Importance Of Brown Adipose Tissue Research Articles

Impact of brown adipose tissue vascular density on body adiposity in healthy Japanese infants and children.

Background and ObjectiveThe importance of brown adipose tissue (BAT) is well recognized in healthy infants and children. However, information regarding age‐related changes in BAT vascular density (BAT‐d) and the impact of BAT‐d on body adiposity are lacking. This study aimed to evaluate the normal values of BAT‐d, factors influencing BAT‐d, and the impact of BAT‐d on body adiposity in healthy infants and children.MethodsThis study included 240 participants (127 girls and 113 boys) aged 1 month to 5 years. The tissue total hemoglobin concentration in the supraclavicular region adjusted according to the subcutaneous adipose tissue thickness (SAT) ([total‐Hb‐Adj]sup) as BAT‐d. SAT in the deltoid and interscapular regions (SATdel+int), the Kaup index (body weight [g]/height or length [cm]/height or length [cm] × 10) as body adiposity, and fertilization season were also measured.ResultsThe [total‐Hb‐Adj]sup of boys was higher than that of girls (r = 0.277, p = 0.009). Younger children had a significantly higher Kaup index (r = 0.495, p < 0.001) and SATdel+int (r = 0.614, p < 0.001) than older children. Children who had higher [total‐Hb‐Adj]sup had a significantly lower Kaup index (r = 0.495, p = 0.037) and SATdel+int (r = 0.614, p < 0.001).ConclusionThe [total‐Hb‐Adj]sup, as a parameter of BAT‐d, is negatively correlated with body adiposity in children aged 1 month to 5 years, and BAT might affect human obesity to a much greater extent than expected. To prevent or treat obesity in early childhood, the level of BAT‐d should be considered when using a dietary intervention.

Embryonic exposure to hyper glucocorticoids suppresses brown fat development and thermogenesis via REDD1

Maternal stress during pregnancy is prevailing worldwide, which exposes fetuses to intrauterine hyper glucocorticoids (GC), programming offspring to obesity and metabolic diseases. Despite the importance of brown adipose tissue (BAT) in maintaining long-term metabolic health, impacts of prenatal hyper GC on postnatal BAT thermogenesis and underlying regulations remain poorly defined. Pregnant mice were administrated with synthetic GC dexamethasone (DEX) at levels comparable to fetal GC exposure of stressed mothers. Prenatal GC exposure dose-dependently reduced BAT thermogenic activity, contributing to lower body temperature and higher mortality of neonates; such difference was abolished under thermoneutrality, underscoring BAT deficiency was the major contributor to adverse changes in postnatal thermogenesis due to excessive GC. Prenatal GC exposure highly activated Redd1 expression and reduced Ppargc1a transcription from the alternative promoter (Ppargc1a-AP) in neonatal BAT. During brown adipocyte differentiation, ectopic Redd1 expression reduced Ppargc1a-AP expression and mitochondrial biogenesis; and the inhibitory effects of GC on mitochondrial biogenesis and Ppargc1a-AP expression were blocked by Redd1 ablation. Redd1 reduced protein kinase A phosphorylation and suppressed cyclic adenosine monophosphate (cAMP) -responsive element-binding protein (CREB) binding to the cAMP regulatory element (CRE) in Ppargc1a-AP promoter, leading to Ppargc1a-AP inactivation. In summary, excessive maternal GC exposure during pregnancy dysregulates Redd1-Ppargc1a-AP axis, which impairs fetal BAT development, hampering postnatal thermogenic adaptation and metabolic health of offspring.

