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Early improvement of left ventricular function during caloric restriction in obesity.

Left ventricular function (LVF) was studied in 25 obese patients (four males and 21 females) by serial poligraphic measurements, namely systolic time intervals (STI), during a short period of dieting (2721 kJ/day (650 kcal/day) as single daily meal regimen). In the same period, all the patients underwent also three standardized exercise tests at the cycloergometer. At the end of the study (20th day), statistically significant differences were obtained in weight loss (P less than 0.001); two main parameters of STI, namely pre-ejection period index (PEPI) and PEP/LVET ratio were lowered (P less than 0.001): furthermore, peak and recovery systolic blood pressure (SBP) and heart rate (HR) during exercising, were also significantly reduced. These data suggest that an improvement of LVF and cardiac performance are present since the early phases of caloric restriction in obesity.

Adolescent↗

Cardiovascular responses to caloric restriction and thermoneutrality in C57BL/6J mice.

We utilized variations in caloric availability and ambient temperature (T(a)) to examine interrelationships between energy expenditure and cardiovascular function in mice. Male C57BL/6J mice (n = 6) were implanted with telemetry devices and housed in metabolic chambers for measurement of mean arterial pressure (MAP), heart rate (HR), O(2) consumption (VO(2)), and locomotor activity. Fasting (T(a) = 23 degrees C), initiated at the onset of the dark phase, resulted in large and transient depressions in MAP, HR, VO(2), and locomotor activity that occurred during hours 6-17, which suggests torporlike episodes. Food restriction (14 days, 60% of baseline intake) at T(a) = 23 degrees C resulted in progressive reductions in MAP and HR across days that were coupled with an increasing occurrence of episodic torporlike reductions in HR (<300 beats/min) and VO(2) (<1.0 ml/min). Exposure to thermoneutrality (T(a) = 30 degrees C, n = 6) reduced baseline light-period MAP (-14 +/- 2 mmHg) and HR (-184 +/- 12 beats/min). Caloric restriction at thermoneutrality produced further reductions in MAP and HR, but indications of torporlike episodes were absent. The results reveal that mice exhibit robust cardiovascular responses to both acute and chronic negative energy balance. Furthermore, we conclude that T(a) is a very important consideration when assessing cardiovascular function in mice.

Animals↗

C-reactive protein and coronary artery disease: influence of obesity, caloric restriction and weight loss.

C reactive protein (CRP) values in blood are a good indicator of the likelihood of acute coronary and cerebral events in both healthy subjects and patients with coronary artery disease. This indicates that atherosclerotic lesions rich in inflammatory cells and cytokines are more likely to produce acute events either through vasospasm and/or thrombosis and also can be readily detected through elevations in CRP when measured using a high sensitivity assay (hsCRP). However the arterial wall is only one potential source of cytokines which induce CRP production. Fat cells also produce cytokines, in particular IL-6 which induces the synthesis of CRP by the liver. Obesity, especially abdominal obesity, is associated with elevations of hsCRP. This may be of pathogenic significance as CRP stimulates the uptake of LDL by macrophages, induces complement activation which may cause cellular damage in the artery, and enhances monocyte production of tissue factor, thus enhancing the risk of thrombosis. Caloric restriction and weight loss lowers IL-6 and CRP levels and may beneficially suppress an immune response. Whether particular dietary macronutrients or micronutrients alter IL-6 or CRP is unknown but this issue is clearly becoming more important.

Journal Article↗

Caloric restriction and aging as viewed from Biosphere 2.

The low-calorie nutrient-dense diet consumed for 2 yr by the eight persons sealed inside the closed ecological space known as Biosphere 2, near Tucson, AZ, constituted a unique "experiment of nature," amounting to the first well-monitored application of a nutritional regimen proven in animals to substantially inhibit and delay time of onset of most age-related diseases, induce physiological changes characteristic of a functionally "younger" age, and extend both average and maximum lifespans. Over the 2 yr the eight persons demonstrated a substantial weight loss, remarkable fall in blood cholesterol, blood pressure, fasting blood sugar, and low white blood cell counts--exactly as seen in rodents on such a regimen. Studies in progress involving levels of cortisol, insulin, and glycosylated hemoglobin support the rodent similarity. Further studies will seek to determine whether additional among the large battery of physiologic changes induced in animals by caloric restriction are also induced in humans on a similar nutrient-dense, calorie-limited diet. Such evidence will pertain to the question whether the increased disease resistance and aging retardation shown by calorie-restricted rodents might also be expected to occur in humans.

