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Am J Physiol Regul Integr Comp Physiol 283: R1198-R1209, 2002. First published August 1, 2002; doi:10.1152/ajpregu.00525.2001
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Vol. 283, Issue 5, R1198-R1209, November 2002

Effects of rearing temperature on sympathoadrenal activity in young adult rats

James B. Young, Jeffrey Weiss, and Nadine Boufath

Department of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Animals reared at 18°C exhibit enhanced innervation of brown adipose tissue (BAT) and greater cold tolerance as adults, yet gain more weight when fed an enriched diet compared with rats reared at 30°C. To explore this paradox, sympathoadrenal activity was examined using techniques of [3H]norepinephrine ([3H]NE) turnover and urinary catecholamine excretion in male and female rats reared until 2 mo of age at 18 or 30°C. Gene expression in BAT was also analyzed for several sympathetically related proteins. Although [3H]NE turnover in heart did not differ between groups, [3H]NE turnover in BAT was consistently elevated in the 18°C-reared animals, even 2 mo after removal from the cool environment. Gene expression for uncoupling proteins 1 and 3, GLUT-4, leptin, and the alpha 1A-adrenergic receptor was more abundant in BAT and the increase in epinephrine excretion with fasting suppressed in 18°C-reared animals. These studies demonstrate that obesity consequent to exposure to 18°C in early life occurs despite tonic elevation of sympathetic input to BAT. Diminished adrenal epinephrine responsiveness to fasting may play a contributory role.

adrenal medulla; brown fat; epinephrine; norepinephrine; sympathetic nervous system


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

DEVELOPMENT OF THE MAMMALIAN nervous system continues well after birth. As a result, sensory experience exerts a formative influence over the maturation of numerous components of the nervous system, including visual and auditory pathways (20, 28, 45) and the somatosensory and olfactory systems (5, 49) among others. Central nervous system regions governing thermoregulation are also susceptible to environmental influences during development. Rearing at lower environmental temperatures improves an animal's tolerance on subsequent exposure to cold (8, 18, 22) and, conversely, rearing at elevated temperatures increases later tolerance to heat (19, 21). These effects of early temperature exposures have been noted in humans as well as in experimental animals (12, 15).

Development of the peripheral sympathetic nervous system (SNS) also appears sensitive to environmental temperature during early life. The sweating response in humans, which is regulated by sympathetic nerves of cholinergic phenotype, is influenced by heat exposure during infancy (12). Adults raised in a hot, humid environment during the first 2 years of life activate a greater number of sweat glands on exposure to heat, a response probably secondary to enhanced innervation of the sweat glands themselves (12). The temperature threshold for initiation of the sweating response is also raised, however (12). Early exposure to cold, on the other hand, fosters development of sympathetic innervation in interscapular brown adipose tissue (IBAT) in animals. Rats raised at 16-18°C display increased norepinephrine (NE) content in IBAT before weaning compared with that in pups housed at 28-30°C, an increase that is associated with a greater number of postganglionic sympathetic fibers innervating IBAT (1, 30). Consequently, early temperature exposure may augment development of that portion of the SNS most responsible for defending body temperature against subsequent exposure to the same temperature conditions.

Despite evidence of improved cold tolerance and enhanced sympathetic innervation in BAT of rats reared at 18°C, male and female rats reared at 18°C are fatter than 30°C-reared controls and exhibit a predisposition to gain weight and accumulate fat when fed an enriched diet (58). The common occurrence of increased body fat in mammals living in polar regions or in other areas exposed to winter cold may represent similar physiology in free-living animals. Data from human studies are also consistent with a role for exposure to cool temperatures during early life on body fatness and obesity in adulthood (34, 40, 58). Because the view is widespread that obesity arises, in part, from diminished energy expenditure secondary to a deficit in sympathetically mediated thermogenesis due either to low SNS activity or to depressed expression of beta 3-adrenergic receptors (beta 3-AR) (3, 7), the current studies were undertaken to explore this apparent paradox of a predisposition to obesity in animals with an enhanced capacity for sympathetic stimulation of BAT, the principal heat-producing tissue in rodents. Studies were carried out in both male and female rats to determine if the effects of early temperature exposure were similar in both sexes. The findings indicate that the predilection to fat accretion in animals reared at 18°C in early life occurs despite tonic elevation of sympathetic outflow to BAT in both male and female rats and increased expression of beta 3-AR in female animals.


