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Development of Compensatory Thermogenesis in Response to Overfeeding in Hypothyroid Rats¹

Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-900, Brazil

Address all correspondence and requests for reprints to: Antonio C. Bianco, M.D., Ph.D., Room 560, Harvard Institutes of Medicine, 77 Louis Pasteur Avenue, Boston, Massachusetts 02115. E-mail: acbianco{at}usp.br

	Abstract

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Intact or surgically thyroidectomized (Tx) adult male Wistar rats, weighing 150–200 g, were fed a standard chow diet (1.8 Cal/g) or a high calorie (3.8 Cal/g) diet (cafeteria diet) for up to 30 days. Daily energy intake was about 5-fold higher in the rats fed the cafeteria diet regardless of their thyroid status. The cafeteria diet caused the retroperitoneal white fat pad to increase by approximately 2-fold, the volume of isolated white adipocytes to increase by 2-fold, and the total body fat to increase by a factor of approximately 3, again regardless of thyroid status. It also increased basal metabolic rate by about 20% in intact rats and by about 50% in Tx rats. The brown fat thermal response to norepinephrine (NE) infusion was approximately 2-fold increased in the intact rats fed the cafeteria diet. However, in the Tx rats, the brown fat thermal response to NE was blunted regardless of the dietary regimen adopted. In both intact and Tx rats, the cafeteria diet increased total brown fat mitochondria, uncoupling protein percentage, and total brown fat uncoupling protein by about 3-, 2-, and 5-fold, respectively. Serum leptin levels also increased approximately 4-fold in intact rats fed the cafeteria diet. However, in Tx rats, leptin levels did not change significantly during overfeeding. In conclusion, hypothyroidism caused the brown fat to become unresponsive to NE, even after 1 month on the cafeteria diet. However, these rats were able to increase basal metabolic rate and, as assessed by several different parameters, did not gain fat beyond that observed in intact controls kept on a similar overfeeding schedule.

	Introduction

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THYROID HORMONES are major determinants of the basal metabolic rate (BMR) in homeothermic animals (1). During the transition from hypo- to hyperthyroidism there is about a 2-fold difference in BMR. The mechanisms by which thyroid hormones increase oxygen consumption are not entirely clear and include stimulation of several substrate and ionic cycles leading to increased ATP turnover and hence heat production. Recently, it has been proposed that thyroid hormones induce uncoupling of oxidative phosphorylation by stimulating the expression of newly identified mitochondrial uncoupling proteins (UCP-2 and UCP-3) in skeletal muscle and white adipose tissue (2, 3).

Thyroid hormones are also essential for the life-sustaining increase in energy expenditure observed during cold exposure in mammals, the so-called cold-induced facultative thermogenesis. This is achieved by a combination of shivering and sympathetic-dependent nonshivering mechanisms that culminate in a 2- to 3-fold increase in oxygen consumption and proportional heat production (4). Thyroidectomized (Tx) rats, however, present hypothermia and rapidly die when placed in the cold despite increased norepinephrine (NE) turnover in several tissues (5). Even exogenous administration of large amounts of NE will not restore the thermal response or core temperature in Tx rats (6). However, cold- or NE-induced facultative thermogenesis are rapidly restored upon administration of subphysiological doses of T₄, reinforcing the key role of thyroid hormones for triggering and sustaining cold-induced thermogenesis (7).

Feeding a hypercaloric diet (cafeteria diet) can also activate nonshivering facultative thermogenesis, the so-called diet-induced thermogenesis (8). Previous publications have indicated that both cold- and diet-induced thermogenesis are controlled basically by the hypothalamus, which, in turn, regulates sympathetic activity in several tissues, of which brown fat is the most thermogenically active (9). By various morphophysiological, cellular, and biochemical criteria it is possible to demonstrate an association between changes in brown fat and diet-induced thermogenesis that resemble the changes in brown fat during cold-induced thermogenesis. The capacity of brown fat to liberate heat is so high that within 30 min of NE infusion interscapular brown fat increases its temperature by 2–3 C (10), whereas in Tx rats this response is blunted (6). In brown fat, NE and T₃ strongly up-regulate UCP-1 gene expression by transcriptional (11) and posttranscriptional mechanisms (12). Lipogenesis, a major source of brown fat fuel, is also 2- to 3-fold up-regulated by a complex interaction between NE and T₃ (13).

Previous work has indicated that the administration of thyroid hormones increases diet-induced thermogenesis in rats (14), whereas in birds the peripheral transformation of T₄ to T₃ has been implicated (15). In addition, based on the full dependence of cold-induced thermogenesis on thyroid hormones, it is logical to suppose a role for these hormones in diet-induced thermogenesis. However, hypothyroid animals do not seem to have an impaired capacity to regulate body fat. If anything, they tend to be leaner because of less stimulation of thyroid hormones upon lipogenic enzymes (16). Therefore, the major goal of the present investigation was to study diet-induced thermogenesis in hypothyroid rats, particularly the modifications of energy intake and BMR, brown fat UCP content, and thermal response, and consequent changes in body composition during feeding with a cafeteria diet.

