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J Appl Physiol 99: 1336-1342, 2005. First published June 2, 2005; doi:10.1152/japplphysiol.01380.2004
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Homeostatic responses to caloric restriction: influence of background metabolic rate

S. A. Evans, A. D. Parsons, and J. M. Overton

Department of Biomedical Sciences, Florida State University, Tallahassee, Florida

Submitted 14 December 2004 ; accepted in final form 1 June 2005


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
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 2 wk of 30–40% CR in male FBNF1 rats housed in cool (Ta = 12°C) or thermoneutral (TMN; Ta = 30°C) conditions. Rats were instrumented with telemetry devices and housed continuously in home-cage 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 kcal), oxygen consumption (O2; 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 beats/min). Cool-CR rats exhibited greater CR-induced weight loss (cool = –62 ± 3; TMN = –42 ± 3 g) and reductions in O2 (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 beats/min). CR had no effect on arterial blood pressure or locomotor activity in either group. Unexpectedly, weight maintenance produced significant reductions in O2 and heart rate. At thermoneutrality, a single day of refeeding effectively abolished CR-induced reductions in O2 and heart rate. The results reveal that rats with low or high baseline metabolic rate exhibit comparable compensatory reductions in O2 and heart rate and suggest that Ta can be used to modulate the metabolic background on which the more prolonged effects of CR can be studied.

thermoneutrality; energy homeostasis; heart rate; oxygen consumption; locomotor activity

AT AMBIENT TEMPERATURES (Ta) below the zone of thermoneutrality (~28–32°C), thermoregulation is a major component of energy expenditure in rodents (10). Our laboratory has recently shown that Ta is also a primary determinant of heart rate and arterial blood pressure in both rats and mice (25, 36, 41). In addition to elevating baseline metabolic rate and blood pressure, cool Ta also fundamentally alters the physiological response to caloric restriction (CR) in mice (41). At standard Ta (23°C), CR reduces oxygen consumption (O2) and heart rate; however, we also observed that these mice exhibit torporlike bouts with marked bradycardia and metabolic suppression. These bouts were accompanied by pronounced increases in light-phase locomotor activity and disruption of normal circadian differences in heart rate and blood pressure. Neither torpor nor augmented light-phase locomotor activity was observed when CR was imposed at thermoneutrality (Ta = 30°C), although mice exhibited the expected homeostatic reductions in O2 and heart rate (41). It is currently not known whether Ta also produces fundamental alterations in the physiological responses to CR in rats. The primary purpose of these studies was to determine whether the metabolic, cardiovascular and behavioral responses to short-term CR in rats are influenced by alterations in baseline energy expenditure produced by manipulating Ta.

We hypothesized that the metabolic and cardiovascular adjustments to CR in rats would be diminished in animals studied at thermoneutrality. The hypothesis was based in part on the lack of nonshivering thermogenesis required at thermoneutrality and the prediction that this component of energy expenditure is regulated by CR (6). Because caloric intake is elevated in animals housed at cool Ta, we attempted a priori to design this study so that CR rats housed in cool Ta had energy intakes equivalent to ad libitum rats housed at thermoneutrality. Thus we were also able to examine the metabolic and cardiovascular responses of rats with equivalent caloric intakes but in markedly different states of energy balance.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Male FBNF1 rats (n = 24; age = 5–6 mo; Harlan, Indianapolis, IN) were anesthetized (pentobarbital sodium, 50 mg/kg) and instrumented with a catheter in the descending aorta coupled with a sensor and transmitter (model TA11PA-C40, Data Sciences, St. Paul, MN) for telemetric monitoring of blood pressure and determination of cardiovascular variables as described previously (25). FBNF1 rats are hybrids (derived from a cross between female Fisher 344 and male Brown Norway) that exhibit greater life span than either parental strain as well as reduced incidence of neoplasia and thus are an ideal model for aging research (16, 38). Animals recovered for ~10 days in standard polycarbonate cages containing wood chip bedding maintained on 12:12-h light-dark cycle (lights off at 1100) in rooms controlled at cool (Ta = 12.0 ± 1.0°C) or thermoneutral (TMN; Ta = 30.0 ± 1.0°C) Ta with ad libitum access to powdered chow (Purina 5001; physiological caloric value = 3.3 kcal/g) and deionized water.