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Animals. One-day-old male or female CD rats with multiparous foster mothers were obtained from Charles River Breeding Laboratories (Wilmington, MA). On the day of arrival, litters were standardized at 10 pups each. Cages containing individual mothers and litters were then placed into one of two temperature-controlled chambers set at 18 and 30°C (±0.2°C). Both chambers (model 66NL, Percival Scientific, Boone, IA; 66 ft3 internal volume) were equipped with double glass doors so that illumination was provided by room lighting. Pups were weaned at 21 days and housed three per cage, except as noted. Pups remained in the chambers until 60 days of age, at which time they were housed at a common room temperature (21 ± 2°C with a light-dark cycle of 14:10 h). Animals were studied no earlier than 18 days after removal from the chambers. Animals used in this study were maintained in accordance with the guidelines and approval of the Animal Care and Use Committee of the Feinberg School of Medicine of Northwestern University and in accord with the APS "Guiding Principles in the Care and Use of Animals."

Feeding protocol. Unless otherwise specified, animals were provided free access to water and standard laboratory chow (NIH-07 Open Formula Mouse/Rat Diet, Harlan Teklad, Madison, WI). In the sucrose feeding studies, animals received either chow or chow supplemented with 10% sucrose (wt/vol) to drink. Sucrose feeding commenced 7 days before the start of the turnover study and continued throughout the turnover measurement. Bottles containing sucrose were replaced daily.

[3H]NE turnover procedure. L-[Ring-2,5,6-3H]NE (40-60 Ci/mmol sp act; DuPont-NEN Research Products, Boston, MA) was diluted with 0.9% NaCl and injected intravenously into the tail veins of unanesthetized animals in a total volume of 1.0 ml, beginning at ~9:00 AM. The dose of [3H]NE used in the current studies was 30-45 µCi/kg (~0.12-0.18 µg NE/kg). The rats were killed at preselected times by CO2 inhalation. For each time point in the NE turnover studies, four to six animals were killed from each experimental group. The tissues were rapidly removed, frozen on dry ice, and stored at -20°C for later processing (usually within 2 wk).

Extraction and analysis of tissue catecholamines. For NE analysis, the organs were weighed and homogenized in iced 0.2 N perchloric acid in a Polytron homogenizer (Brinkmann Instruments, Westbury, NY) to extract the catecholamines. After addition of the internal standard 3,4-dihydroxybenzylamine (DHBA; Sigma, St Louis, MO), catecholamines were isolated from the perchloric acid extract by adsorption onto alumina (Woelm neutral, ICN Nutritional Biochemicals) in the presence of 2 M Tris buffer (pH 8.7; Sigma) containing 2% EDTA. Catecholamines were eluted from the alumina with 0.2 N perchloric acid. Aliquots of the alumina eluate were injected onto a liquid chromatographic system for catecholamine analysis following the method of Eriksson and Persson (14) with slight modification. Unless otherwise specified, all chemicals were obtained from Fisher Scientific, Fair Lawn, NJ. Aliquots of the alumina eluates were counted for [3H]NE by scintillation spectrometry in a Packard Tri-Carb 2100TR liquid scintillation analyzer (Packard Instrument, Meriden, CT). Efficiency for 3H is >= 58% in this system.

Urine collection. Collections began 1 wk after the animals were transferred to individual metabolism cages; baseline and fasting collections occurred over 3 consecutive days, although the two periods were separated by an interval of 4 days. Urine was collected daily under light mineral oil in the presence of 0.5-2.0 ml 2 N HCl and 40 mg sodium metabisulfite. The internal standard, DHBA (Sigma), was added to the entire urine sample before processing and the pH adjusted to between 2 and 3, if necessary, before storage at -20°C. Samples were subsequently analyzed within 2-4 wk.

Determination of catecholamines in urine. Analysis of catecholamines in urine followed the method of Smedes et al. (43) as modified by Macdonald and Lake (25). The pH of the samples was adjusted to 7.5 and this mixture was then added to 30-50 mg of Analytichem Bondesil SCX (Varian Associates, Sunnyvale, CA), previously activated by exposure to 1 ml of 0.2 M NaH2PO4, pH 7.5, and mixed vigorously. After removal of the supernatant, the SCX was washed twice with water. Catecholamines were eluted with 1 ml of 1 M NaH2PO4, pH 2.9. This supernatant was transferred quantitatively into screw-topped glass tubes. Approximately 1.0 ml of NH4Cl/NH4OH buffer containing 0.2% (wt/vol) diphenylboric acid ethanolamine complex (Aldrich Chemical, Milwaukee, WI) and 0.5% EDTA, 2.0 ml 2 M (NH4)2HPO4, pH 9.0, and ~150 µl 5 N NaOH were added to bring pH to 8.6. After addition of 2.5 ml of n-heptane containing 1% (vol/vol) octanol and 0.35% (wt/vol) tetraoctylammonium bromide (Fluka AG, Buchs, Switzerland), tubes were capped and shaken. The heptane supernatant was then transferred to a centrifuge tube and 1 ml octanol and 0.2 ml of 0.4 N acetic acid containing 10-15 mg glutathione were added. After being mixed and centrifuged, aliquots of the acetic acid phase were injected onto a chromatographic system for quantitation of catecholamines. In the urine assays presented here, intra-assay coefficients of variation were 2-3% and interassay coefficients of variation were 2-4% for epinephrine (Epi) and NE.

