Thermogenic Response Of Brown Adipose Tissue Research Articles

NPFF signalling is critical for thermosensory and dietary regulation of thermogenesis

Thermogenesis is a centrally regulated physiological process integral for thermoregulation and energy homeostasis. However, the mechanisms and pathways involved remain poorly understood. Importantly, in this study we uncovered that in an environment of 28 °C that is within the mouse thermoneutral zone, lack of NPFF signalling leads to significant increases in energy expenditure, resting metabolic rate and brown adipose tissue (BAT) thermogenesis, which is associated with decreased body weight gain and lean tissue mass. Interestingly, when exposed to a high-fat diet (HFD) at 28 °C, Npff−/− mice lost the high energy expenditure phenotype observed under chow condition and exhibited an impaired diet-induced thermogenesis. On the other hand, under conditions of increasing levels of thermal demands, Npff−/− mice exhibited an elevated BAT thermogenesis at mild cold condition (22 °C), but initiated comparable BAT thermogenic responses as WT mice when thermal demand increased, such as an exposure to 4 °C. Together, these results reveal NPFF signalling as a novel and critical player in the control of thermogenesis, where it regulates thermosensory thermogenesis at warm condition and adjusts thermoregulation under positive energy balance to regulate diet-induced thermogenesis.

An oxytocinergic neural pathway that stimulates thermogenic and cardiac sympathetic outflow.

Oxytocin alters autonomic functions besides social behaviors. However, the central neuronal links between hypothalamic oxytocinergic neurons and the autonomic nervous system remain unclear. Here we show that oxytocinergic neurons in the rat paraventricular hypothalamic nucleus (PVH), a pivotal site for energy homeostasis, innervate sympathetic premotor neurons in the rostral medullary raphe region (rMR) to stimulate brown adipose tissue (BAT) thermogenesis and cardiovascular functions. Oxytocin receptor stimulation in the rMR evokes BAT thermogenesis and tachycardia. Invivo optogenetic stimulation of the PVH→rMR long-range oxytocinergic pathway, using a virus-mediated system for amplified gene expression in oxytocinergic neurons, not only elicits BAT thermogenic and cardiac responses but also potentiates sympathetic responses evoked by glutamatergic transmission in the rMR. The PVH→rMR oxytocinergic pathway connects the hypothalamic circuit for energy homeostasis to thermogenic and cardiac sympathetic outflow, and, therefore, its defects may cause obesity and impaired thermoregulation, as seen in Prader-Willi syndrome.

BMP8 and activated brown adipose tissue in human newborns

The classical dogma states that brown adipose tissue (BAT) plays a major role in the regulation of temperature in neonates. However, although BAT has been studied in infants for more than a century, the knowledge about its physiological features at this stage of life is rather limited. This has been mainly due to the lack of appropriate investigation methods, ethically suitable for neonates. Here, we have applied non-invasive infrared thermography (IRT) to investigate neonatal BAT activity. Our data show that BAT temperature correlates with body temperature and that mild cold stimulus promotes BAT activation in newborns. Notably, a single short-term cold stimulus during the first day of life improves the body temperature adaption to a subsequent cold event. Finally, we identify that bone morphogenic protein 8B (BMP8B) is associated with the BAT thermogenic response in neonates. Overall, our data uncover key features of the setup of BAT thermogenesis in newborns.

Activation of Transient Receptor Potential Vanilloid 1 Channels in the Nucleus of the Solitary Tract and Activation of Dynorphin Input to the Median Preoptic Nucleus Contribute to Impaired BAT Thermogenesis in Diet-Induced Obesity.