Maternal obesity impairs fetal mitochondriogenesis and brown adipose tissue development partially via upregulation of miR-204-5p

Maternal obesity (MO) predisposes offspring to metabolic disorders, but the mechanisms remain poorly defined. Recent studies emphasize the importance of brown adipose tissue (BAT) in maintaining metabolic health, and MO was recently demonstrated to impair BAT thermogenic function in offspring. The current study aimed to investigate the mechanisms leading to the impairment in fetal BAT development due to MO. Female C57BL/6J mice were fed a control diet or a 60% high-fat diet for 10 weeks, mated and maintained on their respective diets during pregnancy. Fetal tissue was collected at E18.5, the late stage of pregnancy. Fetal BAT contained more triglycerides compared to the control, which was correlated with higher expression of white adipogenic markers. On the other hand, the expression of BAT markers was down-regulated in the MO fetal BAT. Based on RNA-sequencing analyses, genes related to mitochondriogenesis and myogenesis were found to be down-regulated, while those related to white adipocyte differentiation were up-regulated in MO fetal BAT. Because brown adipocytes are derived from myogenic progenitors, the down-regulation of myogenic genes might partially explain hampered brown adipogenesis in MO fetal BAT. Consistently, mitochondrial DNA and mitochondrial biogenesis markers were also down-regulated in MO fetal BAT. MicroRNA-sequencing identified that miR-204-5p expression was elevated in MO fetal BAT. This microRNA targeted the 3′-untranslated regions of PGC1α and Sirt1 mRNA to suppress their expression and impair mitochondriogenesis. In summary, MO impaired fetal BAT development through suppressing myogenesis and brown adipogenesis while enhancing white adipogenic commitment, and inhibited mitochondriogenesis partially through enhancing miR-204-5p expression.

Cross talk between Skeletal muscle and Brown adipose tissue during cold and diet induced thermogeneis

The importance of brown adipose tissue as a site of nonshivering thermogenesis has been well documented. Emerging studies suggest that skeletal muscle is also an important site of thermogenesis especially when brown adipose tissue function is lacking. We recently showed that sarcolipin (SLN), an uncoupler of the sarco(endo) plasmic reticulum Ca2+ ATPase (SERCA) pump, could contribute to heat production in skeletal muscle. In this study, we sought to understand how loss of UCP1 or SLN is compensated during cold exposure and whether they are both necessary for thermogenesis. Toward this goal, we generated a UCP1; SLN double knock‐out (DKO) mouse model and challenged the single and DKO mice to acute and long‐term cold exposures. Results from this study show that there is up‐regulation of SLN expression in UCP1‐KO mice, and loss of SLN is compensated by increased expression of UCP1 and browning of white adipose tissue. We found that the DKO mice were viable when reared at thermoneutrality. When challenged to acute cold, the DKO were extremely cold‐sensitive and became hypothermic Paradoxically, the DKO mice were able to survive gradual cold challenge, but these mice lost significant weight and depleted their fat stores, despite having higher caloric intake. Interestingly loss of either SLN or UCP1 alone was sufficient to cause high fat diet‐induced obesity. No compensatory upregulation of UCP1 in SLN−/− mice or vice versa was found. However loss of both mechanisms failed to exacerbate the obesity phenotype. These studies imply that brown adipose tissue and skeletal muscle are recruited differently during cold vs diet induced thermogenesis.Support or Funding InformationNIH R01‐HL‐088555 and R01‐DK098240‐01American Diabetes Association Basic Science Research Award (7‐13‐BS‐131) (to MP) and by the NIDDK‐NIH Award (K01‐DK102772) (to NCB).

The Effects of High Fat Diet and Resveratrol on Mitochondrial Activity of Brown Adipocytes

BackgroundResveratrol (RSV) is a polyphenolic phytoalexin that has many effects on metabolic diseases such as diabetes and obesity. Given the importance of brown adipose tissue (BAT) for energy expenditure, we investigated the effects of RSV on brown adipocytes.MethodsFor the in vitro study, interscapular BAT was isolated from 7-week-old male Sprague Dawley rats. For the in vivo study, 7-week-old male Otsuka Long Evans Tokushima Fatty (OLETF) rats were divided into four groups and treated for 27 weeks with: standard diet (SD); SD+RSV (10 mg/kg body weight, daily); high fat diet (HFD); HFD+RSV. RSV was provided via oral gavage once daily during the in vivo experiments.ResultsRSV treatment of primary cultured brown preadipocytes promoted mitochondrial activity, along with over-expression of estrogen receptor α (ER-α). In OLETF rats, both HFD and RSV treatment increased the weight of BAT and the differentiation of BAT. However, only RSV increased the mitochondrial activity and ER-α expression of BAT in the HFD-fed group. Finally, RSV improved the insulin sensitivity of OLETF rats by increasing the mitochondrial activity of BAT, despite having no effects on white adipocytes and muscles in either diet group.ConclusionRSV could improve insulin resistance, which might be associated with mitochondrial activity of brown adipocyte. Further studies evaluating the activity of RSV for both the differentiation and mitochondrial activity of BAT could be helpful in investigating the effects of RSV on metabolic parameters.