	Materials and Methods

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Animals and diets
Unless specified otherwise, all drugs and reagents were purchased from Sigma Chemical Co. (St. Louis, MO). Experiments were performed on male Wistar rats, weighing 150–200 g, obtained from our breeding colony. Studies were conducted in accordance with the highest standards of humane animal care. Animals were maintained on a 12-h dark, 12-h light cycle at 28–30 C and had free access to standard animal chow and water. Surgical thyroidectomy (Tx) was carried out under light ether anesthesia; immediately after surgery, the animals were placed on 0.05% methimazole in the drinking water and then used 4 weeks later. Methimazole was also dissolved in soda (see below) to assure hypothyroidism during the experiments.

Control animals remained on a standard diet throughout the 30-day experimental period. The cafeteria dietary regimen used was adapted from previous studies (8, 17). Rats were offered large amounts of various palatable food items in addition to standard chow. The diet consisted largely of chocolate, cookies, biscuits, cakes, peanuts, ham, and cheese, totaling about 3.8 Cal/g, as opposed to the approximately 1.8 Cal/g of the chow diet. Coca-Cola (São Paulo, Brazil) and Guaraná Antartica (São Paulo, Brazil), a local soda brand, were alternated daily. Enough food was offered daily so that despite increased consumption rats could not eat all of it. Each day leftovers were collected and replaced with new and different items. This was a key point of our experiment that assured success of the hypercaloric regimen. Food consumption was recorded, and feces were collected during 3 days of each week. Feces were then dried at 60 C, stored at -20 C, and later homogenized and burned in an adiabatic calorimeter (C400, IKA, Wilmington, NC).

Oxygen consumption at rest
Resting oxygen consumption (VO₂) was measured in an open circuit respirometer system (S-3A/1, Ametek, Pittsburgh, PA) as previously described (18) during the last 3–4 days of the experiment. All measurements were carried out over a period of 1 h during the morning (0900–1400 h) at room temperature (>25 C). Animals were studied under two conditions: not fasted or overnight fasted. Animals were maintained in their normal experimental conditions until immediately before the measurements. Online data were collected and analyzed with a computer system running on a DataCan V software (Sable Systems, Salt Lake City, UT). Results were corrected for environmental temperature and atmospheric pressure and expressed in terms of milliliter of O₂ per min/g BW.

Interscapular brown fat thermal response to NE infusion
The response was determined during the last 3–4 days of the experimental period as previously described in detail (19). All animals were anesthetized with urethane (1.2 g/kg, ip) in the morning (9–10 h) of the experiment. A polyethylene (P-50) cannula was inserted into the left jugular vein and later used for NE infusion. Interscapular brown fat (T_IBAT) temperatures were measured using a precalibrated thermistor probe secured under the brown fat pad. T_IBAT was measured during a period of approximately 15 min to obtain a stable baseline, and then NE infusion was started. NE infusion (6–8 µg/kg·min) was performed with an infusion pump (model 2274, Harvard Apparatus, Holliston, MA) at a rate of 0.643 µl/min for 60 min. Raw data were plotted over time and expressed in terms of maximum T_IBAT (C) or area under the T (C) vs. time (min), AUC_IBAT (C·min).

Body composition
This was measured during the last 3–4 days of the experimental period, as described in detail previously (20), by dual energy x-ray absorptiometry using DPX- equipment (Lunar Corp., Madison, WI) running on a software set to a high resolution mode specially developed for small animals. For the scan, the animals were anesthetized with ketamine and xylazine (15 and 90 mg/kg BW, respectively) and scanned in the prone position over an acrylic platform.

Analytical procedures
At the end of the experimental period rats were killed by decapitation, and the interscapular brown fat was rapidly removed and processed for mitochondrial isolation (7). Procedures were performed at 4 C or in an ice-cold water bath as needed. Protein measurement was made using the Bradford method (21). UCP was quantified after mitochondrial proteins were size fractionated by 12% SDS-PAGE as previously described (19). The gel was then stained with Coomassie blue and scanned with a transmission densitometer at 595 m (CS-9310PC, Shimadzu, Tokyo, Japan). Serum concentrations of T₄ were measured by RIA as described previously (22), and serum leptin was measured by RIA at Linco Research, Inc. (St. Charles, MO).