The impairment of cold-evoked activation of brown adipose tissue (BAT) in rats fed a high-fat diet (HFD) requires the activity of a vagal afferent to the medial nucleus of the solitary tract (mNTS). We determined the role of transient receptor potential vanilloid 1 (TRPV1) activation in the mNTS, and of a dynorphin input to the median preoptic nucleus (MnPO) in the impaired BAT thermogenic response to cold in HFD-fed rats. The levels of some linoleic acid (LA) metabolites, which can act as endogenous TRPV1 agonists, were elevated in the NTS of HFD rats compared with chow-fed rats. In HFD rats, nanoinjections of the TRPV1 antagonist, capsazepine (CPZ) in the NTS rescued the impaired BAT sympathetic nerve activity (BAT SNA) and thermogenic responses to cold. In contrast, in chow-fed rats, cold-evoked BAT SNA and BAT thermogenesis were not changed by nanoinjections of CPZ into the NTS. Axon terminals of NTS neurons that project to the dorsal lateral parabrachial nucleus (LPBd) were closely apposed to LPBd neurons that project to the MnPO. Many of the neurons in the LPBd that expressed c-fos during cold challenge were dynorphinergic. In HFD rats, nanoinjections of the κ opioid receptor (KOR) antagonist, nor-binaltorphimine (nor-BNI), in the MnPO rescued the impaired BAT SNA and thermogenic responses to cold. These data suggest that HFD increases the content of endogenous ligands of TRPV1 in the NTS, which increases the drive to LPBd neurons that in turn release dynorphin in the MnPO to impair activation of BAT.

Median preoptic area neurons are required for the cooling and febrile activations of brown adipose tissue thermogenesis in rat

Within the central neural circuitry for thermoregulation, the balance between excitatory and inhibitory inputs to the dorsomedial hypothalamus (DMH) determines the level of activation of brown adipose tissue (BAT) thermogenesis. We employed neuroanatomical and in vivo electrophysiological techniques to identify a source of excitation to thermogenesis-promoting neurons in the DMH that is required for cold defense and fever. Inhibition of median preoptic area (MnPO) neurons blocked the BAT thermogenic responses during both PGE2-induced fever and cold exposure. Disinhibition or direct activation of MnPO neurons induced a BAT thermogenic response in warm rats. Blockade of ionotropic glutamate receptors in the DMH, or brain transection rostral to DMH, blocked cold-evoked or NMDA in MnPO-evoked BAT thermogenesis. RNAscope technique identified a glutamatergic population of MnPO neurons that projects to the DMH and expresses c-Fos following cold exposure. These discoveries relative to the glutamatergic drive to BAT sympathoexcitatory neurons in DMH augment our understanding of the central thermoregulatory circuitry in non-torpid mammals. Our data will contribute to the development of novel therapeutic approaches to induce therapeutic hypothermia for treating drug-resistant fever, and for improving glucose and energy homeostasis.

MON-LB016 Sex and Sex Steroid Effects on Brown Adipose Tissue Temperature in Healthy Humans

Retrospective studies indicate that women have more brown adipose tissue (BAT) than men. Furthermore, animal studies show that sex steroids modulate BAT activity, wherein estrogen increases BAT function. We aimed to characterize BAT thermogenesis using infrared thermography (IRT) in healthy men (n=14; age 23.07 ± 0.7 years, BMI 23.22 ± 0.7 kg/m2) and in women during 2 stages of the menstrual cycle (luteal, n=9; age 25.22 ± 1.7 years, BMI 21.56 ± 0.4 kg/m2 and follicular, n=11; age 24.64 ± 1.2 years, BMI 22.12 ± 0.9 kg/m2). We measured cutaneous temperature in the supraclavicular (BAT positive) and the manubrium (BAT negative) regions, at baseline and in response to dietary and cold stimuli. Temperature recordings were at 1 min intervals, at an ambient temperature of 18.5-20°C. To activate cold-induced thermogenesis, one hand was immersed into water at 15°C for 5 min. Post-prandial thermogenesis was stimulated by the consumption of a liquid meal (Ensure, 10 kcal/ kg body weight). In fasted participants, baseline BAT temperature was higher (P<0.05) in women during the luteal phase than in either women during the follicular phase or men. Innate variation in baseline temperature was correlated (P<0.001) with serum progesterone concentrations, without being associated with estrogen or testosterone concentrations. The temperature response to cold exposure was biphasic, with an initial increase during cold exposure and a secondary increase approximately 20 min later; the latter phase has been referred to as adaptive thermogenesis. Women had greater (P<0.05) adaptive thermogenic responses to cold and dietary stimuli and this effect was greater (P<0.05) during the luteal phase of the menstrual cycle. During cold-exposure, the increase in BAT temperature was lower (P<0.05) in females during the follicular phase than during the luteal phase. Post-cold and post-prandial adaptive thermogenesis was greater in women than men, irrespective of the stage of menstrual cycle. Regression analyses showed that the degree of adaptive thermogenesis was positively correlated with serum estrogen concentrations (cold; P<0.05, meal; P=0.07), but negatively associated with serum testosterone concentrations (cold; P=0.07, meal; P<0.05). In summary, women typically display greater thermogenic responses than men, with an influence of the stage of menstrual cycle in women. Furthermore, we highlight that innate variation in BAT temperature and thermogenic responses to cold and diet are associated with fluctuations in the circulating levels of estrogen, progesterone and testosterone. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Brown adipose tissue thermogenic response in children with hypothyroidism