RT-PCR. mRNA levels were quantitated using the Applied Biosystems Taqman system (PE; Norwalk, CT). This method uses a double-labeled oligonucleotide probe (fluorescent dye/quenching molecule) that anneals between the PCR primers. Fluorescence occurs only after digestion by the polymerase during the extension phase of each PCR cycle. Emitted fluorescence is detected using the Sequence Detector 7700 instrument. Analysis is performed using the Sequence Detector software. The manufacturer's protocol was followed with the exception that the concentration of certain reagents was adjusted as follows: each reaction tube contained 0.25 µg total RNA, 2.5 µl Taqman Buffer A (10×), 2 µl dNTP mix (2.5 mM dATP, 2.5 mM dCTP, 2.5 mM dGTP, 5 mM dUTP), 0.375 µl each forward and reverse primers (20 µM), 4 µl MgCl2 (25 mM), 0.025 µl probe (100 µM), 0.25 µl murine leukemia virus RT (50 U/µl), and 0.25 µl Amplitaq Gold (5 U/µl) in a total volume of 25 µl. Values in parentheses indicate stock, not final, concentrations. RNA samples were prepared by tissue extraction with guanidine thiocyanate, purified using CsCl2 centrifugation, and treated with DNase before assay to destroy any contaminating genomic DNA. Each RNA sample was assayed in triplicate; a fourth tube per sample containing no RT was included as a control for contaminating genomic DNA. One tube per assay contained water in place of RNA as a control for RNA or DNA contamination of the solutions. The temperature profile was 30 min at 42°C, 10 min at 95°C, 15 s at 95°C/1 min at 60°C for 40 cycles, 5 min at 23°C. All equipment and reagents were from PE. Primers and probes used in the RT-PCR assays are presented in Table 1 (2, 6, 9, 16, 23, 24, 26, 31). In this assay, the number of cycles to reach a given threshold value is inversely related to the initial abundance of a specific mRNA at the start of the reaction. Tissues for analysis of mRNA were stored at -80°C before assay.

                              
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  		Table 1.   Primers and probes used in RT-PCR assays

Data analysis. Data are displayed as means ± SE. Statistical ANOVA and analysis of covariance (ANCOVA) were performed using Data Desk 6.1 statistical software (Data Description, Ithaca, NY) (48). Post hoc pair-wise comparisons after ANOVA used Scheffé's test. Analyses employed P < 0.05 as the criterion for statistical significance; P values between 0.05 and 0.1 are provided in text and tables, whereas P values >= 0.1 are indicated by NS (not significant).

In studies of NE turnover, the data were plotted semilogarithmically. The method of least squares was used to calculate the slope (k) of decline in NE specific activity over time after tracer injection (32). In all measurements of [3H]NE turnover, no significant variation in endogenous NE was observed over the 24 h of the experiment. The statistical significance of each computed regression line was assessed by ANOVA, and ANCOVA was used in comparison of fractional turnover rates. In the studies comparing sucrose-induced changes in [3H]NE turnover between animals reared at different environmental temperatures, indicator variables were used for rearing temperature (Trear) and diet and the slopes of the regression lines analyzed in a 2 × 2 ANCOVA model (33). Goodness-of-fit for each regression line was evaluated by examination of externally studentized residuals. NE turnover rates were calculated as the product of the fractional turnover rate and the endogenous NE concentration (4) and confidence intervals computed as previously described (44).