Indirect calorimetry and behavioral monitoring.   Measurements of gas exchange and monitoring of animal behavior were performed using previously published approaches (25). Rats were transferred to a standard shoebox cage fitted with a custom-made polycarbonate lid providing a near air-tight seal for continuous determination of oxygen consumption (O2; ml/min) and carbon dioxide production (CO2; ml/min) every 4 min. Respiratory quotient (RQ; CO2/O2) was calculated from these measures. Total energy expenditure was estimated using the Weir equation: energy expenditure = (kcal/min) = 3.91(O2) + 1.1(CO2)/1,000 (31). Our housing conditions do not allow for urine collection and assessment of nitrogen balance during indirect calorimetry. Energy expenditure was estimated separately for the dark phase and the light phase. Gas-exchange data were obtained for 23 h. During the remaining 1 h, the rats were alert and handled (see below); thus the equivalent of an additional 1 h of average dark-phase energy expenditure was added to estimate total daily energy expenditure. Daily energy balance was estimated as the difference between caloric intake and caloric expenditure.

These cage calorimeters were housed inside environmental chambers to provide more precise control of cage Ta (±0.1°C). The shoebox cage was positioned on a custom-designed force platform to obtain quantification of locomotor activity. Feeding behavior was monitored by an infrared photobeam sensor positioned across the entrance to the feeder. Drinking behavior was monitored using a lickometer (28). Food intake, water intake and body weight of each rat were determined during a daily maintenance period that occurred 1 h before the beginning of the dark phase. At this time, daily behavioral, cardiovascular, and metabolic data were compiled and transferred for offline processing.

Protocol.   After recovery from surgery (10 days) and acclimation to the cage calorimeters (4–5 days), baseline data were obtained for all animals during a period of ad libitum access to food and deionized water at Ta = 12°C or 30°C. Rats at each Ta were assigned to either continued ad libitum feeding (Cool-AL, n = 4 and TMN-AL, n = 5) or subjected to 14 days of 30% (Cool-CR, n = 4) or 40% (TMN-CR, n = 5) CR. TMN-AL rats were in positive energy balance and gained weight at the rate of ~1 g/day during the study, whereas Cool-AL rats did not gain weight during the 3-wk protocol. Thus an additional group housed at thermoneutrality (n = 6) was fed only enough calories to maintain baseline body weight (5% CR). All animals were fed once daily at the onset of the dark phase during the daily maintenance period. After 2 wk, CR groups were provided ad libitum food for 4 days during which refeeding patterns and recovery kinetics in cardiovascular and metabolic variables were examined.

Data analysis and statistics.   The final hour of the light phase (during which daily chamber maintenance procedures were performed) was excluded from analysis, resulting in 12-h averages for the dark phase and 11-h averages for the light phase. All results are reported as means ± SE and analyzed using t-test and ANOVA (SPSS 11.0). Tukey's post hoc test was used when appropriate. Significance levels of P < 0.05 were accepted.


   RESULTS
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DISCUSSION
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Caloric intake, body weight, and metabolism.   Rats housed in cool had higher baseline caloric intake and energy expenditure and lower energy balance than rats housed in thermoneutrality (Table 1; Fig. 1, A–D). Because of the difference in energy balance, TMN-AL control rats gained body weight (14 ± 2 g) during the 2-wk treatment period, whereas Cool-AL rats did not gain weight (0 ± 2 g).