Brown adipose tissue thermogenic response in children with hypothyroidism

Brown Adipose Tissue Exhibits a Glucose-Responsive Thermogenic Biorhythm in Humans

High abundance of brown adipose tissue (BAT) is linked to lower glycaemia in humans, leading to thebelief that BAT may protect against diabetes. The relationship between BAT glucose utilization and systemic glucose homeostasis has not been defined.In this paper we have characterized glycaemic excursions and BAT thermogenic responses in human brown adipocytes, BAT explants, and healthy adults through supraclavicular temperature profiling, revealing their circadian coupling invivo and invitro, orchestrated by UCP1, GLUT4, and Rev-erbα biorhythms. Extent of glycated haemoglobin also correlated positively with environmental temperature among community-dwelling patients. These data uncover potential crosstalk between BAT and glucose regulatory pathways, evident on cellular, tissue, individual, and population levels, and provide impetus to search for BAT harnessing strategies for therapeutic purposes.

Transgenic rats with ataxin3-mediated destruction of orexin neurons have a diminished brown adipose tissue (BAT) thermogenic response to confrontation with an intruder rat

Brown adipose tissue (BAT) thermogenesis is activated when rats explore the environment (1–2). We now examine BAT thermogenic responses to salient stimuli (introduction of an intruder rat) in transgenic rats with ataxin3-mediated destruction of orexin neurons, compared with wild type controls (3). Under inhaled isoflurane (2% in oxygen) anaesthesia, transgenic or wild type rats (300–450g) were instrumented with chronically implanted thermistors to measure BAT and body temperature (Blessing et al., 2012).

Central efferent pathways for cold‐defensive and febrile shivering

Shivering is a remarkable somatomotor thermogenic response that is controlled by brain mechanisms. We recorded EMGs in anaesthetized rats to elucidate the central neural circuitry for shivering and identified several brain regions whose thermoregulatory neurons comprise the efferent pathway driving shivering responses to skin cooling and pyrogenic stimulation. We simultaneously monitored parameters from sympathetic effectors: brown adipose tissue (BAT) temperature for non-shivering thermogenesis and arterial pressure and heart rate for cardiovascular responses. Acute skin cooling consistently increased EMG, BAT temperature and heart rate and these responses were eliminated by inhibition of neurons in the median preoptic nucleus (MnPO) with nanoinjection of muscimol. Stimulation of the MnPO evoked shivering, BAT thermogenesis and tachycardia, which were all reversed by antagonizing GABA(A) receptors in the medial preoptic area (MPO). Inhibition of neurons in the dorsomedial hypothalamus (DMH) or rostral raphe pallidus nucleus (rRPa) with muscimol or activation of 5-HT1A receptors in the rRPa with 8-OH-DPAT eliminated the shivering, BAT thermogenic, tachycardic and pressor responses evoked by skin cooling or by nanoinjection of prostaglandin (PG) E2, a pyrogenic mediator, into the MPO. These data are summarized with a schematic model in which the shivering as well as the sympathetic responses for cold defence and fever are driven by descending excitatory signalling through the DMH and the rRPa, which is under a tonic inhibitory control from a local circuit in the preoptic area. These results provide the interesting notion that, under the demand for increasing levels of heat production, parallel central efferent pathways control the somatic and sympathetic motor systems to drive thermogenesis.