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Effects of Trear on [3H]NE turnover. Although sympathetic innervation in IBAT is increased in rats reared at 16-18°C (1, 30), levels of NE themselves provide little information about the activity of sympathetic nerves within the tissue. Consequently, the impact of Trear on [3H]NE turnover was compared on separate occasions in male and female rats. The results of these comparisons of cardiac and IBAT [3H]NE turnover in 18°C- and 30°C-reared rats are presented in Table 2 (male rats) and in Table 3 (female rats). Although the studies were performed after 2 mo of housing both groups at a common room temperature, NE levels in IBAT remained markedly elevated in 18°C-reared male and female rats, whereas cardiac NE was increased (as ng/heart) only in 18°C-reared male animals. In male rats (Table 2), fractional NE turnover rates were slightly, although not significantly, greater in the 30°C- than in 18°C-reared rats in heart and IBAT. Total NE turnover rates were greater in IBAT of 18°C-reared rats, but did not differ between groups in heart. In female rats (Table 3) fractional NE turnover rates were slightly lower in 30°C- than in 18°C-reared animals in heart and IBAT. Due to reciprocal changes in fractional NE turnover and in tissue NE content, differences in cardiac [3H]NE turnover in the two rearing groups were minimal. In IBAT, however, higher tissue NE levels led to substantial increases in total [3H]NE turnover rates in the 18°C-reared animals. Thus, although living at room temperature and consuming a lab chow diet ad libitum, animals reared at 18°C exhibit a selective increase in [3H]NE turnover in IBAT consequent to the marked increase in tissue NE in contrast to that seen in rats reared at 30°C.

                              
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  		Table 2.   Effect of Trear on [3H]NE turnover in 120-day-old male rats


                              
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  		Table 3.   Effect of Trear on [3H]NE turnover in 121-day-old female rats

Effects of Trear on sucrose-induced stimulation of tissue [3H]NE turnover in male rats. Inasmuch as 18°C-reared rats gained more weight when fed a sucrose-enriched diet than 30°C-reared animals and because dietary sucrose is a known stimulant of sympathetic activity in peripheral tissues (53, 54, 57), comparisons of [3H]NE turnover were carried out to assess the impact of Trear on dietary stimulation of sympathetic activity. Both groups of animals were studied at 80 days of age, 20 days after removal from the temperature-controlled chambers. Animals reared at both temperatures were divided into two subgroups of equivalent body weight; both subgroups ate lab chow, but one also received 10% sucrose to drink for 7 days before and during the turnover study.

The results for male rats are presented in Fig. 1 and Table 4. In both 18°C- and 30°C-reared rats, sucrose feeding increased cardiac and IBAT [3H]NE turnover. In heart, the acceleration in [3H]NE turnover with sucrose feeding was less in the 18°C-reared rats than in the 30°C-reared animals. Fractional NE turnover increased from 6.2 ± 0.6 to 7.7 ± 0.5%/h (P < 0.05) in rats reared at 18°C, and from 4.1 ± 0.4 to 8.5 ± 1.2%/h (P = 0.002) in 30°C-reared males, a difference in effect of sucrose that was of borderline statistical significance. Moreover, whereas total NE turnover was 75% greater in sucrose-fed rats reared at 30°C compared with chow-fed controls, it was only 5% greater in sucrose-fed animals reared at 18°C. In IBAT, the principal difference between the two rearing groups was the marked elevation in tissue NE levels in the 18°C-reared animals. Fractional NE turnover increased overall with sucrose feeding (P = 0.02), from 4.9 ± 0.8 to 7.5 ± 1.1%/h in rats reared at 18°C, and from 5.0 ± 0.5 to 7.0 ± 1.1%/h in 30°C-reared males; unlike in heart, the effect of sucrose was not statistically different in the two rearing groups (Trear × diet interaction, P = NS). Moreover, whereas total NE turnover increased 44% with sucrose-fed rats reared at 30°C and 45% in sucrose-fed animals reared at 18°C, total NE turnover was more than twice as great in 18°C-reared animals as in 30°C-reared ones.


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  		Fig. 1.   Effects of rearing temperature (Trear) on [3H]norepinephrine ([3H]NE) turnover in 80-day-old male rats fed lab chow or chow supplemented with sucrose. Sucrose-fed rats received 10% sucrose in the drinking water for 1 wk before and throughout the [3H]NE turnover study. Data are plotted as means ± SE for specific activity of NE in peripheral tissues from 4-6 animals in each group at each time point. open circle , Rats fed chow alone; , rats given 10% sucrose in addition to chow. Summary and results of statistical analyses are presented in Table 4.