Isolation of white adipocytes and determination of cell number and volume
Immediately after the animals were killed, the retroperitoneal white fat pads were dissected and weighed, and the adipocytes were isolated as described previously (23). The average cell volume and number were determined as previously described (24).

Statistical analysis
Results are expressed as the mean ± SD throughout the text, tables, and figures. Multiple comparisons were performed by one-way ANOVA, followed by Students-Newman-Keuls test.

	Results

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Characterization of the metabolic changes associated with diet-induced thermogenesis in intact rats. In pilot experiments (data not shown) we tested the efficiency of the cafeteria diet employed in the present investigation. Control animals kept on the chow diet ingested an average of 20–30 Cal/rat·day, whereas the rats fed the cafeteria diet ingested 5–7 times more, about 200 Cal/day·rat. The increased energy intake caused BMR to increase about 25%, and the brown fat thermal response to NE to be 2- to 3-fold greater. Total brown fat mitochondria were increased by about 60%, UCP percentage was increased by 40%, and total brown fat UCP was increased by 2.2-fold. Together these results confirm the diet-induced thermogenesis and the activation of brown fat in rats fed the cafeteria diet.

Diet induced thermogenesis in hypothyroid rats. Tx rats and appropriate controls were subjected to the same feeding conditions as described above. The serum T₄ concentration did not differ among intact rats regardless of the dietary regimen (57 ± 3 vs. 66 ± 12 ng/ml). On the other hand, all Tx rats presented serum T₄ below the detection limit of the assay (<5 ng/ml).

The results regarding energy balance are shown in Table 1. As expected, intact rats increased food ingestion by a factor of approximately 5.7 (P < 0.05) when fed the cafeteria diet. Hypothyroidism alone did not influence energy intake when the results were expressed per kg BW. In addition, and quite remarkably, when Tx rats were fed the cafeteria diet they also showed a much higher daily calorie intake (5.0-fold; P < 0.05). This is a new finding and indicates that hypothyroid rats are equally susceptible to the appeal of the cafeteria feeding. One possibility, however, was that hypothyroidism could reduce nutrient absorption, and therefore, the increased energy intake would not be translated into absorbed/metabolized energy. To study this possibility we measured the average daily energy eliminated in the feces. Table 1 indicates that only minor changes were detected among the four experimental groups. Energy excretion in Tx rats was only slightly higher (20%; P < 0.05) than that in intact rats fed the chow diet. In addition, the cafeteria diet did not affect energy excretion in intact or Tx rats. This indicates that hypothyroidism does not impair food absorption when rats are fed a hypercaloric diet; therefore, the metabolized energy is equivalently high in these cafeteria diet-fed animals regardless of their thyroidal status.

View larger version (20K): [in this window] [in a new window]   Figure 1. Brown fat thermal response to infusion with NE in intact or hypothyroid rats fed chow or a cafeteria diet. NE infusion lasted 60 min, and the dose was 6–8 µg/kg·min. The baseline brown fat temperature of all rats was normalized to 0 C in the graph. Maximal responses [TIBAT (C)] and the integrated area under the curves [AUCIBAT (C·min)] are shown in Table 4. Values are the mean ± SD of four rats. Open circles indicate control intact rats fed the chow diet, black circles intact rats fed the cafeteria diet, open squares indicate Tx rats fed the chow diet, and closed squares indicate Tx rats fed the cafeteria diet. Intact rats fed the cafeteria diet had thermal responses significantly different from controls (P < 0.05) at 40–60 min. All thermal responses found in Tx rats, regardless of the diet they received, were significantly different (P < 0.05) from intact controls. All comparisons were made using ANOVA.

	Discussion

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Hypothyroid rats die within hours of being placed in the cold (1). This is a dramatic illustration of the important role of thyroid hormones for cold-induced thermogenesis, particularly at the brown fat level (7, 25). Accordingly, based on the association between diet-induced thermogenesis and brown fat, we expected to see a deficient diet-induced thermogenesis in hypothyroid rats. However, the results obtained in the present investigation clearly indicate that severely hypothyroid rats under increased caloric intake maintain the ability to respond to the dietary caloric challenge, doubling their BMR. In agreement, hypothyroid rats did not become obese, not even when subjected to a sustained approximately 5-fold increase in caloric intake over a period of 4 weeks. They increased their BMR, and as assessed by different parameters, their fat gain was not higher than that observed in intact control rats kept on a similar overfeeding schedule.

The logical place to look for the increased oxygen consumption was brown fat. As discussed in the introduction, brown fat is considered a major site of diet-induced thermogenesis (8, 26). In the intact rats fed the cafeteria diet brown fat showed many biochemical signs of stimulation, including increased UCP content. In addition, NE infusion resulted in a marked increase in brown fat temperature similar to that observed during cold acclimation. This is the basis for the assumption that brown fat is a major tissue responsible for diet-induced thermogenesis, and NE is its most important mediator. However, the present findings in hypothyroid rats challenge these concepts and require further interpretation.