Opposite actions of testosterone and progesterone on UCP1 mRNA expression in cultured brown adipocytes.

The brown adipose tissue (BAT) thermogenic response to diet-induced obesity and cold has been found to be gender dependent. In the present work, we aimed to investigate the effects of the main physiological male and female sex hormones, i.e. testosterone, progesterone and 17-beta-estradiol, on the expression of uncoupling protein I (UCP1)--the main mediator of BAT thermogenesis--and on UCP2 and lipid accumulation in rodent brown adipocytes differentiated in culture. Testosterone-treated cells showed fewer and smaller lipid droplets than control cells and a dose-dependent inhibition of UCP1 mRNA expression, under adrenergic stimulation by norepinephrine (NE). These effects were reverted by the androgen receptor antagonist flutamide, suggesting they are dependent, at least in part, on the androgen receptor. Progesterone- and 17-beta-estradiol-treated cells showed more and larger lipid droplets and progesterone stimulated NE-induced UCP1 mRNA expression at the lower concentration tested, but not at higher concentrations, suggesting that for brown adipocytes, this hormone is dose dependent. 17-beta-Estradiol did not have any remarkable effect either on UCP1 or UCP2 mRNA expression. Interestingly, the specific progesterone receptor antagonist RU486 induced UCP1 and UCP2 mRNAs, including UCP1 mRNA expression in non-NE-treated brown adipocytes, suggesting a profound effect of this antiprogestagen on brown adipocyte thermogenic capacity. Thus, are conclude that testosterone, 17-beta-estradiol, progesterone and RU486 have distinct actions on brown adipocytes, thus modulating UCP1 and UCP2 mRNA expression and/or lipid accumulation, and that sex hormones are factors that may explain in part the gender-dependent BAT thermogenic response.

Reduced Rearing Temperature Augments Responses in Sympathetic Outflow to Brown Adipose Tissue

Sympathetic outflow to brown adipose tissue (BAT) contributes to both thermoregulation and energy expenditure in rats through regulation of BAT thermogenesis. Acute cold exposure in mature animals augments BAT thermogenesis; however, the enhanced BAT thermogenic response returns to normal shortly after cessation of the cold exposure. In this study, we sought to determine whether cold exposure in early neonatal life could induce enhanced responses in the sympathetic outflow to BAT and whether this altered sympathetic regulation would be sustained after the cold stimulus was removed. BAT sympathetic nerve activity (SNA) was recorded in urethane-chloralose-anesthetized, artificially ventilated rats that were raised from birth in either 18 or 30 degrees C environments and then, at 8 weeks of age, were maintained in 23 degrees C for at least 4 weeks. An acute hypothermic stimulus, disinhibition of a brainstem thermogenic network in the raphe pallidus, or electrical stimulation in this raphe site produced increases in BAT SNA that were twice as great in rats reared at 18 degrees C as in those reared at 30 degrees C. The norepinephrine content of the interscapular BAT (IBAT) and the number of sympathetic ganglion cells projecting to interscapular BAT were 70% greater in the 18 degrees C-reared rats. We conclude that neonatal exposure to a cold environment induces a permanent developmental alteration in the capacity for sympathetic stimulation of BAT thermogenesis that may be mediated, in part, by a greater number of sympathetic ganglion cells innervating BAT in cold-reared animals.

