Cross adaption between stress and cold in rats

Three-hour immobilization stress was imposed on male adult rats of Wistar strain by restraining them on a board 6 days a week for 1–8 weeks. The stressed rats showed less body weight gain during the experiment compared to the controls. These stressed animals manifested an improved cold tolerance as shown by no significant fall in colonic temperature in the cold at –5° C for 300 min during the experimental period, while the colonic temperature of the controls fell progressively. Nonshivering thermogenesis as assessed by noradrenaline-induced increase in oxygen consumption was significantly potentiated in the stressed rats. The weight and protein content of the intercapsular brown adipose tissue (BAT) increased and BAT mitochondria were more packed in the stressed rats. Plasma insulin, insulin/glucagon molar ratio and thyroxine levels were lowered in the stressed rats, while the plasma triiodothyronine level remained unchanged. Removal of interscapular BAT led to a loss of improved cold tolerance and a significant reduction of nonshivering thermogenesis in the stressed rats.These results indicate that repetitive stress may induce cross adaptation between stress and cold through an enhanced capacity of nonshivering thermogenesis mediated, at least in part, via stimulation of BAT function.     

Effect of immobilization stress on in vitro and in vivo thermogenesis of brown adipose tissue.

Repetitive intermittent stress such as immobilization has been shown to induce an improved cold tolerance through an enhanced capacity of nonshivering thermogenesis (NST), causing positive cross adaptation between nonthermal stress and cold. In the present study, effect of 3-h-daily immobilization stress for 4-5 weeks was investigated on in vitro and in vivo thermogenesis of interscapular brown adipose tissue (BAT). In vitro thermogenesis was measured in the minced tissue blocks incubated in Krebs-Ringer phosphate buffer with glucose and albumin at 37 degrees C, using a Clark-type oxygen electrode. The stressed rats showed less body weight gain during the experiment. The BAT weight, its protein and DNA contents were significantly greater in the stressed rats. Basal, noradrenaline- and glucagon-stimulated oxygen consumptions were significantly greater in the stressed rats. In vivo thermogenesis was assessed by the changes of temperatures in colon (Tcol), BAT (TBAT), and tail skin (Tsk) induced by noradrenaline or glucagon infusion in the anesthetized rats. Noradrenaline and glucagon increased the TBAT and the extent of increase was greater in the stressed rats. These results indicate that cross adaptation between nonthermal stress and cold may be mediated through an enhanced thermogenic activity of BAT.     

Thermogenesis in brown adipose tissue with age: Post-receptor activation by forskolin

₃-Adrenergic-stimulated thermogenesis in brown adipose tissue (BAT) is diminished with age. ₃-Adrenergic receptors are positively coupled to adenylyl cyclase in BAT. To determine whether thermogenesis, in response to direct activation of adenylyl cyclase, is also impaired with age, we examined whole body oxygen consumption, mitochondrial guanosine diphosphate (GDP) binding and BAT mitochondrial uncoupling protein (UPC) mRNA levels in 4- and 24-month-old F-344 rats following forskolin administration. We also examined the forskolin-induced change in body temperature in 4-month-old rats. In some instances, the results were compared with administration of the specific ₃-adrenergic agonist, CGP-12177. Forskolin (3.5 mg/kg) increased oxygen consumption but decreased body temperature. In subsequent experiments the BAT was unilaterally denervated. In these rats, the forskolin-(1.8 mg/kg) stimulated increase in oxygen consumption was similar in young and old rats. Forskolin increased GDP binding and UCP mRNA levels in both the denervated and innervated BAT pads. The increases were equal or greater in the BAT from senescent rats. These findings, coupled with our previous report of an impaired CGP-12177-stimulated increase in GDP binding in senescent rats, suggests ₃-adrenergic-stimulated, but not post-receptor-stimulated, thermogenesis is diminished with age.     