Apelin Enhances Brown Adipogenesis and Browning of White Adipocytes

Brown adipose tissue expends energy in the form of heat via the mitochondrial uncoupling protein UCP1. Recent studies showed that brown adipose tissue is present in adult humans and may be exploited for its anti-obesity and anti-diabetes actions. Apelin is an adipocyte-derived hormone that plays important roles in energy metabolism. Here, we report that apelin-APJ signaling promotes brown adipocyte differentiation by increasing the expressions of brown adipogenic and thermogenic transcriptional factors via the PI3K/Akt and AMPK signaling pathways. It is also found that apelin relieves the TNFα inhibition on brown adipogenesis. In addition, apelin increases the basal activity of brown adipocytes, as evidenced by the increased PGC1α and UCP1 expressions, mitochondrial biogenesis, and oxygen consumption. Finally, we provide both in vitro and in vivo evidence that apelin is able to increase the brown-like characteristics in white adipocytes. This study, for the first time, reveals the brown adipogenic and browning effects of apelin and suggests a potential therapeutic route to combat obesity and related metabolic disorders.

Uncoupling Protein 1 and Sarcolipin Are Required to Maintain Optimal Thermogenesis, and Loss of Both Systems Compromises Survival of Mice under Cold Stress

The importance of brown adipose tissue as a site of nonshivering thermogenesis has been well documented. Emerging studies suggest that skeletal muscle is also an important site of thermogenesis especially when brown adipose tissue function is lacking. We recently showed that sarcolipin (SLN), an uncoupler of the sarco(endo)plasmic reticulum Ca(2+) ATPase (SERCA) pump, could contribute to heat production in skeletal muscle. In this study, we sought to understand how loss of UCP1 or SLN is compensated during cold exposure and whether they are both necessary for thermogenesis. Toward this goal, we generated a UCP1;SLN double knock-out (DKO) mouse model and challenged the single and DKO mice to acute and long-term cold exposures. Results from this study show that there is up-regulation of SLN expression in UCP1-KO mice, and loss of SLN is compensated by increased expression of UCP1 and browning of white adipose tissue. We found that the DKO mice were viable when reared at thermoneutrality. When challenged to acute cold, the DKO were extremely cold-sensitive and became hypothermic. Paradoxically, the DKO mice were able to survive gradual cold challenge, but these mice lost significant weight and depleted their fat stores, despite having higher caloric intake. These studies suggest that UCP1 and SLN are required to maintain optimal thermogenesis and that loss of both systems compromises survival of mice under cold stress.

Tyk2 and Stat3 Regulate Brown Adipose Tissue Differentiation and Obesity

Mice lacking the Jak tyrosine kinase member Tyk2 become progressively obese due to aberrant development of Myf5+ brown adipose tissue (BAT). Tyk2 RNA levels in BAT and skeletal muscle, which shares a common progenitor with BAT, are dramatically decreased in mice placed on a high-fat diet and in obese humans. Expression of Tyk2 or the constitutively active form of the transcription factor Stat3 (CAStat3) restores differentiation in Tyk2(-/-) brown preadipocytes. Furthermore, Tyk2(-/-) mice expressing CAStat3 transgene in BAT also show improved BAT development, normal levels of insulin, and significantly lower body weights. Stat3 binds to PRDM16, a master regulator of BAT differentiation, and enhances the stability of PRDM16 protein. These results define Tyk2 and Stat3 as critical determinants of brown fat lineage and suggest that altered levels of Tyk2 are associated with obesity in both rodents and humans.

Adipokine expression in brown and white adipocytes in response to hypoxia.