Difference in brown adipose tissue effector response and associated thermoresponsiveness of ventromedial hypothalamic (VMH) neurons of 21°C vs. 4°C acclimatized rats to scrotal thermal stimulation

The present study was designed (1) to determine if scrotal thermal stimulation would activate brown adipose tissue (BAT) thermogenesis, indicated by increases in interscapular BAT temperature (T IBAT) of cold acclimatized (CA, kept at 4°C for 4 weeks) and room temperature acclimatized rats (RA, kept at 21°C for 4 weeks) and (2) to compare the thermoresponsiveness of VMH neurons of both groups to scrotal heating and cooling. VMH extracellular activity was recorded in male RA and CA Sprague-Dawley rats when scrotal temperatures (T sc) were changed between 5–40°C via localized thermode (3 mm 2) along with measurements of T scs and T IBATs. The CA-group showed significant increases in T IBATs during scrotal cooling compared to respective T IBATs of the RA-group. The ratio of VMH warm responsive (WRN), cold responsive (CRN) and temperature non-responsive (TNRN) neurons in the CA-group changed compared to that in the RA-group as a greater percentage of CRNs occurred in the CA-group. Also, the thermoresponsiveness of individual VMH CRNs of the CA rats was significantly increased compared to VMH CRNs of the RA-group. The results indicated that localized scrotal cooling of CA-rats (not RA-rats) can activate BAT thermogenesis. Furthermore, VMH CRNs increased their thermoresponsiveness with chronic cold exposure which may be an important neuronal adaptive response for the subsequent enhanced BAT thermogenic effector response seen in that group.

Role of mast cell histamine in brown adipose tissue thermogenic response to VMH stimulation.

Electrical stimulation of the ventromedial hypothalamic area in rats caused a significant but transient increase in interscapular brown adipose tissue temperature. This response was markedly reduced by cimetidine, a histamine H2-receptor antagonist, but not by pyrilamine, an H1-receptor antagonist. Histamine is present in substantial amounts within mast cells in brown adipose tissue as injections of compound 48/80, which cause degranulation of connective tissue mast cells, reduced the tissue histamine content by > 85%. In contrast, histamine content in brown adipose tissue was not affected by loss of sympathetic neural input (with 6-hydroxydopamine) or sensory neural input (with capsaicin). Neither cimetidine nor histamine had any effect on basal and norepinephrine-stimulated rates of O2 consumption by isolated brown adipocytes. These results indicate that histamine released from mast cells acting on H2-receptors may play an important but indirect role in the thermogenic response of brown adipose tissue to stimulation of the ventromedial hypothalamic area.

Differences in brown adipose tissue thermogenic responses between Long-Evans and Sprague-Dawley rats.

Temperature experiments of 4- and 21 degrees C-acclimated conscious and anesthetized Sprague-Dawley (SD) and Long-Evans (LE) rats revealed that the LE groups or SD rats acclimated to 4 degrees C had significant increases in intracapsular brown adipose tissue (IBAT) temperature above core after ventromedial hypothalamic nucleus (VMH) electrical stimulation or after norepinephrine (NE) infusion (50 micrograms/kg total dose), whereas IBAT temperatures of SD rats (acclimated to 21 degrees C) rose only after intravenous NE. Another study of 21- or 4 degrees C-acclimated SD rats revealed that only the 4 degrees C-acclimated group showed graded increases in IBAT temperature after VMH electrical stimulation as current amplitude or total current duration (not pulse frequency) of the electrical stimulus was increased. In vitro analysis of isolated IBAT tissues of age-matched anesthetized LE or SD rats acclimated to 21 degrees C showed that many indicators of thermogenic capacity including mitochondrial uncoupling protein were significantly lower in the SD group. The results demonstrate that lean male SD rats acclimated to 21 degrees C have suppressed IBAT temperature responses to VMH electrical stimulation compared with lean LE rats due to a reduced thermogenic capacity of that tissue.