                              
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  		Table 4.   Effect of Trear on [3H]NE turnover in tissues from chow- and sucrose-fed 80-day-old male rats

The responses in renal NE turnover to sucrose feeding were qualitatively different in 18°C- and 30°C-reared rats. Renal NE turnover was slightly lower in sucrose-fed than in chow-fed rats reared at 18°C, from 10.1 ± 0.4 to 8.6 ± 0.7%/h, and was slightly higher in sucrose-fed than in chow-fed rats reared at 30°C, from 7.2 ± 0.7 to 8.6 ± 0.9%/h. Although these pair-wise comparisons were not statistically significant, the difference in responses to sucrose feeding in the two rearing groups was statistically significant (Trear × diet interaction, P < 0.04). As a consequence, fractional NE turnover was greater in chow-fed 18°C-reared rats than in chow-fed 30°C-reared animals (P = 0.001), but was equivalent in sucrose-fed rats reared at the two temperatures. Total renal NE turnover thus fell with sucrose feeding in 18°C-reared male rats and rose slightly in the animals reared at 30°C. In summary, acceleration of [3H]NE turnover with sucrose feeding was greater in heart and kidney of 30°C-reared rats than in 18°C-reared males, whereas in IBAT, the elevated rates of [3H]NE turnover in 18°C-reared animals were consequent to the greater number of sympathetic nerves innervating the tissue.

Effects of Trear on sucrose-induced stimulation of tissue [3H]NE turnover in female rats. A similar study was performed in female rats, and the results are presented in Fig. 2 and Table 5. The findings in heart and kidney of female rats were less striking than noted previously in the male animals, as sucrose feeding elicited less activation of [3H]NE turnover in the 30°C-reared female rats than that seen in the 30°C-reared male animals. The effect of sucrose feeding on [3H]NE turnover was not statistically significant in either heart or kidney of 30°C-reared female rats. In IBAT, while tissue NE levels were higher in the 18°C-reared females as noted before in males, fractional NE turnover rates were lower overall in the 18°C-reared rats (P = 0.02). Moreover, the increment in fractional NE turnover with sucrose feeding was not statistically significant in the 18°C-reared female rats, from 6.4 ± 0.8 to 8.3 ± 1.1%/h (P = NS), but was highly significant in the 30°C-reared females, from 7.4 ± 0.6 to 11.3 ± 0.8%/h (P = 0.0005). Consequently, whereas total NE turnover increased 20% with sucrose feeding in 18°C-reared rats, it rose 47% in the 30°C-reared animals, narrowing the difference in NE turnover between the two rearing groups. Thus, although fractional NE turnover in IBAT was less in 18°C-reared female rats than in the 30°C-reared cohort, overall NE turnover in IBAT was still greater in the 18°C-reared rats due to the increase in sympathetic innervation in the tissue.


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  		Fig. 2.   Effects of Trear on [3H]NE turnover in 80-day-old female rats fed lab chow or chow supplemented with sucrose. Sucrose-fed rats received 10% sucrose in the drinking water for 1 wk before and throughout the [3H]NE turnover study. Data are plotted as means ± SE for specific activity of NE in peripheral tissues from 4-6 animals in each group at each time point. open circle , Rats fed chow alone; , rats given 10% sucrose in addition to chow. Summary and results of statistical analyses are presented in Table 5.


                              
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  		Table 5.   Effect of Trear on [3H]NE turnover in tissues from chow- and sucrose-fed 80-day-old female rats

Effects of Trear on sucrose-induced stimulation of gene expression in IBAT of female rats. In an attempt to determine how differences in [3H]NE turnover might affect IBAT function, gene expression for several sympathetically related proteins was examined in tissue obtained from 18°C- and 30°C-reared female rats fed chow with or without 10% sucrose to drink for 1 wk before death. The results from these analyses are presented in Table 6. Uncoupling protein 1 (UCP1) was taken as the prototype of a sympathetically related protein because its activity and synthesis are both under the control of sympathetic nerves in BAT (11, 39). As seen in the table, expression of UCP1 was greater overall in rats reared at 18°C or fed sucrose for 1 wk, but, in addition, the effect of dietary sucrose was greater in 30°C- than in 18°C-reared rats (Trear × diet interaction, P = 0.04). The marked difference between rearing groups evident in chow-fed animals (P = 0.006) disappeared when the animals were given sucrose to drink. As amplification of the PCR product was ~1.7-fold with each cycle in these assays, the changes observed in UCP1 gene expression with sucrose feeding represented an increase of approximately threefold in 18°C-reared rats and 40-fold in 30°C-reared animals. This pattern for gene expression of UCP1 in the two rearing groups paralleled that noted for IBAT [3H]NE turnover in the preceding study (Table 5).