Adipose tissue has emerged as an important endocrine regulator by secreting hormones referred to as adipokines. Recent studies showed that adipose tissue considerably responds to hypoxia. Although the impact of white adipose tissue on regulative processes is established, the importance of brown adipose tissue in adults has emerged just recently. Brown (BA) and white adipocytes (WA) were cultured either in the presence of chemical hypoxia-mimetics or under hypoxic atmosphere of 1% oxygen. Expression of hypoxia-inducible factor 1α (HIF- 1α) was assessed by western blot. The expression levels of several known HIF-1α-regulated proteins [vascular endothelial growth factor (VEGF), leptin, adiponectin, and angiotensinogen (AGT)] were quantified. Both chemical hypoxia-mimetics and physical hypoxia led to increased nuclear HIF-1α expression and to decreased cytoplasmatic adiponectin in both cell types. In contrast, VEGF and AGT expression did not change upon hypoxic stimulation. Leptin was exclusively detectable in WA, while uncoupling-protein 1 (UCP-1) was expressed in BA only. WA and BA are sensitive to hypoxia, in which HIF-1α expression is induced. Protein expression of adiponectin is hypoxia-dependent, whereas AGT, VEGF, leptin, and UCP-1 expression do not change secondary to hypoxia.

Knockdown of NPY Expression in the Dorsomedial Hypothalamus Promotes Development of Brown Adipocytes and Prevents Diet-Induced Obesity

Hypothalamic neuropeptide Y (NPY) has been implicated in control of energy balance, but the physiological importance of NPY in the dorsomedial hypothalamus (DMH) remains unclear. Here we report that knockdown of NPY expression in the DMH by adeno-associated virus-mediated RNAi reduced fat depots in rats fed regular chow and ameliorated high-fat diet-induced hyperphagia and obesity. DMH NPY knockdown resulted in development of brown adipocytes in inguinal white adipose tissue through the sympathetic nervous system. This knockdown increased uncoupling protein 1 expression in both inguinal fat and interscapular brown adipose tissue (BAT). Consistent with the activation of BAT, DMH NPY knockdown increased energy expenditure and enhanced the thermogenic response to a cold environment. This knockdown also increased locomotor activity, improved glucose homeostasis, and enhanced insulin sensitivity. Together, these results demonstrate critical roles of DMH NPY in body weight regulation through affecting food intake, body adiposity, thermogenesis, energy expenditure, and physical activity.

Importance of brown adipose tissue to the thermal effect and weight loss induced by central administration of C75

C75, an inhibitor of the fatty acid synthase, is a potential drug to combat the weight excess. Because brown adipose tissue (BAT) is an important site for thermogenesis we hypothesized that this tissue could be involved in the antiobesity effects of C75. Wistar rats (~230 g) were submitted to BAT sympathetic denervation following by stereotaxic surgery and implant of i.p. temperature transponders. 7d later, C75 (150μg/7,5μL) or RPMI was administered intracerebroventricularly in 24h-fasted animals. Values are expressed as mean±SEM (ANOVA One-Way, p<0.05). Denervation did prevent (AUC: 16.5±2.3) the increase of internal temperature induced by C75 (25.9±2.9 vs. 16.5±2.5 in control) along 24h of injection without alter the motor activity (denervated: 24.3±2.3, C75: 21.9±1.8 and control: 25.3±2.5). C75 induced a higher body heating rate from 30min until 6h of injection and this thermal effect was completely abolished by denervation until 4h. C75 produced hypophagia for 1 day, weight loss for 3 days and weight regain to control by day 4. The denervation did not affect the lower consumption of food, attenuated the weight loss on day 1 and reestablished the weight gain induced by C75 on day 2. These results suggest a role for BAT in the C75-evoked increase in body temperature and weight loss in rats. Financial support: FAPESP (08/06694-6).