Effect of Total Sleep Deprivation on 5′-Deiodinase Activity of Rat Brown Adipose Tissue*

Prolonged sleep deprivation of the rat produces a progressive increase in energy expenditure and an eventual decrease in body temperature, which suggests a profound derangement in thermoregulation. Because increased thermogenic activity in brown adipose tissue (BAT) is a likely mechanism mediating the observed increase in energy expenditure, we focused our attention on the effect of total sleep deprivation on BAT type II 5'-deiodinase (5'D-II), since its activation indicates BAT stimulation and is essential for full BAT thermogenic response. Five euthyroid rats were subjected to total (92%) sleep deprivation (euD-rats). Sharing the sleep deprivation apparatus, yoked control rats (euC-rats) received the same degree of physical stimulation as the D-rats, but were only partially (25%) sleep deprived. Additional cage controls (euCC-rats) were housed in the same room. Since during sleep deprivation the animals undergo a reduction in plasma T4 concentration and inability to maintain body temperature heralds death, an identical study was performed in five trios of hyperthyroid rats (hyperD-, hyperC-, and hyper CC-rats) given daily ip injections of 15 micrograms T4/100 g BW, 10 days before and throughout the deprivation period. Experiments were carried out at an ambient temperature of 29 C, close to thermoneutrality for rats. Sleep deprivation in hyperD-rats was maintained until death seemed imminent (9-14 days), and in euD-rats for 12-15 days. Sleep deprivation induced a significant increase in BAT 5'D-II activity in both hyperD- and euD-rats compared with that in euCC-rats (P less than 0.01). BAT 5'D-II in euC-rats was also significantly higher than that in euCC-rats (P less than 0.05), probably because they were partially sleep deprived. BAT 5'D-II activity in hyperD-rats was increased compared to that in both hyperC- and hyperCC-rats (P less than 0.05), in which the activity was slightly but not significantly lower than that in euCC-rats. No significant differences were observed in liver and kidney type I 5'-D (5'D-I) and in pituitary 5'D-II among euD-rats, euC-rats, and euCC-rats. As expected, the hyperthyroid groups (hyperD-rats, hyperC-rats, and hyperCC-rats) had significantly higher kidney 5'D-I and lower pituitary 5'D-II than the euCC-rats. Liver 5'D-I was also significantly increased in the hyperC-rats and hyperCC-rats, but not in the hyperD-rats. These observations indicate that total sleep deprivation is associated with a marked increase in BAT 5'D-II activity in both euthyroid and hyperthyroid rats.(ABSTRACT TRUNCATED AT 400 WORDS)

Brown adipose tissue thermogenic responses of rats induced by central stimulation: effect of age and cold acclimation.

1. Urethane-anaesthetized, age-matched cold-(4 degrees C) and room (21 degrees C)-acclimated groups of Sprague-Dawley rats were given repeated (three) ventromedial hypothalamic electrical stimulations. Interscapular brown adipose tissue (IBAT), colonic, surface tail temperatures and blood pressure were monitored before and after each electrical stimulation. Propranolol HCl (2.5 mg kg-1 i.v.) was given 10 min prior to the last (third) ventromedial hypothalamic stimulation. 2. Repeated electrical stimulation of the ventromedial hypothalamic (VMH) nucleus to either small or large rats (kept at 21 degrees C) caused no significant change in interscapular brown fat, colonic or surface temperatures compared to respective pre-stimulation control values whereas mean arterial pressure was slightly but significantly increased during the 30 s stimulation period. 3. Electrical stimulation of the ventromedial hypothalamic nucleus of small or large rats, kept at 4 degrees C for 3 weeks prior to testing, caused significant (greater than 0.25 and greater than 0.40 degrees C, respectively) rises in interscapular BAT temperature from respective prestimulation control values. Colonic temperatures increased following ventromedial hypothalamic electrical stimulation only in the small, 4 degrees C-acclimated group whereas surface tail temperatures did not significantly change after stimulation of either cold-exposed group. Mean arterial pressures were significantly increased during ventromedial hypothalamic electrical stimulation in both 4 degrees C-acclimated groups, compared to pre-stimulation control levels and, in addition, were above those of age-matched rats kept at 21 degrees C. Intravenous propranolol, which decreased interscapular brown fat and colonic temperatures in all groups, blocked the rise in interscapular brown fat and colonic temperatures of the 4 degrees C-acclimated rats following the last electrical stimulation of the ventromedial hypothalamic nucleus. 4. In vitro biochemical analysis of the interscapular brown fat pads of another four groups of age-matched, small and large 21 and 4 degrees C-acclimated rats revealed that the thermogenic capacity of the 4 degrees C-acclimated groups was, in all cases, significantly increased from age-matched groups previously kept at 21 degrees C, as shown by significant increases in brown adipose tissue mass, BAT DNA and protein content, BAT mitochondrial protein and BAT mitochondrial GDP binding.(ABSTRACT TRUNCATED AT 400 WORDS)