                              
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  		Table 6.   Effect of Trear on relative gene expression in IBAT of chow- and sucrose-fed 81-day-old female rats

Several other genes showed patterns similar to that for UCP1. Expression of GLUT-4 (the insulin-sensitive glucose transporter) and ribosomal protein L19 (RPL19, a putative reference gene) was increased to a greater extent by dietary sucrose in IBAT from 30°C-reared rats than in that obtained from 18°C-reared animals; consequently, differences in gene expression between rearing groups were noted in chow-fed (P < 0.0001 and P = 0.002, for GLUT-4 and RPL19, respectively), but not in sucrose-fed animals (P = NS for both). For other genes, such as UCP3, leptin, and beta 3- and alpha 1A-adrenergic receptors (AR), statistically significant elevations in expression were noted in 18°C-reared compared with 30°C-reared chow-fed rats, but not between the two groups of sucrose-fed animals, although the interaction terms in the ANOVA did not achieve statistical significance. Thus, for seven of nine genes examined, gene expression was greater in animals reared at 18°C than in those raised at 30°C when fed the control, lab chow diet.

Effect of Trear on adrenal medullary response to fasting in male rats. Adrenal medullary function was examined by comparing urinary catecholamine excretion before and during a 3-day fast. The results for urinary Epi after logarithmic transformation are presented in Fig. 3. Trear exerted no overall effect on Epi excretion (P = NS). Whereas Epi excretion was increased by fasting (P = 0.0003), this effect differed in the two rearing groups (Trear × period interaction, P = 0.026). The fasting-related rise in Epi excretion was apparent in 30°C-reared rats (P = 0.0001), but not in 18°C-reared animals (P = NS) and, therefore, although no difference was evident between rearing groups during the feeding period (P = NS), Epi excretion was lower in 18°C-reared rats during the 3-day fast (P = 0.004). Urinary NE, by contrast, was slightly but not significantly higher overall in the 18°C-reared rats, averaging 6.1 ± 0.5 nmol/day with feeding and 6.6 ± 0.6 nmol/day with fasting, compared with 5.2 ± 0.3 and 5.5 ± 0.5 nmol/day, respectively, in 30°C-reared rats. Fasting exerted no statistically significant effect in either group, nor in the study overall (all P = NS). Thus the impact of Trear on catecholamine excretion during feeding and fasting was limited to the absence of an expected increase in Epi excretion with fasting in 18°C-reared male rats.


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  		Fig. 3.   Effect of Trear on urinary catecholamine excretion in male rats 78 days of age. Urine was collected simultaneously from 9 rats reared at 18°C until 60 days of age and 9 rats reared at 30°C for the same period. All rats were fed a lab chow diet ad libitum and given distilled water to drink during the first 3 days of urine collection. After an interval of 4 days the animals underwent 3 days of fasting during which they received 0.45% NaCl to drink. Data are presented as means ± SE of log-transformed 24-h epinephrine (Epi) excretion. open circle , Rats reared at 30°C; , rats reared at 18°C.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The findings reported here show that exposure to an environmental temperature of 18°C in early life produced a tonic increase in sympathetic nerve activity within BAT that was apparent up to 2 mo after the animals were removed from the temperature chambers. Heightened SNS activity to BAT was indicated by the consistent demonstration of elevated [3H]NE turnover in IBAT of 18°C- compared with 30°C-reared animals. In addition, gene expression for UCP1, GLUT-4, and the alpha 1A-AR, which are increased by sympathetic input to BAT during exposure to cold (11, 17, 42), were elevated in chow-fed rats reared at 18°C compared with those reared at 30°C. Interestingly, the increase in IBAT [3H]NE turnover in 18°C-reared animals was consequent to a higher level of NE, which was, in turn, due to the increase in sympathetic innervation of BAT (30). This finding suggests that rearing-induced hyperplasia in sympathetic innervation to BAT was not accompanied by a compensatory decrease in efferent nerve impulse traffic. Despite the tonic elevation in SNS activity to BAT, however, the 18°C-reared rats were fatter and more prone to gain weight when fed an enriched diet than animals reared at 30°C (58). These observations provide evidence that a deficiency in sympathetically mediated thermogenesis is not required for development of obesity in experimental animals.