The role and importance of brown adipose tissue in energy homeostasis

Children and adults have two major types of adipocytes, which represent the predominant cells in white adipose tissue, which is involved in energy storage, and brown adipose tissue (BAT), which is responsible for thermogenesis and energy expenditure. This review discusses BAT physiology and evaluates the recent discoveries regarding its development, identification, and function. Last year, multiple independent research teams using combined PET and computed tomography imaging, immunohistochemistry, and gene and protein expression have proven conclusively that adult humans have functional BAT. In parallel, basic studies defined BAT origins, its transcriptional regulation, and the role of hormones in BAT growth and activation. These methods have begun to be applied to children to understand pediatric BAT anatomy and physiology. Adult humans have functional BAT, which plays a role in energy balance. BAT is more prevalent in children, suggesting an even greater physiological role than that seen in adults. Future studies will identify safe ways to quantify BAT mass and activity and which interventions might be used to increase BAT mass, thermogenesis, or both to treat obesity.

Beneficial effects of PTP1B deficiency on brown adipocyte differentiation and protection against apoptosis induced by pro- and anti-inflammatory stimuli

Insulin is an inducer of brown fat adipogenesis through the activation of a signalling network that involves positive/negative modulators. Given the importance of brown adipose tissue (BAT) for basal thermogenic energy expenditure, we investigated the role of PTP1B in the acquisition of terminal differentiated phenotype and in the apoptotic responses of brown adipocytes. Immortalized brown preadipocytes lacking (PTP1B -/-) or expressing (PTP1B +/+) PTP1B have been generated. PTP1B deficiency accelerated a full program of brown adipogenesis including induction of transcription factors, coactivators, adipogenic markers and signalling molecules. Fully differentiated PTP1B -/- brown adipocytes were resistant to tumor necrosis factor (TNFα)–induced apoptosis as these cells were protected against caspase-8 activation, FLIP degradation, Bid cleavage and caspase-3 activation compared to wild-type controls. These events were recovered by PTP1B rescue. Survival signalling including phosphorylation of IRS-1 and Akt/PKB and BclxL expression were decreased in TNFα-treated PTP1B -/- cells but not in the wild-type. Similarly, PTP1B -/- brown adipocytes were protected against resveratrol-induced apoptosis. Phosphorylation of Akt/PKB and Foxo1 phosphorylation/acetylation decreased exclusively in resveratrol-treated wild-type cells, leading to nuclear localization of Foxo1 and up-regulation of Bim. Thus, PTP1B inhibition could be of benefit against obesity by counteracting TNFα-induced brown fat atrophy, and combined with resveratrol might improve low-grade inflammation.

Identification and Importance of Brown Adipose Tissue in Adult Humans

Although brown adipose tissue in infants and young children is important for regulation of energy expenditure, there has been considerable debate on whether brown adipose tissue normally exists in adult humans and has physiologic relevance in this population. In the last decade, radiologic studies in adults have identified areas of adipose tissue with high 18F-fluorodeoxyglucose (18F-FDG) uptake, putatively identified as brown fat. This radiologic study assessed the presence of physiologically significant brown adipose tissue among 1972 adult patients who had 3640 consecutive 18F-FDG positron-emission tomographic and computed tomographic whole-body scans between 2003 and 2006. Brown adipose tissue was defined as areas of tissue that were more than 4 mm in diameter, had the CT density of adipose tissue, and had maximal standardized uptake values of 18F-FDG of at least 2.0 gm per mL. A sample of 204 date-matched patients without brown adipose tissue served as the control group. Using these criteria, positron-emission tomographic and computed tomographic scans identified brown adipose tissue in 106 of the 1972 patients (5.4%). The most common location for substantial amounts of brown adipose tissue was the region extending from the anterior neck to supraclavicular region. Immunohistochemical staining for uncoupling protein 1 in this region confirmed the identity of immunopositive, multilocular adipocytes as brown adipose tissue. More brown adipose tissue was detected in women (7.5% {lsqb;76/1013{rsqb;) than in men (3.1% {lsqb;30/959{rsqb;); the female:male ratio was 2.4:1.0 (P < 0.001). The mass and activity of brown adipose tissue was also greater in women than in men. The probability of having substantial brown adipose tissue decreased with increasing age (<50–>64) (P < 0.001), short-term or long-term use of beta-blockers (P < 0.001), increasing mean outdoor temperature at the time of the scan (P < 0.02), and increasing tissue and increasing body mass index among patients in the top third for age (>64 years) (P for trend = 0.007). These findings show that functional brown adipose tissue is prevalent in adult humans, and significantly more frequently in women. The inverse correlation of body mass index with the amount of brown adipose tissue, especially in older patients, suggests to the investigators a possible role of brown adipose tissue in protecting against obesity.