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  		Table 1. Baseline variables of FBNF1 rats housed in TMN (30°C) or cool (12°C) Ta

 


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  		Fig. 1. Effects of 2-wk ad libitum feeding (AL; black symbols), caloric restriction (CR; 30–40%; white symbols), or weight maintenance (MT; 5% CR; gray symbols) and refeeding on 24-h caloric intake (A), body weight (B), total energy expenditure (C), and energy balance (D) for FBNF1 rats housed in thermoneutral (TMN; ambient temperature = 30°C; triangles) or cool (Cool; ambient temperature = 12°C; circles) conditions. Values are means ± SE; n, no. of rats. Total energy expenditure was calculated using the Weir equation.

 
Two weeks of CR produced greater body weight reductions (Fig. 1B; P < 0.01) in Cool-CR (–62 ± 3 g) vs. TMN-CR (–41 ± 3 g) rats, due to differences in energy balance status and to the greater reduction in absolute calorie intake in Cool-CR rats (Cool-CR: –24 kcal; TMN-CR: –21 kcal). Similarly, CR reduced energy expenditure to a greater extent in cool compared with thermoneutrality (Fig. 1C). Energy balance was transiently reduced due to CR in both Cool-CR and TMN-CR groups during the first week, but it was not significantly different from control by the end of the restriction period (Fig. 1D).

After 2 wk of CR in cool or thermoneutrality, ad libitum access to food resulted in refeeding hyperphagia (Fig. 1A) that was sustained 3–4 days, while mild CR used for weight maintenance in the thermoneutrality condition was associated with only a single day of hyperphagia. Interestingly, refeeding hyperphagia was associated with prompt increases in energy expenditure in both CR groups (Fig. 1C), although energy expenditure remained below ad libitum controls during refeeding in the Cool-CR group.

Cardiovascular variables.   At baseline, cool Ta was associated with 25-mmHg greater mean arterial pressure (Table 1, Fig. 2, A and B), 10-mmHg greater pulse pressure (Table 1), 100 beats/min greater heart rate (Table 1; Fig. 2, C and D), and reduced heart rate variability as determined by the standard deviation of the interbeat interval (SDIBI; Table 1; Fig. 2, E and F; all P < 0.01). During the 3 wk of study, arterial pressure was stable in all Cool and TMN groups (Fig. 2, A and B). Heart rate was also stable in TMN-AL rats, but it decreased over time in Cool-AL rats during both dark (–19 ± 2; P = 0.02; Fig. 2C) and light phases (–19 ± 7; not significant; Fig. 2D).



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  		Fig. 2. Effects of 2-wk AL (black symbols), CR (30–40%; white symbols), or MT (5% CR; gray symbols) and refeeding on dark- and light-phase mean arterial pressure (MAP; A and B), heart rate (HR; C and D), and standard deviation of interbeat interval (SDIBI; E and F) for FBNF1 rats housed in TMN (ambient temperature = 30°C; triangles) or Cool (ambient temperature = 12°C; circles) conditions. Values are means ± SE; n, no. of rats.

 
CR had no effect on blood pressure, but reduced heart rate (TMN-CR: dark = –45 ± 3, light = –49 ± 6; Cool-CR: dark = –40 ± 7, light= 59 ± 1 beats/min; Fig. 2, C and D; all P < 0.01) and increased light-phase heart rate variability (Cool-CR: 4.4 ± 0.9; TMN-CR: 1.5 ± 0.5 ms; Fig. 2F; both P < 0.05). Unexpectedly, rats assigned to weight maintenance exhibited substantial light-phase bradycardia (–25 ± 2 beats/min; Fig. 2D; P < 0.01). Unlike the response to CR in rats housed at thermoneutrality, this bradycardia was not evident in the dark phase, nor was it accompanied by an increase in variability.

Refeeding resulted in prompt normalization of heart rate and heart rate variability. By the second day of refeeding, CR-induced reductions in light-phase heart rate (Fig. 2D) and increases in variability (Fig. 2F) were completely absent.

