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-The effects of long-term cold exposure on brown adipose tissue (BAT) thermogenesis in hypothyroid rats have been examined. Thyroid ablation was performed in normal rats after 2 mo of exposure to 4°C, when BAT hypertrophy and thermogenic activity were maximal. After ablation, hypothyroid and normal controls remained in the cold for 2 additional months. At the end of the 4-mo cold exposure, all untreated hypothyroid rats were alive, had normal body temperature, and had gained an average 12.8% more weight than normal controls. Long-term cold exposure of hypothyroid rats markedly increased BAT weight, mitochondrial proteins, uncoupling protein (UCP)-1, mRNA for UCP-1, and oxygen consumption to levels similar to those seen in cold-exposed normal rats. The results indicate that thyroid hormones are required for increased thermogenic capacity to occur as an adaptation to long-term cold exposure. However, cold adaptation can be maintained in the absence of thyroid hormone. cold acclimation; uncoupling protein-1; hypothyroidism; oxygen consumption; norepinephrine THE IMPORTANCE OF THE BROWN ADIPOSE TISSUE (BAT) thermogenic response to acute cold stress has been widely recognized (for reviews see Refs. 21,22,30). Numerous complex phenomena take place in BAT after exposure to low temperatures, leading to the synthesis of mitochondrial proteins involved in heat production. A critical role in this process is the synthesis of uncoupling protein-1 (UCP-1), strongly promoted by norepinephrine (NE) through a synergism between ␣-and ␤-adrenergic receptors (24,32,40). The presence of the thyroid hormones is essential to initiate BAT heat production, because triiodothyronine (T 3 ) potentiates the action of NE on UCP-1 gene transcription (2-4, 37). This explains the development of hypothermia in hypothyroid rats soon after exposure to low temperatures, an effect corrected by the administration of thyroid hormones but not by the administration of NE (39).Thyroid hormones are active regulators of basal metabolic rate (BMR) and energy expenditure by a number of mechanisms (9,12,38,39). However, earlier studies had suggested that the thyroid hormone may not be necessary for a sustained normothermia after acclimation to cold has been achieved (for review see Ref. 13). Thus Hsieh and Carlson (25) observed a high metabolic rate and normal life survival in hypothyroid rats adapted to cold before thyroidectomy. Despite numerous studies, the influence of thyroid function on the maintenance of normothermia in rodents exposed to prolonged low temperature is not clearly understood.The purpose of the present study was to assess the role of the thyroid hormones in BAT thermogenesis during long-term cold exposure. After a period of time in the cold, rats were made hypothyroid. Hypothyroid and normal controls were then maintained for an additional period of time in the cold, and thereafter BAT was studied. Accordingly, hypothyroidism was induced after BAT hypertrophy and thermogenic activity were maximally activated. In contrast, room temperaturea...

The effects of cadmium on 5'-deiodination of thyroxine (T4) by rat liver and on the hepatic concentration of non-protein sulfhydryl groups (NPSH) were studied in Wistar rats of 200-250 g body weight. A group of ten rats was injected with cadmium chloride (300 micrograms/100 g body weight i.p.) daily for 4 days. Another group of six rats received, in addition, dithiothreitol (DTT; 1 mg/100 g body weight i.p.) daily for the same period. A group of eight normal untreated rats served as control. T4 deiodination was also determined in aliquots of liver from untreated rats, with cadmium (2 or 5 mmol/l) and with or without DTT (0, 2.5, 5 or 10 mmol/l) plus 1 microCi 125I-labelled T4. Hepatic NPSH were measured by a colorimetric method employing dithioldinitrobenzoic acid. Homogenates were incubated for 90 min at 37 degrees C and chromatographed in a tertiary amyl alcohol:hexane:ammonia (2 mol/l) (10:1:12) system. Cadmium-injected rats showed a significant (P < 0.01) decrease in T4 deiodination and in the generation of 125I (P < 0.01) and tri-iodothyronine (T3) (P < 0.02). NPSH were also decreased (P < 0.02). Administration of DTT restored T4 deiodination and NPSH to normal. In-vitro addition of cadmium or DTT to normal rat liver homogenates induced similar effects on the degradation of T4. Serum concentrations of T4 (P < 0.01) and T3 (P < 0.01) declined significantly in cadmium-injected rats, whereas DTT administration failed to normalize serum hormone levels. The data suggest that cadmium may have decreased 5'-deiodinating activity through binding to sulfhydryl groups of 5'-deiodinase as it does in other enzymes.(ABSTRACT TRUNCATED AT 250 WORDS)