The Importance of Brown Adipose Tissue

To the Editor: In the April 9 issue, van Marken Lichtenbelt et al., Cypess et al., and Virtanen et al. report on functioning supraclavicular brown adipose tissue in adult humans. Van Marken Lichtenbelt et al. conclude that brown-adipose-tissue activity induced by exposure to cold is impaired in overweight healthy subjects, and Cypess et al., using epidemiologic-association techniques, conclude that older subjects and those with a higher body-mass index (BMI) have less brown adipose tissue. It is suggested that obesity is associated with reduced brown-adipose-tissue function or activity. However, disseminated brown adipocytes within the large subcutaneous adipose-tissue mass may cumulatively represent substantial brown-adipocyte activity that may not be detected with the use of integrated positron-emission tomography and computed tomography (PET–CT) or crude biochemical studies. Using gene profiling, we found an indication that the brown-adipose-tissue marker uncoupling protein 1 (UCP1) is positively associated with BMI in human subcutaneous adipose tissue (from 33 subjects) (Fig. 1A), as is angiopoietin 2 (ANGP2), a brown-adipose-tissue–enriched angiogenic gene that is a surrogate for F-fluorodeoxyglucose (F-FDG) uptake. Furthermore, cell death–inducing DNA-fragmentation factor (CIDEA), a negative regulator of lipolysis, which is inversely associated with the basal metabolic rate in humans (potentially through indirect UCP1 activation), is reduced in obese subjects matched for glycemic control (Fig. 1B). Such BMI associations are markedly influenced by the presence of diabetes (Fig. 1C and 1D), tempering conclusions about disease drawn from these studies. We have found brown-adipose-tissue markers in obese subjects without diabetes, suggesting that anatomically dispersed brown adipocytes may promote metabolic homeostasis. James A. Timmons, Ph.D.

Identification and Importance of Brown Adipose Tissue in Adult Humans

Obesity results from an imbalance between energy intake and expenditure. In rodents and newborn humans, brown adipose tissue helps regulate energy expenditure by thermogenesis mediated by the expression of uncoupling protein 1 (UCP1), but brown adipose tissue has been considered to have no physiologic relevance in adult humans. We analyzed 3640 consecutive (18)F-fluorodeoxyglucose ((18)F-FDG) positron-emission tomographic and computed tomographic (PET-CT) scans performed for various diagnostic reasons in 1972 patients for the presence of substantial depots of putative brown adipose tissue. Such depots were defined as collections of tissue that were more than 4 mm in diameter, had the density of adipose tissue according to CT, and had maximal standardized uptake values of (18)F-FDG of at least 2.0 g per milliliter, indicating high metabolic activity. Clinical indexes were recorded and compared with those of date-matched controls. Immunostaining for UCP1 was performed on biopsy specimens from the neck and supraclavicular regions in patients undergoing surgery. Substantial depots of brown adipose tissue were identified by PET-CT in a region extending from the anterior neck to the thorax. Tissue from this region had UCP1-immunopositive, multilocular adipocytes indicating brown adipose tissue. Positive scans were seen in 76 of 1013 women (7.5%) and 30 of 959 men (3.1%), corresponding to a female:male ratio greater than 2:1 (P<0.001). Women also had a greater mass of brown adipose tissue and higher (18)F-FDG uptake activity. The probability of the detection of brown adipose tissue was inversely correlated with years of age (P<0.001), outdoor temperature at the time of the scan (P=0.02), beta-blocker use (P<0.001), and among older patients, body-mass index (P=0.007). Defined regions of functionally active brown adipose tissue are present in adult humans, are more frequent in women than in men, and may be quantified noninvasively with the use of (18)F-FDG PET-CT. Most important, the amount of brown adipose tissue is inversely correlated with body-mass index, especially in older people, suggesting a potential role of brown adipose tissue in adult human metabolism.