Aging↗

Resistance weight training during caloric restriction enhances lean body weight maintenance.

To assess the individual and combined effects of weight loss and weight training on body weight and body composition, 40 obese women were randomly assigned to one of four groups for an 8 wk weight-loss study. These groups were control (C); diet without exercise (DO); diet plus weight training (DPE); and weight training without diet (EO). Body weight decreased for DO (-4.47 kg) and DPE (-3.89 kg) compared with C (-0.38 kg) and EO (0.45 kg). Lean body weight (LBW) increased for EO (1.07 kg) compared with DO (-0.91 kg) and C (-0.31 kg) and for DPE (0.43 kg) compared with DO. Upper-arm muscle areas (determined by radiograph) increased for DPE (11.2 cm2) and EO (10.4 cm2) compared with C (2.7 cm2) and DO (2.1 cm2). It was concluded that weight training results in comparable gains in muscle area and strength for DPE and EO. Adding weight training exercise to a caloric restriction program results in maintenance of LBW compared with DO.

Adult↗

Thromboelastographic assays of the clotting process in situations of obesity and caloric restriction.

A study on blood clotting has been carried out in a number of obese individuals and compared to a group of non-obese persons, in order to assess if the former can be considered to be in "high risk" regarding the onset of a thromboembolic process. The technique of thromboelastography was chosen. The results point out that in obese people a series of alterations take place, both in the time of clot formation, which is enlarged, as in the organization of its nets, which appear strongly structured, favoured by the hyperfibrinogenemia and thrombocytosis detected in these subjects. Likewise, the effect of a hypocaloric diet on clotting in obese persons has been evaluated and compared with the former groups. Clotting in treated obese individuals is modified in the same way as in the untreated group when compared to the non-obese population; nevertheless, when both groups of obese people are compared, no significant difference is observed in the different parameters studied, even though constants determined in citrated whole blood are closer to normality in the subjects undergoing caloric restriction.

Adolescent↗

Effects of caloric restriction on body composition and total body nitrogen as measured by neutron activation.

The purpose of this study was to compare the effects of two isocaloric diets (800 Kcals) on the changes in body composition during weight reduction. While the protein content of both diets was 70 g, the carbohydrate content of diet A was 10 g and that of diet B was 70 g. The various parameters of body composition were determined as follows: Total body potassium (TBK) by 40K counting, total body water (TBW) by the tritiated water technique, total body nitrogen (TBN) by prompt gamma neutron activation analysis (PGNAA) and total body fat was estimated by measuring the skinfold thickness. Routine serum chemistries were performed every 2 wk and serum insulin and triiodothyronine by radioimmunoassay were done at 4-wk intervals. Seventeen obese women who were at least 30% above ideal body weight volunteered for the outpatient study, (group A--10 subjects, group B--7 subjects). At the end of the 12 wk study, the percent changes in the above parameters of body composition were not significantly different for the two groups. The biochemical changes were consistent with the degree of caloric restriction. We conclude that: (1) the technique of prompt gamma neutron activation analysis can be used effectively to determine long term changes in total body nitrogen during weight reduction, (2) loss of lean tissue (water, potassium and nitrogen) as well as fat tissue occurred during weight reduction. The loss of TBN in absolute quantities was less for diet A compared to diet B; however, there was no significant difference between the two diets when the data was expressed as a percent change from the baseline values, and (3) TBK determination probably provides the best estimate of total body fat.

Adult↗

The effect of obesity and drastic caloric restriction on serum prolactin and thyroid stimulating hormone.

