreactive insulin levels increased with age in hyperinsulinemic Koletsky obese rats, being almost four times as high as in lean siblings at 3 mo (40 +/- 5 muU/ml) and rising steadily to 82 +/- 4 muU/ml at 6 mo (about seven times higher than lean siblings). Restricting the food intake of the obese rats markedly reduced but did not normalize the hyperinsulinemia, which in these rats was accompanied by normal plasma glucose concentrations. The incorporation in vivo of D-U-14C-glucose into tissue lipids and glycogen was measured 1 hr after the intravenous injection of 1 g glucose (containing 100 muDi D-U-14C-glucose) per kg body weight in obese rats eating ad libitum, obese rats after 3 mo on a restricted food intake, and lean siblings. All tissues (heart, diaphragm, skeletal muscle, and adipose tissues and liver) of obese rats exhibited a significantly greater lipogenesis from glucose than those of lean siblings. Dietary restriction of the obese rats reduced the 14C incorporation into lipid to levels not significantly different from lean controls in all tissues except skeletal muscle and liver, where, although greatly reduced, lipogenesis was still significantly higher than in lean rats. Glycogen synthesis tended to be greater in all tissues of obese rats than in lean animals. Dietary restriction of obese rats did not greatly affect glycogen synthesis.

Animals

[Preliminary considerations on the behavior of single plasmatic free fatty acids in obese subjects exposed to lipolytic stimulus before and after a period of caloric restriction].

The compositions of the plasma free fatty acid picture changes in relation of the metabolic situation, which is not that theoretically predictable from the adipocyte triglycerides. After a meal, this is due to the existence of a labile storage pool, which derives its features directly from those of the food lipids. In the fasting subject, when this compartment has exhausted its remains, the failure of the NEFA picture to correspond to that of the fats constituting the stabel pool may be attributable to selective release, or to preferential utilisation of each fatty acid. Analysis of the composition performed a very short time after a supramaximal lipolytic stimulus, i.e. when the release of fatty acids surpasses their peripheral removal, by confirming the differences noted under basal conditions, suggests that the first theory used to explain the phenomenon is most likely the correct one.

Adult