Metabolic variables and locomotor activity.   Cool Ta produced a nearly twofold elevation in O2 compared with thermoneutral conditions (Table 1; Fig. 3, A and B). Similar to heart rate, O2 of Cool-AL rats decreased during the 2-wk protocol (Fig. 3, A and B; P < 0.05). CR produced sustained reductions in O2 (TMN-CR: dark = –1.67 ± 0.20, light = –1.32 ± 0.13; Cool-CR: dark = –2.90 ± 0.14; light = –2.62 ± 0.05 ml/min; Fig. 3, A and B; all P < 0.01). Surprisingly, weight maintenance produced significant reductions in light phase O2 (Fig. 3B; –0.47 ± 0.11 ml/min; P < 0.01). These reductions remained significant when O2 was normalized for estimated metabolic mass (data not shown). In both cool and thermoneutrality, CR reduced light-phase RQ (Fig. 3F). As CR continued, light-phase RQ gradually increased toward baseline. After 2 wk of CR, light-phase RQ was still significantly reduced in the Cool-CR group (P < 0.01), but reductions were no longer significant in the TMN group (P = 0.20). Surprisingly, weight maintenance, which had no effect on RQ, produced reductions in absolute (P < 0.01) and normalized O2 (P < 0.01). CR had no effect on home cage locomotor activity (Fig. 3, C and D).



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  		Fig. 3. Effects of 2-wk AL (black symbols), CR (30–40%; white symbols), or MT (5% CR; gray symbols) and refeeding on dark- and light-phase oxygen consumption (O2; A and B), locomotor activity (C and D), and respiratory quotient (RQ; E and F) for FBNF1 rats housed in TMN (ambient temperature = 30°C; triangles) or Cool (ambient temperature = 12°C; circles) conditions. Values are means ± SE; n, no. of rats. CO2, carbon dioxide production.

 
Both Ta and circadian phase clearly modulated the influence of refeeding on O2. In rats housed in cool, dark-phase O2 remained significantly reduced for the 4 days, whereas in the light-phase recovery was evident within 3 days. In rats housed in thermoneutrality, the recovery in O2 was also delayed in the dark phase, but it was prompt and evident after only 1 day of refeeding in the light phase. In both Ta, refeeding was associated with an elevation in RQ that is probably indicative of lipogenesis.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Several key findings emerge from these studies. As expected, rats housed in cool Ta exhibited increased O2, food intake, heart rate, and blood pressure compared with rats housed at thermoneutrality. Nonetheless, 2 wk of CR produced substantial reductions in heart rate and O2, with minimal effects on blood pressure and locomotor activity, in rats housed in either cool or thermoneutral Ta. We found that CR implemented with once daily feeding at the onset of the dark phase produced reductions in heart rate and RQ, and increases in heart rate variability, that were much more prominent during the light phase. In addition, we observed that very mild CR, which does not cause weight loss or a reduction in RQ, is associated with reduced O2 and heart rate in FBNF1 rats. Importantly, it is clear that many of the metabolic and cardiovascular responses to 2 wk of CR are promptly negated on refeeding. The observations support recent reports suggesting that there is additional need for careful evaluation of the biological responses to CR over the entire life span (24). Our study design produced two groups of rats with equivalent caloric intake but with markedly different heart rate and O2. Rats housed at thermoneutrality and fed ad libitum have lower heart rate and O2 than rats housed in cool and treated with CR. This paradigm may be a unique strategy to determine the respective components of negative energy homeostasis and metabolic rate in the life span extension produced by CR.