Subnormal prolactin (PRL) and thyroid stimulating hormone (TSH) responses to thyrotropin releasing hormone (TRH) have been reported in massive obesity, while fasting and very-low-calorie diets have been shown to impair the reaction of PRL to TRH. The mechanism of these changes is poorly understood. We studied a group of moderately obese women on weight maintenance diets to determine whether PRL and TSH responses are reduced in moderate obesity, and repeated the TRH tests during treatment with a 320 kcal diet, with and without the addition of triiodothyronine (T3). Basal and maximal PRL levels after stimulation were not significantly different in the obese patients before dietary restriction from levels in non-obese controls. During the use of the diet the PRL response to TRH was significantly lower than the initial value (P less than 0.025) while basal PRL levels remained unchanged. The percentage reduction in PRL response showed a significant positive correlation with the percentage decrease in serum T3 (r = 0.80, P less than 0.05). Administration of 75 micrograms of T3 daily to the patients, however, was associated with a further significant decrease in the PRL response to TRH. Plasma oestradiol levels did not change with use of the diet. TSH response to TRH was normal in these patients and did not change with use of the diet alone. T3 treatment resulted in an almost complete suppression of the TSH response. In conclusion the reaction of prolactin to stimuli is normal in the moderately obese patient, but reduced during drastic caloric restriction. This decreased responsiveness is probably not due to changes in T3 or oestrogen levels.

Adolescent↗

Variability in body protein loss during protracted, severe caloric restriction: role of triiodothyronine and other possible determinants.

Six morbidly obese subjects were maintained in a metabolic ward for 64 days on liquid diets providing 600 to 800 kcal/day. Three received protein at a level of 1.5 g/kg desirable weight per day. The other three were given an identical diet in which half the protein was replaced by carbohydrate. Because there were no significant differences in either mean protein or mean fat losses between the two groups, the data on all six subjects were combined. Over the 64 days, the mean weight loss (+/- SEM) of the subjects per 1000 kcal deficit was 174.3 +/- 25.5 g. The composition of this weight loss was 36.0% water, 58.9% fat, and 5.1% protein. Although the rate of fat loss was relatively constant throughout the study, wide interindividual variations in cumulative protein (nitrogen) deficit were observed. Total nitrogen losses per subject ranged from 90.5 to 278.7 g. Cumulative nitrogen loss during the first 16 days tended to correlate negatively with initial mean fat cell size and positively with initial lean body mass. Most notable was the strong negative correlation between the size of the decrease in serum triiodothyronine over the 64-day study and the magnitude of the concurrent cumulative N deficit. During severe caloric restriction, one's ability to decrease circulating serum triiodothyronine levels may be critical to achievement of an adaptational decrease in body protein loss.

Adaptation, Physiological↗

Long-term weight control study. II (weeks 34 to 104). An open-label study of continuous fenfluramine plus phentermine versus targeted intermittent medication as adjuncts to behavior modification, caloric restriction, and exercise.

Between weeks 34 and 104, we explored different schema for administering fenfluramine plus phentermine in open-label fashion. At week 34, the original placebo group participants began taking fenfluramine plus phentermine (placebo-to-active group). Those receiving fenfluramine plus phentermine between weeks 6 and 34 either continued to receive medication or began targeted intermittent therapy. Participants who did not lose 10% of initial weight received an augmented dose (60 mg fenfluramine plus 30 mg phentermine. The placebo-to-active group lost an additional 9.1 +/- 0.8 kg (mean +/- SEM) in the period from week 34 to week 60. At week 60, they were assigned to either continue medication, intermittent therapy, or augmented therapy. More than 68% (83) of the original participants completed up to study week 104. At that point, overall weight loss was 10.8 +/- 0.7 kg (11.6 +/- 0.8% of initial weight); participants who continued to receive fenfluramine plus phentermine lost 11.6 +/- 0.8 kg, participants receiving intermittent therapy lost 11.6 +/- 1.3 kg, and participants receiving augmented therapy lost 6.5 +/- 1.5 kg. Although 41% of the participants complained of dry mouth, neither serious adverse effects nor evidence of medication abuse appeared. There were 29 dropouts in the period from weeks 34 to 104. Sixteen of those were related to medication (adverse effects, lack of efficacy, and fear of medication). Overall, fenfluramine plus phentermine used in conjunction with behavior modification, caloric restriction, and exercise continued to be efficacious for up to 2 years.