If SNS activity within BAT in 18°C-reared animals is increased, not diminished, compared with that in rats reared at 30°C, what might account for their predilection to accumulate fat and gain weight? The first hypothesis examined was that although baseline SNS activity was increased, perhaps sympathetic reactivity to a dietary stimulus, such as sucrose, might be reduced in the 18°C-reared rats, as seen in obesity-prone rats reared in small litters (52). In support of this conjecture, 18°C-reared female rats exhibited a rise in [3H]NE turnover of only 20% with dietary sucrose in contrast to an increment of 47% in the 30°C-reared animals (Table 5). On the other hand, male rats showed no difference between rearing groups in IBAT NE turnover response to sucrose (Table 4). Moreover, even though 18°C-reared female rats showed a lower proportional response to sucrose than did those reared at 30°C, the rate of [3H]NE turnover in IBAT of sucrose-fed, 18°C-reared rats was still slightly greater than that seen in the 30°C-reared females and expression of genes for UCP1, GLUT-4, and the alpha 1A-AR, among others, was at least as abundant in the 18°C- as in the 30°C-reared animals.

Because adrenal medullary secretion is frequently reduced in human and animal models of obesity (50, 55), the second hypothesis tested was that adrenal medullary function, in contrast to SNS activity in BAT, was lower in the 18°C-reared animals. During the baseline period at room temperature, urinary Epi did not differ between rearing groups (Fig. 3); however, the increase in adrenal medullary secretion that frequently accompanies fasting was substantially blunted in the 18°C-reared male rats (56). Although a role for the adrenal medulla in the regulation of energy metabolism is unclear, the observation that weight loss in humans during a medically supervised program of caloric restriction correlates directly with the rise in urinary Epi implies a role for the adrenal medulla in the regulation of body weight under some circumstances (10).

A third hypothesis that was not tested directly in the current studies pertains to the level of sympathetic activity in white adipose tissue (WAT). Unlike sympathetic nerves in BAT, those innervating epididymal and retroperitoneal fat become more, not less, active with fasting (27). Moreover, efferent impulses in sympathetic fibers to WAT decrease with hyperglycemia and increase with hypoglycemia (37), responses opposite to those observed in sympathetic nerves to BAT (37). Because changes in adrenal nerve activity and in indexes of adrenal medullary secretion in response to fasting or to fluctuations in blood glucose parallel changes in sympathetic nerve activity to WAT, not BAT (35, 36, 56), the possibility exists that blunted activation of adrenal medullary secretion by fasting noted in the 18°C-reared rats may extend to sympathetic innervation of WAT as well. Recent experiments, moreover, demonstrate suppression of SNS activity by fasting in WAT of 18°C-reared, but not of 30°C-reared, male rats (J. B. Young, unpublished observations). Because food intake in 18°C-reared animals in relation to body weight did not differ from that in 30°C-reared animals (58), the 18°C-reared animals may accumulate body fat by storing similar amounts of energy in the immediate postprandial period, but mobilizing less between meals than 30°C-reared animals. The implications of these preliminary observations for the regulation of body weight warrant further study.

SNS activity in BAT was assessed not only by measurement of [3H]NE turnover but also by analysis of gene expression. Since group differences in sympathetic innervation of BAT (tissue NE levels) complicated interpretation of the [3H]NE turnover measurements in IBAT, indexes of BAT function consequent to SNS stimulation were examined as well. The abundance of expression for UCP1, GLUT-4, and alpha 1A-AR in IBAT from the four rearing:diet groups corresponded with measurements of [3H]NE turnover in similar animals, a finding that reinforces the contention that rates of [3H]NE turnover reflected differences in IBAT SNS activity. Increased expression of these genes also suggest that metabolic activity in BAT of chow-fed rats is greater in 18°C-reared than 30°C-reared animals, although it must be acknowledged that metabolic activity in BAT may not be precisely reflected in measurements of gene expression. On the other hand, it would seem highly unlikely that metabolic activity in IBAT of 18°C-reared rats would be less than that in 30°C-reared animals when seven of the nine genes examined were more abundantly expressed in IBAT of the 18°C-reared rats.

Two of the differences in gene expression between rearing groups noted in Table 6 deserve additional comment. First, expression of leptin in adipose tissue and its secretion into the circulation are increased in obesity (46). Greater abundance of message for leptin in 18°C-reared rats is consistent with their being fatter and more susceptible to weight gain than those reared at 30°C. Second, GLUT-4 expression in IBAT of chow-fed animals was also strikingly higher in the 18°C-reared females. As cold-induced stimulation of SNS activity in BAT increases both glucose uptake and GLUT-4 expression (38, 41, 42, 47), greater abundance of GLUT-4 message 20 days after removal of the 18°C-reared rats from their cool environment may be related to persistent activation of the SNS in BAT. This would, in turn, raise the possibility that peripheral glucose uptake would likewise remain elevated in the 18°C-reared animals. Because [3H]NE turnover remains greater in 18°C-reared rats for at least 2 mo after removal of the animals from the 18°C chamber (Tables 2 and 3) and levels of NE in IBAT are demonstrably higher in 18°C-reared rats even at 6 mo of age (J. B. Young, unpublished observations), GLUT-4 expression and glucose uptake may remain higher in 18°C-reared than in 30°C-reared rats for an extended period of time, an hypothesis that warrants further study.