CR elicits a wide array of homeostatic, physiological responses, including reduced body temperature (15, 27), altered neuroendocrine function (24), increased appetite (43), reduced sympathetic activity to the heart and brown adipose tissue (44), and decreased heart rate and blood pressure (12, 41, 42). Interestingly, we did not observe CR-induced reductions in blood pressure in rats housed in either cool or thermoneutral conditions in this study. Blood pressure remained at control levels despite markedly decreased heart rate in both CR groups. Both resting heart rate and blood pressure are highly correlated with metabolic rate in ad libitum-fed rodents (36). Thus increasing Ta from standard conditions (22–23°C) to thermoneutrality is generally associated with a reduction in heart rate of 50 beats/min and a reduction in MAP of 10 mmHg. It is intriguing that CR reduced metabolic rate and heart rate, yet has minimal effect on blood pressure. Indeed, CR tended to increase blood pressure in the Cool group (~5 mmHg) in the dark phase. The data suggest fundamental differences in blood pressure regulation during reductions in metabolic rate produced by caloric or thermoregulatory mechanisms, as well as a complex interaction. Clearly, measures of total and regional (particularly tail) conductances would help to clarify these observations.

The bradycardia of CR is accompanied by greater heart rate variability, as measured by SDIBI, particularly in the light phase. It should be noted that this is not simply an indication of lower heart rate. Note that, in the light-phase, TMN-AL rats have lower heart rate, but less heart rate variability than Cool-CR rats (Fig. 2, D and F). CR-induced bradycardia is not likely to be explained only by reductions in sympathetic activity. Mice lacking dopamine {beta}-hydroxylase (37), mice treated with atenolol (40), and mice lacking all {beta}-receptors (T. D. Williams, A. D. Parsons, and J. M. Overton, unpublished results) exhibit CR-induced bradycardia. Increased vagal tone and/or reductions in intrinsic heart rate are likely to contribute to CR-induced bradycardia and increases in heart rate variability.

Exposure to cold elevates caloric intake in rodents (23), but depending on the severity of cold, it may not elevate it to levels needed to maintain growth and development of obesity observed in rats housed at standard temperatures (13). To control for the reduced growth in rats housed in cool temperatures in this study, we included a very mild (5%) CR group in thermoneutrality that was designed to produce weight maintenance. Interestingly, mild CR of this level is now sometimes used to produce a nonobese control group for studies of long-term CR (4). Unexpectedly, this group of rats exhibited reductions in O2 and heart rate that represent nearly 50% of the total response observed with more severe CR. This occurs without any reduction in RQ indicative of lipolysis and without an increase in heart rate variability, which we consistently observe with more severe CR. The findings suggest that mechanisms involved in energy homeostasis are engaged in growing rats when caloric intake is even slightly reduced. Additional studies are required to determine whether differential signaling mechanisms contribute to the physiological responses to this very mild CR.

An additional unique feature of this work was the examination of the restoration of physiological responses when CR rats were allowed ad libitum access to food. In general, we observed that CR rats exhibited sustained hyperphagia for the 4 days of recovery studied; thus signals presumably associated with restoration of adipose mass (or lean mass) clearly activate mechanisms involved in appetite regulation. The hyperphagia was associated with elevations of light-phase RQ (Fig. 3F), suggesting lipogenesis as well as a shift in substrate utilization (reduced lipolysis and increased carbohydrate oxidation). Interestingly, we observed that FBNF1 rats housed at thermoneutrality exhibited prompt normalization of O2, heart rate, and heart rate variability with refeeding. This is somewhat surprising because Sprague-Dawley rats have been shown to demonstrate a long-lasting suppression of energy expenditure after short-term CR (3, 7). However, our laboratory has recently reported that Long-Evans rats also exhibit sustained hyperphagia and prompt recovery of heart rate and O2 after 2 wk of CR (8). Thus it appears that the physiological responses to refeeding after CR are strain dependent. Indeed, it is now clear that even the life span extension effects of CR in mice are also strain dependent (9). These strain differences may provide experimental models that increase understanding of key mechanisms responsible for regulation of energy homeostasis.