Brown adipose tissue and thermogenesis in hypophysectomized rats in relation to temperature acclimation

The aim of this work was to test the role of pituitary dependent hormones in cold-induced non-shivering thermogenesis. In the 28°C-acclimated rat, hypophysectomy inhibited body growth and led to an atrophy of thyroid and adrenals. In brown adipose tissue (BAT) some alterations were induced which are usually observed after cold acclimation of the animal: increase in relative weight, decreases in the relative amount of lipids, increases in the amounts of protein and DNA and modification of the proportions of several phospholipid fatty acids; moreover, basal lipolysis, in vitro, was enhanced to the same extent as that following cold acclimation of the normal rat. The in vivo stimulation by norepinephrine (NE) of O₂ consumption (test for nonshivering thermogenesis) and of fatty acid release into blood were suppressed.Progressive cold acclimation of the hypophysectomized rats at 15°C led to a hypertrophy of BAT to the same extent as in the sham-operated animals. The in vivo sensitivity to NE was partially restored. The results suggest that hypophysectomy does not suppress the ability to acclimate to moderate cold by means of BAT dependent non-shivering thermogenesis. However, the low ability to produce heat seems to indicate that pituitary or pituitary-dependent hormones are necessary to optimize the cold stimulation of brown fat thermogenesis.     

Effects of histamine antagonists on noradrenaline-stimulated blood flow and oxygen consumption of brown adipose tissue in the rat

The effects of histamine antagonists on noradrenaline-stimulated metabolic rate, tissue blood flow (estimated from the distribution of radiolabelled microspheres) and brown adipose tissue (BAT) oxygen extraction were studied in male anaesthetised rats. Injection of cimetidine (H2-receptor antagonist), reduced the noradrenaline-stimulation of metabolic rate and the increase in blood flow to BAT, but did not affect blood flow to white adipose tissue, skin, leg muscle, kidney, brain, or testes. Following noradrenaline, in vivo oxygen consumption of BAT, estimated from blood flow and oxygen extraction was depressed to 31% of control values by treatment with cimetidine, blood pressure was unaffected. Injection of the histamine (H1-receptor) antagonist, mepyramine, did not affect tissue blood flow or metabolic rate. In conscious animals, cimetidine did not affect resting oxygen consumption, but depressed the thermogenic responses to noradrenaline. These data suggest that the stimulation of BAT blood flow and thermogenesis by noradrenaline may be mediated in part by histamine acting on an H2-type receptor.     

Effects of glucagon and noradrenaline on the blood flow through brown adipose tissue in temperature-acclimated rats

After 30 min infusion of glucagon or noradrenaline, blood flow through brown adipose tissue (BAT) from various sites was investigated with the aid of 113Sn-labeled microspheres under hexobarbital anesthesia in cold-acclimated (CA), heat-acclimated (HA), and warm control (WC) rats. Glucagon increased cardiac output in both CA and HA, while noradrenaline increased it in HA but not in CA. Blood flow through BAT as well as the fractional distribution of cardiac output to BAT increased by glucagon dose-dependently and reached a maximum level in a dose of 2 micrograms/min. These glucagon-induced responses were significantly higher in CA and smaller in HA as compared with WC. Noradrenaline in a dose of 2 microgram/min caused larger responses than glucagon in all groups. Glucagon- or noradrenaline-induced blood flow per unit weight of BAT increased or tended to increase by cold acclimation. These results suggest that an in vivo enhanced glucagon-induced thermogenesis in cold-acclimated BAT is partly due to an increased blood flow through this tissue.     