Adult↗

Dihydrolipoyl dehydrogenase as a source of reactive oxygen species inhibited by caloric restriction and involved in Saccharomyces cerevisiae aging.

Replicative life span in Saccharomyces cerevisiae is increased by glucose (Glc) limitation [calorie restriction (CR)] and by augmented NAD+. Increased survival promoted by CR was attributed previously to the NAD+-dependent histone deacetylase activity of sirtuin family protein Sir2p but not to changes in redox state. Here we show that strains defective in NAD+ synthesis and salvage pathways (pnc1delta, npt1delta, and bna6delta) exhibit decreased oxygen consumption and increased mitochondrial H2O2 release, reversed over time by CR. These null mutant strains also present decreased chronological longevity in a manner rescued by CR. Furthermore, we observed that changes in mitochondrial H2O2 release alter cellular redox state, as attested by measurements of total, oxidized, and reduced glutathione. Surprisingly, our results indicate that matrix-soluble dihydrolipoyl-dehydrogenases are an important source of CR-preventable mitochondrial reactive oxygen species (ROS). Indeed, deletion of the LPD1 gene prevented oxidative stress in npt1delta and bna6delta mutants. Furthermore, pyruvate and alpha-ketoglutarate, substrates for dihydrolipoyl dehydrogenase-containing enzymes, promoted pronounced reactive oxygen release in permeabilized wild-type mitochondria. Altogether, these results substantiate the concept that mitochondrial ROS can be limited by caloric restriction and play an important role in S. cerevisiae senescence. Furthermore, these findings uncover dihydrolipoyl dehydrogenase as an important and novel source of ROS leading to life span limitation.

Base Sequence↗

Effects of caloric restriction and weight loss on glycemic control, insulin release and resistance, and atherosclerotic risk in obese patients with type II diabetes mellitus.

This study was designed to determine: (1) the effectiveness and safety of protein-sparing fast and gastric bypass surgery for achieving weight reduction in obese patients with type II diabetes mellitus (non-insulin-dependent diabetes mellitus); (2) the effects of these interventions on glycemic control; (3) the effects of weight loss on insulin secretion and action; and (4) the effects of treatment on atherosclerotic risk factors. Six patients consumed only a protein supplement (1.4 g/kg ideal body weight) for up to six months until a final weight below 120 percent of ideal body weight was achieved or weight loss ceased. Six patients underwent gastric bypass surgery. Both groups of patients were studied before and after treatment while consuming a balanced weight-maintaining diet. Both protein-sparing fast and gastric bypass surgery were safe and successful in the short term in producing weight loss. Both treatments improved glycemic control. Mean fasting plasma glucose values fell from 287 to 168 mg/dl (p less than 0.01). Mean total glycosylated hemoglobin values declined from 11.9 to 8.2 percent (p less than 0.01) (normal reference interval 5.85 to 8.85 percent). Patients who achieved a final weight below 125 percent of ideal body weight had significantly better post-treatment fasting plasma glucose values (130 versus 196 mg/dl, p less than 0.05) and total glycosylated hemoglobin values (6.8 versus 9.0, p less than 0.02) than those whose weight remained above 125 percent of ideal. In diet-treated patients, improved glycemic control occurred with caloric restriction alone prior to significant weight loss. Improved glycemic control was accompanied by decreased insulin resistance. Mean steady-state plasma glucose values fell from 377 to 208 mg/dl (p less than 0.008), and mean fasting insulin values fell from 31.0 to 17.0 microU/ml (p less than 0.004). Acute-phase insulin release, which was markedly impaired before treatment, did not improve even in patients who had post-treatment fasting plasma glucose values below 130 mg/dl. Significant improvements in atherosclerotic risk factors occurred. Mean high-density lipoprotein cholesterol values increased from 33.8 to 40.5 mg/dl (0.006 less than p less than 0.008), and factor VIII coagulant activity decreased from 194 to 140 percent (p less than 0.005). Serum fibrinogen also decreased (393 to 347 mg/dl, p = 0.08), although the decrease did not reach clinical significance.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

Energy expenditure and physical performance in overweight women: response to training with and without caloric restriction.