As anticipated from our previous findings (19), the brown fat of hypothyroid rats was thermogenically inactive. Accordingly, the brown fat of hypothyroid rats fed the cafeteria diet did not respond during 1 h of infusion with a maximal dose of NE. It did show unequivocal biochemical signs of stimulation, however, as evidenced by increased mitochondrial and UCP contents. Nonetheless, NE infusion only elicited a very faint thermal response in these rats. As an example, hypothyroid rats fed the cafeteria diet had at least as much brown fat UCP as the intact rats fed the chow diet and still did not respond to NE infusion. In fact, we have previously reported dissociation between brown fat UCP levels and its thermal response to NE infusion in hypothyroid rats (19). The present results corroborate those findings and indicate that an important step of brown fat thermogenesis, other than UCP expression, is impaired in hypothyroid rats, possibly the cAMP generation and/or amplification of its signaling via the cAMP-dependent protein kinase A cascade. In fact, previous data (27) indicate that the capacity of hypothyroid brown adipocytes to generate cAMP in response to NE or CL 316243 is markedly reduced (5- to 6-fold). This is partially explained by an approximately 50% increase in the functional pool of G_i protein (28) and a change in the adenylyl cyclase activity/expression (29).

It is difficult to assert the extent of the brown fat involvement in the increased BMR detected in these hypothyroid rats fed a cafeteria diet. The results seem to indicate defective NE-induced brown fat thermogenesis in hypothyroid rats, suggesting the involvement of additional mechanisms to explain the compensatory increase in BMR that effectively limited the amount of body energy stored as fat. Indeed, more than one pathway and/or thermogenic mechanism should exist to explain impaired cold-induced and functional diet-induced thermogenesis in the same animal. In fact, several lines of evidence indicate the dissociation between cold- and diet-induced thermogenesis. Evidence obtained in rats undergoing weight recovery indicates the existence of a mechanism controlling energy expenditure dissociated from the sympathetic neural modulation of thermogenesis and, by extension, from brown fat and UCP-1 (30). In addition, mice that cannot synthesize NE or adrenaline, although cold intolerant, are not obese. They show increased food intake, but do not become obese because they retain the capacity to increase their metabolic rate (31). One more piece of evidence supporting this idea comes from aP2-UCP mice (32), which show a functional involution of brown fat. These animals are cold intolerant, but do not develop obesity. Taken together, these data suggest that brown fat is essential for protecting the organism against cold, and that the thermogenic capacity of other tissues might compensate against obesity when brown fat is not active. The recent cloning of additional UCP isoforms in other rat and human tissues, particularly white adipose tissue and skeletal muscle, provides new insights into the possible compensatory mechanisms involved (2, 3, 30, 33, 34). Both UCP-2 and UCP-3 expression are positively influenced by leptin and could serve as strong candidates for the compensatory mechanism (35, 36). However, in the present investigation serum leptin did not increase during feeding of a cafeteria diet in Tx rats, as opposed to the nearly 4-fold increase detected in intact rats, probably because hypothyroidism impairs leptin secretion per se (37).

In the present investigation we confirmed and expanded the concept favoring the existence of more than one thermogenic pathway involved in the overall energy homeostasis by showing that thyroid hormone-independent mechanisms are triggered by diet-induced thermogenesis. Indeed, it is interesting to note that body weight regulation is well preserved among vertebrates, whereas endothermic mechanisms are a relatively recent acquisition. In ectothermic vertebrates (fish, amphibians, and reptiles), in which thyroid hormones do not have thermogenic effects and do not participate in the regulation of BMR (38), body weight and substrate storage are not loosely controlled. On the contrary, both are tightly regulated by a complex integration between environmental temperature and food availability (39, 40). As an example, fishes (41), snakes (42), and lizards (43) are all able to sustain prolonged periods of much higher BMR triggered by feeding. The implication is that mechanisms governing the general energy homeostasis, substrate storage and availability, evolved earlier and independently of the metabolic effects of thyroid hormones. Endothermic mechanisms, as seen in birds and mammals, however, are indeed fully dependent on thyroid hormones and in these animals contribute to increasing BMR and initiating/maintaining cold-induced thermogenesis.

	Acknowledgments

 
The authors are grateful to José Luiz dos Santos and Alessandra Crescenzi for excellent technical assistance.

	Footnotes

 
¹ This work was supported in part by a research grant from Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP) (97/12796–0) and scholarships from FAPESP to C.C. (95/04839–5) and A.L. (97/05622–5).

² Both authors deserve to be the first author of this manuscript.

Received November 4, 1998.

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