Defective regulation of thyroxine 5'-deiodinase in brown adipose tissue of ob/ob mice

Genetically obese (ob/ob) and lean (+/?) mice were exposed to a cold (14 degrees C) environment for 1, 3, 6, 12, 16, or 24 h or remained in a warm (28 degrees C) environment. In ob/ob mice the increase in brown adipose tissue (BAT) thermogenesis (mitochondrial GDP binding) was low and the increase in thyroxine 5'-deiodinase (T5'D) was delayed; there was a reduced increase in serum 3,5,3'-triiodothyronine (T3) level and these mice became hypothermic. Content of uncoupling protein (UCP) was low in BAT of obese mice and no cold-induced increase occurred. Adrenalectomy of obese mice before exposure to cold (14 degrees C) improved defective thermogenic response of BAT and thermoregulation, restored to normal the increases in T5'D activity and serum T3 level, and promoted an exaggerated increase in UCP content, detectable after only 6 h. Adrenalectomy of cold-exposed lean mice did not alter thermoregulation, the increase in BAT T5'D activity, or the increase in serum T3 but enhanced the thermogenic response and allowed a higher UCP content in BAT of cold-exposed mice. We conclude that suppression of the cold-induced increase in T5'D activity in BAT can be added to the other known corticosterone-dependent anomalies of the ob/ob mouse. We speculate that lack of the cold-induced increase in T5'D in BAT of the ob/ob mouse prevents the normal participation of T3 in the trophic response of BAT to cold and underlies the abnormality in this response.

The Role of Insulin in Norepinephrine Turnover and Thermogenesis in Brown Adipose Tissue after Acute Cold-Exposure.

The role of insulin in norepinephrine turnover (NE) and thermogenesis in brown adipose tissue (BAT) after acute cold-exposure was studied using streptozocin (STZ)-induced diabetic rats. NE turnover was estimated by the NE synthesis inhibition technique with alpha-methyl-p-tyrosine. BAT thermogenesis was estimated by measuring mitochondrial guanosine-5'-diphosphate (GDP), cytochrome oxidase activity and mitochondrial oxygen consumption in BAT at an ambient temperature of 22 degrees C and during a six-hour cold-exposure at 4 degrees C. In insulin-deficient diabetic rats, the NE turnover, mitochondrial GDP binding, cytochrome oxidase activity and mitochondrial oxygen consumption in BAT at 22 degrees C were significantly reduced, compared with those of control rats. Treatment of STZ-induced diabetic rats with insulin prevented a decrease in NE turnover and BAT thermogenesis. Acute cold-exposure increased the NE turnover of BAT in insulin-deficient diabetic rats. The BAT thermogenic response to acute cold-exposure, however, did not occur in insulin-deficient diabetic rats. These results suggest that insulin is not essential in potentiating NE turnover in BAT after acute cold-exposure, but is required for cold-induced thermogenesis.