It is generally well established that short-term CR produces compensatory, homeostatic reduction in metabolic rate; thus the observed reductions in this study were expected. Nonetheless, there is no consensus regarding whether this adaptive response is sustained and contributes to the life span extending effects of CR (26, 33). Although there is some evidence that longer term CR does not reduce metabolic rate in rodents (21, 22, 30), other reports have suggested that compensatory reductions in metabolism are evident after 6 mo of CR (1, 5, 18, 19). The issue is complicated by the fact that levels of CR used to increase life span (30–40%) reduce both fat and lean mass in rodents. Not surprisingly, reduction in light-phase RQ, indicative of lipolysis is clearly evident during CR in rats housed in both cool and thermoneutral temperatures. The reductions in RQ were to a similar level, suggesting that the background Ta did not markedly alter the pattern of lean and fat mass mobilization during CR. Animals were fed once daily, at the onset of the dark phase. They consume these calories during the dark phase, and they exhibit a greater reliance on fat stores (and probably lean tissue) during the light phase. In addition to skeletal muscle, the reduction in lean mass also clearly includes metabolically active organs, including liver, kidney, and even the heart (11). A limitation to the current studies is that nitrogen excretion was not monitored and used to calculate total energy expenditure. Because the caloric equivalent per liter of oxygen is lower for protein than lipid or carbohydrate (31), it is possible that we have overestimated energy expenditure in groups undergoing CR in these studies.

An important analysis of the effect of long-term CR on energy expenditure, using statistical methods that appropriately correct for lean body mass, suggests that CR-induced reduction in metabolic rate in primates and rodents may indeed be evident when CR is sustained (2). It is irrefutable that body composition must be known and appropriate statistical methods applied to appropriately compare energy expenditure after periods of CR. These approaches were not taken in this study because of our interest in examination of the refeeding response after short-term CR.

The findings from this work may have relevance to the understanding the mechanisms by which CR extends life span. The mechanisms by which CR extends life span remain poorly understood (14, 17, 24, 26, 33). Various lines of evidence support hypotheses related to reduced energy expenditure, reduced oxidative stress, reduced body fat, and engagement of negative energy homeostasis (20, 24, 26, 32, 39). The question of whether lifetime energy expenditure determines intraspecies life span is an important and perplexing issue (33–35). Clearly, variations in Ta provide a mechanism to vary metabolic rate and oxidative stress (29). If the reductions in energy expenditure and oxidative stress produced by CR are sustained in cold-exposed rats, it appears that a direct comparison to rats housed at thermoneutrality may provide an intriguing test of the relative roles of the neuroendocrine adaptations associated with negative energy homeostasis compared with those of metabolic rate and oxidative stress. In this study, rats housed in cool Ta and treated with CR exhibit higher O2 and heart rate than ad libitum-fed rats housed at thermoneutrality even though they are consuming the same number of calories. The paradigm may provide a very intriguing approach to further examine the "rate of living" theory.


   GRANTS
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 ABSTRACT
 METHODS
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 DISCUSSION
 GRANTS
ACKNOWLEDGMENTS
 REFERENCES
 
This work was supported by National Institute on Aging Grant AG-023837 and a Program Enhancement Grant from the FSU Research Foundation.


   ACKNOWLEDGMENTS
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REFERENCES
 
We gratefully acknowledge the technical assistance of the Florida State University (FSU) Neuroscience Program's instrumentation (Ron Thompson and Paul Hendricks) and computer programming (Chris Baker and Ross Henderson) groups.


   FOOTNOTES
 

Address for reprint requests and other correspondence: J. M. Overton, Dept. of Biomedical Sciences and Program in Neuroscience, College of Medicine, 236 Biomedical Research Facility, Florida State Univ., Tallahassee, FL 32306-4340 (e-mail: moverton{at}mailer.fsu.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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B. A. Rikke and T. E. Johnson
Physiological genetics of dietary restriction: uncoupling the body temperature and body weight responses
Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2007; 293(4): R1522 - R1527.
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