内源性精氨酸加压素在昼光期大鼠紧张性体温调节中的作用

目的: 探讨内源性精氨酸加压素(AVP)在昼光期大鼠紧张性体温调节中的作用及其机制。方法: 使用成年雄性SD大鼠,在22 ℃环境温度下,明暗时间各12 h,同步无线遥测体核温度(Tc)和棕色脂肪(BAT)温度。上午10:00给大鼠腹腔注射AVP(10 μg/kg)或精氨酸加压素V_1a(AVP V_1a)受体阻断剂(30 μg/kg)。用酶联免疫吸附测定法,分别检测昼光期和暗光期大鼠血浆中AVP浓度。给AVP 60 min 后测定血清中甘油三酯、游离脂肪酸和甘油浓度变化。给予AVP后间隔10 min 记录大鼠的理毛活动。结果: (1)在昼光期中AVP V_1a受体阻断剂能够升高Tc和BAT温度。(2)在昼光中Tc和BAT温度处于低温期时,血浆中AVP水平则明显提高。(3)腹腔注射AVP引起Tc快速降低时,伴有BAT温度明显降低和大鼠的理毛行为明显增加。(4)AVP可以降低血清游离脂肪酸与甘油浓度,提高血清甘油三酯的浓度。结论: (1)内源性AVP通过AVP V_1a受体参与昼光期大鼠紧张性体温调节过程,因为在昼光期中不仅血浆AVP浓度明显高于暗光期,而且AVP V_1a受体阻断剂也能明显升高Tc和BAT温度。(2)AVP能降低BAT温度、血中游离脂肪酸和甘油浓度,提高理毛活动,证明AVP引起低温的机制可能与抑制脂肪分解、降低BAT产热和提高散热反应有关。     

Effects of estrous cycles and ovarian steroids on body weight and energy expenditure in Syrian hamsters

In Experiment 1, highly significant changes were observed over the estrous cycle in body weight gain, but not in food intake, daytime resting oxygen consumption or brown fat thermogenesis in Syrian hamsters. In Experiments 2 and 3, body weight and composition, food intake, resting oxygen consumption, and brown fat thermogenesis were measured following estradiol or estradiol plus progesterone treatment in ovariectomized hamsters. The significant changes in body weight could not be explained by changes in food intake, and were not accompanied by significant alterations in daytime oxygen consumption or brown fat thermogenic activity. In Experiment 4, resting oxygen consumption and body weight were measured every 6 hours over the estrous cycle. There was a striking absence of the usual nocturnal peak in resting oxygen consumption on the night of estrus (the night of the largest body weight gain). However, brown fat thermogenic activity did not differ among groups of hamsters killed on different nights of the estrous cycle. Estradiol-induced changes in energy storage may be mediated by changes in the daily rhythm of energy expenditure which are not dependent on alterations in brown fat thermogenesis.     

Role of sympathetic nervous system in immobilization- and cold-induced brown adipose tissue thermogenesis in rats

The role of the sympathetic nervous system in 10-min cold (5 degrees C)- or 2-min immobilization-induced thermogenesis in brown adipose tissue (BAT) was studied in warm (25 degrees C)-acclimated rats. Both cold- and immobilization-stresses increased heat production (M), interscapular brown adipose tissue temperature ( Tbat ), and colonic temperature ( Tcol ). Resulting from both stresses, the increase in Tbat was greater than that in Tcol , the differences (delta Tbat ) becoming approximately 0.48 and 0.46 degrees C by the cold exposure and the immobilization, respectively. After sympathectomy, Tbat and delta Tbat did not change on immobilization but increased significantly on the cold exposure. Delta Tbat was 0.31 degrees C in the sympathectomized rats at the end of the cold exposure period. Immobilization-induced BAT thermogenesis may be mainly controlled by the sympathetic nervous system. On the other hand cold-induced BAT thermogenesis seems to be controlled by certain hormonal factors as well as the sympathetic nervous system.     