The metabolic effects of exercise training and the influence of a moderate calorie restriction on the training response were examined in overweight women. Ten healthy women, 119% to 141% of desirable weight, completed the 14-week study. After a 2-week stabilization period, in which diets were designed to maintain body weight (BW), five women were assigned to a 12-week experimental program of diet and exercise (D + EX) that included a 50% reduction in energy intake and a program of moderate intensity aerobic exercise 6 days per week. The other five women were assigned to the same daily exercise (EX) and continued to consume the stabilization diet. Periodic measurements of resting metabolic rate (RMR), thermic effect of food (TEF), energy cost of exercise, and predicted maximal aerobic capacity (VO2 max) were obtained, and the respiratory quotient (RQ) was determined during rest and exercise. Body composition was monitored weekly. Tests of strength and anaerobic capacity were conducted. D + EX lost an average of approximately 1.1 kg/wk, which was 67% fat, 33% lean. EX lost approximately 0.5 kg/wk, which was 86% fat, 14% lean. In both groups, the exercise program resulted in an 11% to 13% improvement in VO2 max and an 8% to 16% decrease in energy expenditure at submaximal workloads. The caloric restriction significantly increased fat utilization during exercise. The RMR declined 9% in D + EX, from 1,550 to 1,411 kcal/d, whereas it was maintained in EX, 1,608 to 1,626 kcal/d. The decrease in RMR observed in D + EX was consistent with the loss of fat-free mass (FFM).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

Chronic nephropathy in ad libitum overfed Sprague-Dawley rats and its early attenuation by increasing degrees of dietary (caloric) restriction to control growth.

The early development and progression of chronic nephropathy and its amelioration by moderate and marked dietary restriction (DR) was determined in Sprague-Dawley (SD) rats at 20, 33, 60, and 113 weeks of age. Both sexes of SD rats were overfed ad libitum (AL) or DR-fed at 72-79%, 68-72%, or 47-48% of the adult AL intake. The AL-fed rats rapidly developed increased body and kidney size, increased glomerular area (GA) and urinary protein loss, followed by declining creatinine clearance. Early increased kidney growth and glomerular hypertrophy by 20 weeks preceded increases in glomerular sclerotic index (GSI), 7-day BrdU tubular labeling index (TLI), and the lesions associated with chronic nephropathy. The glomerular number (GN) or the number of nephrons did not differ between the groups over the course of the study. Moderate DR (68-79% of AL) prevented the increased kidney size and GA at 20 weeks and delayed increases in GSI and TLI until 60 weeks of age. Marked DR (47-48% of AL) prevented increases in kidney size, GA and TLI at 20 weeks, and GSI at 60 weeks of age. In AL-fed rats, the early increase in GA predicted the early onset of proteinuria and the later decrease in creatinine clearance, and increased GSI, TLI, and mortality from severe nephropathy. The temporal and dose-related effects of increasing degrees of DR demonstrated that while nephron numbers were unchanged with age, the early development of glomerular hypertrophy was the critical morphological biomarker predicting the progression and severity of chronic nephropathy. Caloric restriction by DR prevented or delayed the development of glomerulosclerosis, tubulointerstitial damage, functional changes, morbidity, and mortality associated with chronic nephropathy in AL-overfed SD rats by controlling initial body and kidney growth, glomerular size, and nephron hypertrophy. These results indicate that control of body and renal growth by DR may be essential to prevent the development and progression of glomerulosclerosis in spontaneous nephropathy of laboratory rats.

Aging↗