Brown Adipose Tissue Depots Research Articles

The Therapeutic Potential of Brown Adipocytes in Humans.

Obesity and its metabolic consequences represent a significant clinical problem. From a thermodynamic standpoint, obesity results from a discord in energy intake and expenditure. To date, lifestyle interventions based on reducing energy intake and/or increasing energy expenditure have proved ineffective in the prevention and/or treatment of obesity, owing to poor long-term adherence to such interventions. Thus, an effective strategy to prevent or correct obesity is currently lacking. As the combustion engines of our cells, mitochondria play a critical role in energy expenditure. At a whole-body level, approximately 80% of mitochondrial membrane potential generated by fuel oxidation is used to produce ATP, and the remaining 20% is lost through heat-producing uncoupling reactions. The coupling of mitochondrial respiration to ATP production represents an important component in whole-body energy expenditure. Brown adipose tissue (BAT) is densely populated with mitochondria containing the inner mitochondrial proton carrier uncoupling protein 1 (UCP1). UCP1 uncouples oxidative phosphorylation, meaning that mitochondrial membrane potential is dissipated as heat. The recent rediscovery of BAT depots in adult humans has rekindled scientific interest in the manipulation of mitochondrial uncoupling reactions as a means to increase metabolic rate, thereby counteracting obesity and its associated metabolic phenotype. In this article, we discuss the evidence for the role BAT plays in metabolic rate and glucose and lipid metabolism in humans and the potential for UCP1 recruitment in the white adipose tissue of humans. While the future holds much promise for a therapeutic role of UCP1 expressing adipocytes in human energy metabolism, particularly in the context of obesity, tissue-specific strategies that activate or recruit UCP1 in human adipocytes represent an obligatory translational step for this early promise to be realized.

Igfbp2 Deletion in Ovariectomized Mice Enhances Energy Expenditure but Accelerates Bone Loss.

Previously, we reported sexually dimorphic bone mass and body composition phenotypes in Igfbp2(-/-) mice (-/-), where male mice exhibited decreased bone and increased fat mass, whereas female mice displayed increased bone but no changes in fat mass. To investigate the interaction between IGF-binding protein (IGFBP)-2 and estrogen, we subjected Igfbp2 -/- and +/+ female mice to ovariectomy (OVX) or sham surgery at 8 weeks of age. At 20 weeks of age, mice underwent metabolic cage analysis and insulin tolerance tests before killing. At harvest, femurs were collected for microcomputed tomography, serum for protein levels, brown adipose tissue (BAT) and inguinal white adipose tissue (IWAT) adipose depots for histology, gene expression, and mitochondrial respiration analysis of whole tissue. In +/+ mice, serum IGFBP-2 dropped 30% with OVX. In the absence of IGFBP-2, OVX had no effect on preformed BAT; however, there was significant "browning" of the IWAT depot coinciding with less weight gain, increased insulin sensitivity, lower intraabdominal fat, and increased bone loss due to higher resorption and lower formation. Likewise, after OVX, energy expenditure, physical activity and BAT mitochondrial respiration were decreased less in the OVX-/- compared with OVX+/+. Mitochondrial respiration of IWAT was reduced in OVX+/+ yet remained unchanged in OVX-/- mice. These changes were associated with significant increases in Fgf21 and Foxc2 expression, 2 proteins known for their insulin sensitizing and browning of WAT effects. We conclude that estrogen deficiency has a profound effect on body and bone composition in the absence of IGFBP-2 and may be related to changes in fibroblast growth factor 21.

Differential effects of Roux-en-Y gastric bypass surgery on brown and beige adipose tissue thermogenesis

BackgroundThere are numerous reports of increased energy expenditure after Roux-en-Y gastric bypass (RYGB) surgery in humans and rodent models but the underlying mechanisms remain poorly understood. In the present study we assessed at the gene expression level whether RYGB leads to recruitment of brown adipose tissue (BAT) and/or beige adipose tissue (BeAT) as a means of enhanced facultative thermogenesis and increased energy expenditure after surgery. MethodsDiet-induced obese male Wistar rats were randomized into RYGB-operated (n=10), sham-operated ad libitum fed (Sham) (n=7) or sham-operated body weight matched (BWM) to RYGB groups (n=7). At a stage of postoperatively stabilized weight reduction, BAT (interscapular), subcutaneous (inguinal) and visceral (epididymal and perirenal) white adipose tissue (WAT) depots were collected in the fasted state. Expression of thermoregulatory genes (UCP1, CIDEA and PRDM16) in BAT and WAT as well as specific markers of BeAT (Ear2 and TMEM26) in WAT was analyzed using RT-qPCR. ResultsCompared to Sham rats, UCP1 mRNA expression in BAT was significantly reduced in BWM, but not in RYGB rats. No differences in mRNA expression were found for thermoregulatory proteins or for markers of BeAT in subcutaneous or visceral WAT depots between RYGB and Sham groups. ConclusionThe compensatory decrease in BAT thermogenic gene expression typically associated with body weight loss is attenuated after RYGB which, as opposed to recruitment of BeAT, may contribute to overall increases in energy expenditure and weight loss maintenance after surgery.