Pituitary and autonomic responses to cold exposures in man

This review presents hormonal responses to various cold exposures and their calorigenic effects in man and some animals. Previous studies in rats have shown that cold exposures activate the hypothalamic-pituitary-thyroid axis. Increased thyroid hormone concentrations lead to heat production via general stimulation of metabolism (obligatory thermogenesis) and possibly via activation of thyroid hormone receptors and uncoupling protein 1 (UCP 1) and deiodinase enzyme genes in the brown adipose tissue (BAT). In human subjects long-term cold exposures do not seem to activate the pituitary-thyroid axis, but rather accelerate the elimination of triiodothyronine (T3), leading to low serum concentrations of free T3 hormone. In corollary to this a hypothyreotic condition with increased serum thyroid-stimulating hormone and impaired mood and cognitive performance can be observed after long-term cold exposures such as wintering. During cold exposures the sympathetic nerve system is activated and noradrenaline is released to blood circulation and to BAT, where it leads to production of cAMP, lipolysis and free fatty acids. Free fatty acids open the mitochondrial proton channel protein in BAT. Protons enter the mitochondria and inhibit ATP synthesis (uncoupling). By this way energy is transformed into heat (facultatory or adaptive thermogenesis). In adult human subjects the amount of BAT is small and adaptive thermogenesis (non-shivering thermogenesis) has a smaller role. UCP 1 with other uncoupling proteins may have other functions in the control of body weight, sugar balance and formation of reactive oxygen species.     

Synergistic interactions between airway afferent nerve subtypes regulating the cough reflex in guinea-pigs

In urethane–chloralose anaesthetized, neuromuscularly blocked, artificially ventilated rats, we demonstrated that activation of carotid chemoreceptors inhibits the elevated levels of brown adipose tissue (BAT) sympathetic nerve activity (SNA) evoked by hypothermia, by microinjection of prostaglandin E₂ into the medial preoptic area or by disinhibition of neurones in the raphe pallidus area (RPa). Peripheral chemoreceptor stimulation with systemic administration of NaCN (50 μg in 0.1 ml) or with hypoxic ventilation (8% O₂–92% N₂, 30 s) completely inhibited BAT SNA. Arterial chemoreceptor-evoked inhibition of BAT SNA was eliminated by prior bilateral transections of the carotid sinus nerves or by prior inhibition of neurones within the commissural nucleus tractus solitarii (commNTS) with glycine (40 nmol/80 nl) or with the GABA_A receptor agonist muscimol (160 pmol/80 nl; 77 ± 10% attenuation), or by prior blockade of ionotropic excitatory amino acid receptors in the commNTS with kynurenate (8 nmol/80 nl; 82 ± 10% attenuation). Furthermore, activation of commNTS neurones following local microinjection of bicuculline (30 pmol/60 nl) completely inhibited the elevated level of BAT SNA resulting from disinhibition of neurones in the RPa. These results demonstrate that hypoxic stimulation of arterial chemoreceptor afferents leads to an inhibition of BAT SNA and BAT thermogenesis through an EAA-mediated activation of second-order, arterial chemoreceptor neurones in the commNTS. Peripheral chemoreceptor-evoked inhibition of BAT SNA could directly contribute to (or be permissive for) the hypoxia-evoked reductions in body temperature and oxygen consumption that serve as an adaptive response to decreased oxygen availability.     

Cold-induced and diet-induced thermogenesis in progesterone-treated rats

Both cold-acclimated rats and rats at thermoneutrality received 1.5 mg/day of progesterone over a period of 15 days by means of two subcutaneously implanted Silastic capsules. Progesterone treatment increased total food intake and body mass gain in both groups of treated animals when compared with their controls at the same ambient temperature. However, the interscapular brown adipose tissue (BAT) of the treated rats showed the same thermogenic activity (assessed by GDP-binding), mass and gross composition as that of their respective controls. If it is assumed that enhanced food intake is the physiological drive for diet-induced thermogenesis, it could be concluded that progesterone inhibits diet-induced thermogenesis at thermoneutrality, but has no effect in cold-induced thermogenesis. However, if the physiological drive for diet-induced thermogenesis is not enhanced food intake, but an imbalance in the diet, then given that the same diet was offered to all animals thoroughout the experimental period, it could be that progesterone does not affect BAT, either at thermoneutrality or in the cold.     

In vitro thermogenesis and phospholipid fatty acid composition of brown adipose tissue in fasted and refed rats.