Historical Perspectives

There can be little doubt that thermoregulation is one of the major concepts underpinning the care of the preterm infant. In the first half of the 20th century in the United States, most preterm infants were maintained with body temperatures lower than term infants. This month we highlight the article that changed that approach, which was written by Bill Silverman and colleagues. (1) In an accompanying piece, Dr. Silverman provides a personal reminiscence of the setting into which this important paper was introduced. This is an extract of a more extensive reflection on lessons learned from randomized controlled trials, which he prepared for the James Lind Library. (2) Dr. Silverman acknowledges the work of his colleague Richard Day, who many years earlier had demonstrated that preterm infants were homeothermic, but who had his findings dismissed by “the authorities.” As Dr. Day noted in 1964, the ability to produce heat in the neonate “rises progressively with cooler and cooler chambers,” but shivering was not observed. (3) Further investigation of heat production revealed the importance of brown adipose tissue (or brown fat) and the role it played in “nonshivering thermogenesis.” (4) The disadvantage experienced by the “small-for-date” infant in this regard then was emphasized, (5) and the importance of a narrow range of environmental temperatures to minimize energy expenditure gave rise to the concept of a “neutral thermal environment.” (6) It should be mentioned that shivering has been seen occasionally in the neonate who has extreme hypothermia, (7) and it has been hypothesized that shivering might occur as “nonshivering thermogenesis” approaches its full potential. (8) In an accompanying special article …

Thermogenesis in human brown adipose tissue and skeletal muscle induced by sympathomimetic stimulation

The aim of the present work was to elucidate the importance of brown adipose tissue (BAT) and skeletal muscle for ephedrine-induced thermogenesis, and to examine the effect of chronic ephedrine treatment on energy expenditure. The investigations were carried out in vivo on humans, as well as on rats and dogs. In rodents BAT is the major site of cold-induced nonshivering thermogenesis and of facultative thermogenesis: the component of food-induced thermogenesis storage of nutrients. BAT thermogenesis is mediated through an activation of the sympathetic nervous system. Via a sustained stimulation of the sympathetic nervous system, acclimation to cold and overfeeding induces hyperplasia of BAT, and subsequently an increased thermogenic capacity. In a number of obesity syndromes in rodents the sympathetic mediation is defective, and this leads to extreme sensitivity to cold and to obesity. BAT has been reported to be present also in humans, and there has been focused mainly on the interscapular subcutaneous tissue. An ephedrine-induced increase of the interscapular skin temperature has been interpreted as evidence of the presence of thermogenic BAT. This lead to the assumption that BAT, also in humans, plays a significant role in the regulation of energy balance. Likewise, the hypothesis has been advanced that a diminished thermogenesis in BAT may be the cause of some types of human obesity. After validation of the xenon clearance method in rats for blood flow measurements in BAT, the method was applied on humans to examine the ephedrine-induced increase in the interscapular temperature. The warmest interscapular skin area was localized by thermography during ephedrine stimulation. In a second study subcutaneous blood flow and temperature were measured in this area during ephedrine stimulation and compared to the response of white adipose tissue in the lumbar area. The results showed that the increases in blood flow and temperatures were of similar magnitude in the two locations. Biopsies taken from the warmest interscapular spots did not contain brown adipocytes. A histological study on human autopsies confirmed that BAT is rare in the interscapular tissue, but frequently occurring in the perirenal depot. In the next study, the thermogenic function of the perirenal BAT was examined by measurements of blood flow and local temperature. Perirenal BAT thermogenesis was uninfluenced by ephedrine in 4 of 5 subjects. It was estimated that BAT thermogenesis in the single responding subject could account for maximally 15% of the ephedrine-induced increase in whole body oxygen consumption.(ABSTRACT TRUNCATED AT 400 WORDS)

Development of brown adipose tissue thermogenesis in the ovine fetus and newborn.

