The biological responses to caloric restriction (CR) are generally examined in rats with elevated metabolic rates due to being housed at ambient temperatures (Ta) below the zone of thermoneutrality. We determined the physiological and behavioral responses to two weeks of 30-40% CR in male FBNF1 rats housed in cool (Ta=12 degrees C) or thermoneutral (TMN; Ta=30 degrees C) conditions. Rats were instrumented with telemetry devices and housed continuously in homecage calorimeters for the entire experiment. At baseline, rats housed in cool Ta had reduced rate of weight gain, thus a mild CR (5%) group at thermoneutrality for weight maintenance was also studied. Rats housed in cool Ta exhibited elevated caloric intake (cool= 77+/-1; TMN= 54+/-2 kcals), oxygen consumption (VO2; cool= 9.9+/-0.1; TMN=5.5+/-0.1 ml/min), mean arterial pressure (cool= 103+/-1; TMN= 80+/-2 mmHg), and heart rate (cool=374+/-3; TMN= 275+/-4 bpm). Cool-CR rats exhibited greater CR-induced weight loss (cool= -62+/-3; TMN= -42+/-3 g) and reductions in VO2 (cool= -2.6+/-0.1; TMN= -1.5+/-0.1 ml/min), but similar CR-induced reductions in heart rate (cool= -59+/-1; TMN= -51+/-7 bpm). CR had no effect on arterial blood pressure or locomotor activity in either group. Unexpectedly, weight maintenance produced significant reductions in VO2 and heart rate. At thermoneutrality , a single day of refeeding effectively abolished CRinduced reductions in VO2 and heart rate. The results reveal that rats with low or high baseline metabolic rate exhibit comparable compensatory reductions in VO2 and heart rate and suggest that Ta can be used to modulate the metabolic background upon which the more prolonged effects of CR can be studied.

The effects of prolonged caloric restriction on protein kinetics in lean subjects has not been previously investigated. PURPOSE: To test the hypotheses that 21 days of caloric restriction (CR) in lean subjects would a) result in significant losses of lean mass despite a suppression in leucine turnover and oxidation, and b) negatively impact exercise performance. METHODS: Nine young, normal weight men (23+/-5 y, 78.6+/-5.7 kg, VO2peak: 45.2+/-7.3 ml(.)kg(-1)(.)min(-1),mean+/-SD) were underfed by 40% of the calories required to maintain body weight (BW) for 21 days and lost 3.8+/-0.3 kg BW and 2.0+/-0.4 kg lean mass. Protein intake was kept at 1.2 g(.)kg(-1)(.)day(-1). Leucine kinetics were measured using KIC reciprocal pool model in the post-absorptive state during rest and 50 minutes of exercise (EX) at 50% of VO2peak. Body composition, basal metabolic rate (BMR) and exercise performance were measured throughout the intervention. RESULTS: At rest, leucine flux (~131 micromol(.)kg(-1)(.)hr(-1)) and oxidation (Rox; ~19 micromol(.)kg(-1)(.)hr(-1)) did not differ pre- and post- CR. During EX, leucine flux (129+/-6 vs. 121+/-6) and Rox (54+/-6 vs. 46+/-8)were lower following CR than pre-CR. Nitrogen balance was negative throughout the intervention (~3.0gN(.)d(-1)) and BMR declined from 1898+/-262 kcal(.)d(-1) to 1670+/-203. Aerobic performance (VO2peak, endurance cycling) was not impacted by CR, but arm flexion endurance decreased by 20%. CONCLUSIONS: Three weeks of caloric restriction reduced leucine flux and oxidation during exercise in normal weight young men. However, despite negative nitrogen balance and loss of lean mass, whole body exercise performance was well maintained in response to CR.

Calorie restriction (CR) is the only experimental manipulation that is known to extend the lifespan of a number of organisms including yeast, worms, flies, rodents and perhaps non-human primates. In addition, CR has been shown to reduce the incidence of age-related disorders (for example, diabetes, cancer and cardiovascular disorders) in mammals. The mechanisms through which this occurs have been unclear. CR induces metabolic changes, improves insulin sensitivity and alters neuroendocrine function in animals. In this review, we summarize recent findings that are beginning to clarify the mechanisms by which CR results in longevity and robust health, which might open new avenues of therapy for diseases of ageing.

To investigate whether the _expression of uncoupling proteins (UCP2 and UCP3) was affected by a very low calorie diet (VLCD) and growth hormone (GH) treatment for 4 weeks. DESIGN: A randomized, placebo-controlled intervention study of VLCD with or without concomitant GH-treatment. SUBJECTS: Seventeen obese women (body mass index, BMI=42.1+/-1.4 kg/m2 (range 31.8-54.5 kg/m2)) treated with VLCD for 4 weeks and randomized to concomitant placebo treatment (n=9) or GH treatment (n=8). MEASUREMENTS: Fat mass and lean body mass were measured by dual-energy X-ray absorptiometry. Energy expenditure (EE) was measured by indirect calorimetry. UCP2 and UCP3 mRNA were measured in adipose tissue and skeletal muscle biopsies before VLCD and after VLCD+/-GH-treatment by reverse transcription polymerase chain reaction (RT-PCR). RESULTS: VLCD treatment resulted in a mean weight loss of 5.23 kg+/-0.8 (P<0.01), a 4.1% decrease in EE (P<0.05) and a 24% decrease in UCP3 mRNA in adipose tissue (P<0.03), whereas adipose tissue UCP2 mRNA and skeletal muscle UCP2 and UCP3 mRNA levels were unchanged. GH-treatment had no effects on EE, changes in body weight or UCP mRNA level. In multiple regression analysis the change in EE caused by VLCD was significantly correlated with changes in adipose tissue UCP2 mRNA (r=0.66, P<0.02) and a tendency towards a significant association with the change in adipose tissue UCP3 mRNA (r=0.45, P=0.09), but not with change in body weight, skeletal muscle UCP2 or UCP3 mRNA levels. CONCLUSION: VLCD for 4 weeks decreased UCP3 mRNA _expression in human adipose tissue, whereas GH-treatment had no effect on UCP _expression. Multiple regression analysis demonstrated that changes in adipose tissue UCP2 and probably UCP3 mRNA were correlated with the change in EE. These findings indicate that UCPs in adipose tissue in very obese individuals might play a role for the reduction in EE observed during energy restriction.

Uncoupling protein-2 (UCP2) is a mitochondrial protein expressed in a wide range of human tissues. By uncoupling respiration from ATP synthesis, UCP2 might be involved in the control of energy expenditure. We have investigated UCP2 gene _expression in human adipose tissue. In eight subjects, we found a positive correlation (r = 0.91, P < 0.002) between subcutaneous and visceral fat depots UCP2 messenger RNA (mRNA) levels, suggesting that UCP2 mRNA level in subcutaneous adipose tissue is a good index of UCP2 gene _expression in whole body adipose tissues. The effect of a 25-day very-low-calorie diet un UCP2 mRNA level and resting metabolic rate was investigated in eight obese premenopausal women. There was no difference in UCP2 mRNA levels before and during the diet. After 25 days of hypocaloric diet, a positive correlation was found between adipose tissue UCP2 mRNA level and resting metabolic rate adjusted for lean body mass (r = 0.82, P < 0.01). These results show that very-low-calorie diet, unlike short-term fasting, is not associated with an induction in UCP2 mRNA _expression, and that adipose tissue UCP2 mRNA levels may be related to variations in resting energy expenditure in humans.