Membrane phospholipids are known for their role in the regulation of membrane structures and functions. Membrane phospholipid fatty acid docosahexaenoic acid (DHA) has been recently indicated to be important for the regulation of cellular activities, including metabolic regulation. Our previous studies have indicated the involvement of DHA in the regulation of brown adipose tissue (BAT) thermogenesis. The objective of the present study is to examine the changes in BAT phospholipid fatty acid composition including DHA and thermogenic activity in fasted and refed rats. Phospholipid content per microgram DNA was decreased in rats fasted for 72 h and it was not restored to the control level by refeeding for 72 h. Phospholipid fatty acid composition of BAT, as expressed by mol%, was modified in the fasted rats. Most notably, DHA, which constituted about 89% of the n-3 polyunsaturated fatty acids, was decreased concomitant with the increase in the n-6 polyunsaturated fatty acid arachidonic acid. The monounsaturated to saturated fatty acid ratio, which is an index of Delta(9)-desaturase activity and membrane fluidity, was decreased. Thermogenesis, as measured by the in vitro oxygen consumption of BAT, was suppressed in the fasted rats. All of the above changes were restored to normal levels after refeeding the fasted rats for 72 h. In vitro oxygen consumption correlated with the level of DHA and monounsaturated to saturated fatty acid ratio. These results indicate that the modification of phospholipid fatty acid composition, especially the modification of n-3 polyunsaturated fatty acid DHA, and membrane fluidity are related to BAT thermoregulation in fasted and refed rats.     

Orexin-a regulates body temperature in coordination with control of arousal state

Orexin-a regulates body temperature in coordination with control of arousal state     

Exercise and brain catecholamine relationships with brown adipose tissue and whole-body oxygen consumption in rats

Brown Adipose Tissue (BAT) is thought to maintain caloric homeostasis by increasing its metabolic rate during periods of energy surfeit or low environmental temperatures and decreasing it during periods of deprivation or high environmental temperatures. The present study investigated the relationship of BAT and whole-body metabolic rate with negative energy balance induced by a minimally stressful exercise regimen. Twenty-four rats exercised in a running wheel for 2 hours per day for 8 weeks for food reinforcement either under a variable ratio or variable time schedule. Whole-body oxygen consumption and the thermic effect of a test meal were then measured, the rats sacrificed, BAT weight and oxygen consumption measured, and the brains assayed for catecholamines. Food intake was found to be positively correlated with expenditure either in the form of exercise, overnight weight loss, or BAT metabolic rate. Brain dopamine concentrations were found to be related to BAT metabolic rate which was in turn related to the amount of weight lost overnight and the amount of food intake. Running was positively correlated with BAT metabolic rate, suggesting that brown adipose tissue is not simply an organ of caloric homeostasis or thermoregulation. BAT, then, appears to be a multi-purpose tool used by a number of systems which regulate body temperature and energy metabolism.     

Studies on the Mechanism of Shock: The Effect of Catecholamines on the Temperature Response to Injury in the Rat

The effects of adrenaline, noradrenaline, l-isoprenaline and dichloroisoprenaline (DCI) on the temperature, O₂ consumption, heat loss from the tail, blood pressure and non-esterified fatty acid (NEFA) concentrations in the plasma of 20° and 3° acclimated rats subjected to 4 hr. bilateral hind-limb ischaemia have been investigated.In 3° acclimated rats the temperature changes in the interscapular brown adipose tissue under these conditions were also studied.The catecholamines and DCI increased heat production in the injured rats, particularly in those previously acclimated to 3°. Among the catecholamines tested l-isoprenaline was the most effective and adrenaline the least. The order of their effectiveness was the same as that for their action on the plasma NEFA concentration in the injured rats. DCI also increased the plasma NEFA concentration whereas a related compound DCB, which did not raise the temperature, had no lipolytic effect.The increase in heat production caused by these compounds had no survival value for the injured rats.The possible mechanisms of these effects are discussed and it is hoped that these compounds will prove useful in the investigation of the mechanism of the decrease in heat production following injury.     