One unexpected finding in the current studies concerned the impact of Trear on renal sympathetic activity, particularly in male rats. Unlike [3H]NE turnover in IBAT where the proportional increase in NE turnover was similar in 18°C- and 30°C-reared rats, in kidney sucrose feeding lowered NE turnover in the animals reared at 18°C, whereas it raised it slightly in those reared at 30°C. These differential responses to sucrose between BAT and renal sympathetic nerves likely reflect the fact that central regulation of sympathetic outflow is neuroanatomically separate for BAT and kidney. Renal sympathetic activity is governed largely by cardiovascular areas in the rostral ventrolateral medulla or the nucleus of the solitary tract, whereas sympathetic outflow to BAT is controlled principally by neurons in raphe pallidus (29). Consequently, it would appear that environmental temperature during early life exerts separate and distinct effects on pathways leading to these areas or on the areas themselves. Because renal SNS activity is important for the regulation of blood pressure and BAT SNS activity for thermoregulation, it is conceivable that developmentally acquired predispositions for obesity or hypertension may arise separately from one another. In the current example, animals reared at 18°C are more susceptible to weight gain and body fat accumulation than 30°C-reared rats (58), although carbohydrate-induced suppression of renal SNS activity in these animals may render the 18°C-reared males less vulnerable to diet-induced elevations in blood pressure than animals reared at 30°C.

To what extent are the differences noted here between 18°C- and 30°C-reared rats due to neonatal exposure to the cooler environment of 18°C or to the warmer one of 30°C? Since for a variety of practical considerations "room temperature" controls were not included, this question cannot readily be answered. Moreover, there are many phenotypic differences between 18°C- and 30°C-reared rats in addition to those mentioned here (e.g., 30°C-reared rats have longer tails than those reared at 18°C) and the relative importance of cold or heat may vary from one comparison to another. Furthermore, environments warmer than 30°C or colder than 18°C may introduce additional factors that may confound putative effects of temperature per se. Nonetheless, it is possible to discern effects on sympathoadrenal development of rearing animals at an environmental temperature below that of room temperature. Males rats reared at room temperature increase urinary Epi excretion promptly in response to fasting (51); in contrast, male animals reared at 18°C do not (Fig. 3). Fasting also activates sympathetic nerves to WAT in male rats reared at room temperature (27), but not in males reared at 18°C (J. B. Young, unpublished observations). Thus some of the alterations in sympathoadrenal function noted in 18°C-reared rats appear consequent to exposure to an environmental temperature below room temperature.

Perspectives

The findings reported here demonstrate that the alterations in SNS and adrenal medullary activity by early exposure to 18°C induce an obesity-prone phenotype distinct from those previously reported in experimental animals. In contrast to genetically obese rodents (3, 7), SNS activity and expression of beta 3-AR in BAT are not reduced in 18°C-reared rats and may be increased compared with 30°C-reared controls. Furthermore, the stimulatory effect of dietary sucrose on SNS activity in BAT is not attenuated in 18°C-reared animals as it is in mice made obese after treatment with gold thioglucose or in rats reared in small litters (13, 52). These differences among animal models of obesity strongly argue against the presence of a uniform abnormality in sympathoadrenal function in obesity and support the suggestion that alterations in SNS activity may underlie the presence of secondary characteristics associated with the obese condition (55).


    ACKNOWLEDGEMENTS

The skillful technical assistance of Y.-K. Chow and M. Fetzer is gratefully acknowledged.


    FOOTNOTES

These studies were supported in part by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-20378 and DK-54904.

Address for reprint requests and other correspondence: J. B. Young, Northwestern Univ.-Chicago, Ward 4-161, 303 East Chicago Ave., Chicago, IL 60611-3008 (E-mail: jbyoung{at}northwestern.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.

August 1, 2002;10.1152/ajpregu.00525.2001

Received 31 August 2001; accepted in final form 22 July 2002.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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