Despite the importance of brown adipose tissue (BAT) in the regulation of thermogenesis and energy expenditure in both newborn and adult mammals, the functional ontogenesis of this tissue is largely unknown. In the present study, we describe the maturation of several aspects of BAT thermogenesis in fetal and newborn sheep. Cell respiration of brown adipocytes isolated from perirenal BAT was measured using a Gilson differential respirometer. Cells were isolated from four fetal animals at 121-124 days gestation (group 1), five fetal animals at 137-140 days gestation (group 2), and five newborns between birth and 4 days of age (group 3). In addition to basal oxygen consumption, in vitro cell respiration also was measured after the addition of norepinephrine (NE), (Bu)2cAMP, alpha-glycerophosphate (alpha GP), and butyric acid. Mean (+/- SEM) basal respiration (in microliters of O2 per 10(6) cells/h) increased from 11 +/- 1 in group 1 to 31 +/- 2 in group 2 and 45 +/- 7 in group 3. Cell volume increased from 9 +/- 1 pl in group 1 to 13 +/- 2 pl in group 2 and 18 +/- 2 pl in group 3. After adjustment for variations in basal respiration due to differences in cell volume, basal respiration in group 2 was greater than that in group 1 and equal to that in group 3. Maximal NE (10(-6) M)-stimulated respiration increased from 74 +/- 16 in group 1 to 294 +/- 47 in group 2. Maximal NE-stimulated respiration in group 3 (133 +/- 30) was less than that in group 2, but equal to that in group 1. (Bu)2cAMP-stimulated respiration increased from 51 +/- 12 in group 1 to 175 +/- 22 in group II, with no further increase in group III. Neither NE- nor (Bu)2cAMP-stimulated respiration varied significantly with cell volume. alpha GP substrate respiration demonstrated significant increases from group 1 to group 2, with another significant increase in Group 3. Butyric acid substrate respiration in group 1 was less than those measured in groups 2 and 3, while respiration values in groups 2 and 3 were equal. After adjustments for variations due to differences in cell volume, the patterns of development of both alpha GP and butyric acid substrate respiration were unaltered. The following conclusions were reached 1) Full maturation of BAT catecholamine-stimulated cellular respiration occurs before delivery near term in the ovine fetus. 2) In the neonatal lamb, a decrease in catecholamine-stimulated respiration occurs without a decrease in (Bu)2cAMP-stimulated respiration. This suggests that a decrease in BAT sensitivity to NE occurs after delivery at the receptor adenyl cyclase level. 3) The perinatal increase in alpha GP substrate respiration without an increase in butyric acid substrate respiration suggests that mitochondrial alpha-glycerophosphate dehydrogenase activity is increased. This was confirmed by measuring increased alpha-glycerophosphate dehydrogenase activity in crude BAT mitochondrial fractions in group 3 animals.

Fatty acid synthesis in mouse brown adipose tissue the influence of environmental temperature on the proportion of whole-body fatty acid synthesis in brown adipose tissue and the liver

Fatty acid synthesis has been measured in vivo with 3H 2O in mice acclimated at different environmental temperatures (33, 22, 4°C), and the importance of brown adipose tissue and the liver to whole-body fatty acid synthesis at each temperature assessed. At 33°C, when non-shivering thermogenesis is minimal, the rate of fatty acid synthesis in interscapular brown adipose tissue was lower than in the liver, but higher than in white adipose tissue and the carcass. At 4°C, when non-shivering thermogenesis is maximal, the fatty acid synthesis rate in interscapular brown adipose tissue was many times greater than in any other tissue. High fatty acid synthesis rates were also found in other brown adipose tissue depots — subscapular, dorsocervical and axillary — of cold-acclimated mice. In mice maintained at 22°C the rate of fatty acid synthesis was also higher in brown adipose tissue than in other tissues. Overall, the relative importance of brown adipose tissue as a site of fatty acid synthesis increased with lower environmental temperatures, while that of the liver decreased. It was calculated that brown adipose tissue in total accounted for approx. 5% of whole-body fatty acid synthesis at 33°C, 10% at 22°C and 30% at 4°C. In contrast, hepatic synthesis amounted to 32% of whole-body fatty acid synthesis at 33°C, 16% at 22°C and only 11% at 4°C. An estimate of the contribution that de novo synthesis makes to total fatty acid utilization by interscapular brown adipose tissue suggests that fatty acid synthesis and breakdown constitutes a significant heat-dissipating ‘cycle’ in brown adipose tissue of cold-acclimated mice. Such a cycle is not evident in suckling animals since fatty acid synthesis in brown adipose tissue is very low during early development.