Raphe pallidus neurons mediate prostaglandin E2-evoked increases in brown adipose tissue thermogenesis

To elucidate central neural pathways contributing to the febrile component of the acute phase response to pyrogenic insult, I sought to determine whether activation of neurons in the rostral raphe pallidus (RPa) is required for the increase in brown adipose tissue (BAT) thermogenesis evoked by i.c.v. prostaglandin E(2) (PGE(2)) in urethane-chloralose-anesthetized, ventilated rats. BAT sympathetic nerve activity (SNA; +224% of control), BAT temperature (+1.8 degrees C), expired CO(2) (+1.3%), mean arterial pressure (+23 mm Hg), and heart rate (+73 beats per minute) were significantly increased after i.c.v. PGE(2) (2 microg). Microinjection of either the GABA(A) receptor agonist, muscimol (2 mM, 60 nl), or glycine (0.5M, 60 nl) into RPa resulted in a prompt reversal of the PGE(2)-evoked stimulation of BAT SNA, BAT thermogenesis and heart rate, with these variables returning to control levels prior to i.c.v. PGE(2) following the long-lasting, muscimol-induced inhibition of RPa neurons. In conclusion, activation of neurons in RPa, possibly BAT sympathetic premotor neurons, is essential for the increases in BAT SNA and BAT thermogenesis stimulated by i.c.v. administration of PGE(2). The increased heart rate likely contributing to an augmented cardiac output supporting the increased BAT thermogenesis in response to PGE(2) is also dependent on neurons in RPa. These results contribute to our understanding of central neural substrates for the augmented thermogenesis during fever.     

The response of malnourished babies to cold

1. Twelve malnourished Jamaican children, aged 4-16 months, were studied before and after treatment, to see whether malnutrition impaired their response to cold.2. When they were studied in the post-absorptive state and in a neutral thermal environment, they had a lower rate of oxygen consumption per kg body weight, a slower pulse rate, lower body temperatures, lower R.Q., and evidence of a smaller peripheral blood flow on admission to hospital than they did after recovery.3. The malnourished children failed to increase their heat production above resting levels at 25 degrees C, and their rectal temperature fell at a rate of 1 degrees C/hr in spite of a further decrease in peripheral circulation.4. When they had recovered they maintained their body temperature within the normal range on exposure to this temperature, while increasing their heat production by 20%. The thermogenesis was apparently of the non-shivering type.5. There was evidence of increased metabolic activity in the interscapular brown fat pad at 25 degrees C both on admission and before discharge. In the malnourished children this activity was not sufficient to produce a measurable increase in total oxygen consumption.6. Interscapular brown fat was examined at autopsy in thirteen malnourished and fifteen well nourished children aged 1-24 months. Lipid depletion was found in this tissue in the former but not in the latter. This may explain the impaired response of the malnourished child to cold.     

Differential early rearing affects response to overfeeding in B6D2F2 mice

Male and female B6D2F2 mice, reared in small (Sm = 4), medium (Md = 8) and large (Lg = 12) litters, were maintained on high-fat, high-carbohydrate (EXP) or chow (CH) diets beginning at 14 weeks. EXP mice consumed more calories and gained more weight than CH mice; these effects were greatest in the Sm animals. Each sex responded similarly. Caloric efficiency was highest in the Sm EXP and male animals. Total body fat in males showed that Sm greater than Md greater than Lg and EXP greater than CH. The thermogenic capacity was measured by total oxygen consumption and body temperature response during acute cold stress, and protein content and cytochrome c oxidase activity in interscapular brown adipose tissue (1BAT). Sm mice had a smaller decrease in temperature and consumed less oxygen per gram body weight than Lg, suggestive of a contributing role of increased insulation. When oxygen consumption was expressed as a function of body weight0.75, EXP greater than CH, but there were no other significant dietary effects. Neither litter size nor diet appeared to affect protein content or cytochrome c oxidase activity in 1BAT. These results show that early rearing experience effects both behavioural and physiological variables associated with the maintenance of adult body weight in mice, but these effects do not appear to be mediated through 1BAT.