The future of brown adipose tissues in the treatment of type 2 diabetes.

The recent recognition that humans possess active depots of brown adipose tissue has boosted the interest in this tissue as a potential target for the prevention and treatment of obesity and related metabolic disorders. Furthermore, it was also revealed that brown adipose tissue (BAT) in humans may consist of so-called beige or brite adipocytes. So far, cold exposure is recognised as the strongest activator of BAT in humans, but there is much ongoing research focused on finding alternative activators of BAT. The consequences of long-term BAT activation and/or cold exposure on metabolic health are still unknown, and this represents an area of intensive research. This is one of a series of commentaries under the banner '50 years forward', giving personal opinions on future perspectives in diabetes, to celebrate the 50th anniversary of Diabetologia (1965-2015).

Rats Bred For High Aerobic Fitness Are Protected From Ovariectomy-induced Insulin Resistance During Euglycemic Clamp

Ovariectomized (OVX) rodents model human menopause such that they develop metabolic dysfunction including reduced insulin sensitivity (i.e., insulin resistance (IR)) and increased adiposity. How aerobic fitness per se might protect against OVX-associated IR is not known. PURPOSE: To determine whether rats bred for high intrinsic aerobic fitness (HCR) are protected against OVX-induced IR using the gold standard euglycemic hyperinsulinemic clamp procedure, compared to rats bred for low intrinsic aerobic capacity (LCR). METHODS: Female HCR and LCR rats (n=40; age 22 wk) received OVX or sham-surgery (SHM) (groups: HCRSHM, HCROVX, LCRSHM, and LCROVX (n=10/group)). All rats underwent the clamp procedure 27 weeks following surgery. Following recovery from surgical catheterization of arterial and venous lines (3-5 days), rats were fasted for 5 hours and tested with the euglycemic hyperinsulinemic clamp to assess whole body insulin sensitivity. During the clamps, insulin was continuously infused at 4 mU/kg/min and blood samples were collected every 10min for an hour. Following the clamp procedure, a bolus of 14C-2-deoxyglucose (2DOG) was infused for the tissue-specific assessment of glucose uptake. Visceral (perigonadal, omental, and epididymal) and brown adipose tissue depots, and skeletal muscle samples were harvested 25 min following an infusion of 2DOG. RESULTS: While no differences in fasting glucose levels were found, glucose infusion rate (GIR) was lower in LCRSHM compared to HCRSHM (16.6±2.6 vs. 21.9±4.0 mg/kg/min, respectively; p<0.05) and LCR experienced a further reduction in GIR following OVX (-36%, p<0.05) compared to LCRSHM. In contrast, HCR did not exhibit a significant change in GIR following OVX. OVX increased body weight gain (HCR: +10%, LCR: +20%; p<0.05) and visceral adiposity (HCR: +30%, LCR: +62%; p<0.05) regardless of aerobic capacity. CONCLUSION: HCR rats were only slightly protected against OVX-associated gain in adiposity but were completely protected against OVX-associated insulin resistance. Analyses are underway to determine tissue-specific differences in glucose handling between groups in order to gain better mechanistic insight about the protection conferred by intrinsic fitness in this rodent model of menopause.

Inhibition of Sam68 triggers adipose tissue browning

Obesity is associated with insulin resistance and type 2 diabetes; molecular mechanisms that promote energy expenditure can be utilized for effective therapy. Src-associated in mitosis of 68 kDa (Sam68) is potentially significant, because knockout (KO) of Sam68 leads to markedly reduced adiposity. In the present study, we sought to determine the mechanism by which Sam68 regulates adiposity and energy homeostasis. We first found that Sam68 KO mice have a significantly reduced body weight as compared to controls, and the difference is explained entirely by decreased adiposity. Interestingly, these effects were not mediated by a difference in food intake; rather, they were associated with enhanced physical activity. When they were fed a high-fat diet, Sam68 KO mice gained much less body weight and fat mass than their WT littermates did, and they displayed an improved glucose and insulin tolerance. In Sam68 KO mice, the brown adipose tissue (BAT), inguinal, and epididymal depots were smaller, and their adipocytes were less hypertrophied as compared to their WT littermates. The BAT of Sam68 KO mice exhibited reduced lipid stores and expressed higher levels of Ucp1 and key thermogenic and fatty acid oxidation genes. Similarly, depots of inguinal and epididymal white adipose tissue (WAT) in Sam68 KO mice appeared browner, their multilocular Ucp1-positive cells were much more abundant, and the expression of Ucp1, Cidea, Prdm16, and Ppargc1a genes was greater as compared to WT controls, which suggests that the loss of Sam68 also promotes WAT browning. Furthermore, in all of the fat depots of the Sam68 KO mice, the expression of M2 macrophage markers was up-regulated, and that of M1 markers was down-regulated. Thus, Sam68 plays a crucial role in controlling thermogenesis and may be targeted to combat obesity and associated disorders.

Magnetic resonance imaging cooling-reheating protocol indicates decreased fat fraction via lipid consumption in suspected brown adipose tissue.