Zaninovich, Angel A., Iné s Rebagliati, Marcela Raíces, Conrado Ricci, and Karl Hagmü ller. Mitochondrial respiration in muscle and liver from cold-acclimated hypothyroid rats. J Appl Physiol 95: 1584-1590, 2003. First published June 27, 2003 10.1152/japplphysiol.00363.2003.-The effects of long-term cold exposure on muscle and liver mitochondrial oxygen consumption in hypothyroid and normal rats were examined. Thyroid ablation was performed after 8-wk acclimation to 4°C. Hypothyroid and normal controls remained in the cold for an additional 8 wk. At the end of 16-wk cold exposure, all hypothyroid rats were alive and normothermic and had normal body weight. At ambient temperature (24°C), thyroid ablation induced a 65% fall in muscle mitochondrial oxygen consumption, which was reversed by thyroxine but not by norepinephrine administration. After cold acclimation was reached, suppression of thyroid function reduced muscle mitochondrial respiration by 30%, but the hypothyroid values remained about threefold higher than those in hypothyroid muscle in the warm. Blockade of ␤-and ␣1-adrenergic receptors in both hypothyroid and normal rats produced hypothermia in vivo and a fall in muscle, liver, and brown adipose tissue mitochondria respiration in vitro. In normal rats, cold acclimation enhanced muscle respiration by 35%, in liver 18%, and in brown adipose tissue 450% over values in the warm. The results demonstrate that thyroid hormones, in the presence of norepinephrine, are major determinants of thermogenic activity in muscle and liver of cold-acclimated rats. After thyroid ablation, cold-induced nonshivering thermogenesis replaced 3,5,3Ј-triiodothyronine-induced thermogenesis, and normal body temperature was maintained. cold acclimation; oxygen consumption; norepinephrine; adrenergic-receptor blockers ENDOTHERMIC ANIMALS LIVING in a cold environment maintain normothermia and energy balance through an activation of mechanisms that increase heat production and heat conservation. Heat production is commonly classified as either obligatory or adaptive (for reviews, see Refs. 15,23,29,38). The obligatory thermogenesis results from the widespread metabolic activity in many tissues and serves to maintain normal body temperature, which in homeotherms is usually higher than ambient temperature. The thyroid hormones stimulate obligatory thermogenesis by a number of mechanisms that are still incompletely understood (8,32,38). The additional heat needed to preserve body temperature in a cold environment is obtained through adaptive or facultative thermogenesis, a process regulated by the hypothalamus through the sympathetic nervous system. Brown adipose tissue (BAT) is the main site for adaptive thermogenesis primarily because of the mitochondrial uncoupling protein-1 (UCP-1), which uncouples electron transport from the phosphorylation of ADP and appears to be the only protein able to respond to thermal challenge (31, 30).UCP-1 expression is stimulated by norepinephrine (NE) but requires the presence of thyroid hormones (3, 4,...

We have assessed the relative contribution of the thyroid hormones and noradrenaline (NA) on the calorigenic function of brown adipose tissue (BAT) as indicated by GDP binding and O2 consumption of BAT mitochondria. Male Wistar rats of 200 g body weight were made hypothyroid with 131I. Groups of animals were injected s.c., in divided doses, daily for 10 days, with thyroxine (2 micrograms/100 g body weight) or tri-iodothyronine (T3; 0.3 microgram/100 g body weight). Animals were used 7 days after bilateral or unilateral sympathetic nerve excision of BAT (Sx). Sham-operated rats were used as controls. In normal rats kept at 22 degrees C, GDP binding reached 94 +/- 24 pmol/mg protein; untreated hypothyroid rats had normal binding values whereas the T3-treated group showed an increased binding. Sx induced a sharp fall in the three groups (P < 0.01). After 24-h exposure to 4 degrees C GDP binding increased in normal rats to about 410% (P < 0.01) whereas binding failed to increase in response to cold in the untreated hypothyroid and the T3-treated groups. Sx reduced GDP binding in the three groups significantly (P < 0.01). The consumption of O2 by BAT mitochondria showed similar variations in response to Sx and to cold exposure as did GDP binding. The data indicated that, at room temperature, BAT calorigenesis can function without the thyroid hormones, though not without the catecholamines. The findings in rats exposed to cold showed that the lack of NA was significantly more effective than the lack of thyroid hormones in preventing the BAT hyperactive response. This does not negate an active role for T3 in BAT calorigenesis.

The effect of in vivo administration of cadmium chloride on the pituitary-thyroidal axis was assessed in 200 g body weight Wistar rats. A dose of 2.5 mg/kg body weight was injected i.v. 24 h before the experiments were initiated. Plasma thyroxine (T4) and tri-iodothyronine (T3) concentrations in cadmium-treated rats were significantly (P < 0.01) decreased, whereas plasma TSH failed to increase in response to low T4 and T3. However, the TSH response to TRH and the pituitary content of TSH in these rats were both normal. Cadmium induced a significant (P < 0.01) decrease in 4-h thyroidal 131I uptake and in thyroid/plasma radioactivity ratio. The in vitro conversion of T4 to T3 in the pituitary was significantly (P < 0.01) blocked by cadmium whereas there was no in vivo effect. Parameters of peripheral T4 kinetics in cadmium-treated rats, such as metabolic clearance rate (P < 0.01), fractional turnover rate (P < 0.01), absolute disposal rate (P < 0.05), urinary clearance (P < 0.05) and faecal clearance (P < 0.05), were all decreased by cadmium. The lack of response of TSH to low plasma T4 and T3 and the normal response to exogenous TRH in this and in other non-thyroidal illness syndromes produced by other pathologies suggest a decreased stimulation of pituitary thyrotrophs by endogenous TRH.

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