ObjectivesTo evaluate whether a water-fat magnetic resonance imaging (MRI) cooling-reheating protocol could be used to detect changes in lipid content and perfusion in the main human brown adipose tissue (BAT) depot after a three-hour long mild cold exposure.Materials and MethodsNine volunteers were investigated with chemical-shift-encoded water-fat MRI at baseline, after a three-hour long cold exposure and after subsequent short reheating. Changes in fat fraction (FF) and R2*, related to ambient temperature, were quantified within cervical-supraclavicular adipose tissue (considered as suspected BAT, denoted sBAT) after semi-automatic segmentation. In addition, FF and R2* were quantified fully automatically in subcutaneous adipose tissue (not considered as suspected BAT, denoted SAT) for comparison. By assuming different time scales for the regulation of lipid turnover and perfusion in BAT, the changes were determined as resulting from either altered absolute fat content (lipid-related) or altered absolute water content (perfusion-related).ResultssBAT-FF decreased after cold exposure (mean change in percentage points = -1.94 pp, P = 0.021) whereas no change was observed in SAT-FF (mean = 0.23 pp, P = 0.314). sBAT-R2* tended to increase (mean = 0.65 s-1, P = 0.051) and SAT-R2* increased (mean = 0.40 s-1, P = 0.038) after cold exposure. sBAT-FF remained decreased after reheating (mean = -1.92 pp, P = 0.008, compared to baseline) whereas SAT-FF decreased (mean = -0.79 pp, P = 0.008, compared to after cold exposure).ConclusionsThe sustained low sBAT-FF after reheating suggests lipid consumption, rather than altered perfusion, as the main cause to the decreased sBAT-FF. The results obtained demonstrate the use of the cooling-reheating protocol for detecting changes in the cervical-supraclavicular fat depot, being the main human brown adipose tissue depot, in terms of lipid content and perfusion.

A percutaneous needle biopsy technique for sampling the supraclavicular brown adipose tissue depot of humans.

Brown adipose tissue (BAT) has been proposed as a potential target tissue against obesity and its related metabolic complications. Although the molecular and functional characteristics of BAT have been intensively studied in rodents, only a small number of studies have used human BAT specimens due to the difficulty of sampling human BAT deposits. We established a novel positron emission tomography and computed tomography-guided Bergström needle biopsy technique to acquire human BAT specimens from the supraclavicular area in human subjects. Forty-three biopsies were performed on 23 participants. The procedure was tolerated well by the majority of participants. No major complications were noted. Numbness (9.6%) and hematoma (2.3%) were the two minor complications noted, which fully resolved. Thus, the proposed biopsy technique can be considered safe with only minimal risk of adverse events. Adoption of the proposed method is expected to increase the sampling of the supraclavicular BAT depot for research purposes so as to augment the scientific knowledge of the biology of human BAT.

Characterization of brown adipose tissue by water-fat separated magnetic resonance imaging.

To evaluate the possibility of quantifying brown adipose tissue (BAT) volume and fat concentration with a high resolution, long echo time, dual-echo Dixon imaging protocol. A 0.42 mm isotropic resolution water-fat separated MRI protocol was implemented by using the second opposite-phase echo and third in-phase echo. Fat images were calibrated with regard to the intensity of nearby white adipose tissue (WAT) to form relative fat content (RFC) images. To evaluate the ability to measure BAT volume and RFC contrast dynamics, rats were divided into two groups that were kept at 4° or 22°C for 5 days. The rats were then scanned in a 70 cm bore 3.0 Tesla MRI scanner and a human dual energy CT. Interscapular, paraaortal, and perirenal BAT (i/pa/pr-BAT) depots as well as WAT and muscle were segmented in the MRI and CT images. Biopsies were collected from the identified BAT depots. The biopsies confirmed that the three depots identified with the RFC images consisted of BAT. There was a significant linear correlation (P < 0.001) between the measured RFC and the Hounsfield units from DECT. Significantly lower iBAT RFC (P = 0.0064) and significantly larger iBAT and prBAT volumes (P = 0.0017) were observed in the cold stimulated rats. The calibrated Dixon images with RFC scaling can depict BAT and be used to measure differences in volume, and fat concentration, induced by cold stimulation. The high correlation between RFC and HU suggests that the fat concentration is the main RFC image contrast mechanism.

Prevalence and Activation of Human Brown Adipose Tissue

The role of brown adipose tissue (BAT) in human lipid metabolism and whole‐body energy expenditure is not well understood. To study BAT in humans it is necessary to reliably measure the quantitative properties of BAT. The purpose of this study is to assess the volume and activity of BAT prospectively using PET in a cohort of healthy male and female adult humans.Twenty‐five subjects (10 male), aged 21 to 41 years, with a BMI of 20.15 to 31.48 kg/m2 were scanned on a GE Discovery STE PET/CT scanner using the radioactive tracer 18F‐FDG. Each subject underwent two PET‐CT scans on two separate days, once after two hours of cold exposure (16°C) and once after two hours of thermoneutral exposure (24°C). BAT activation was observed on the PET scans of 19 subjects after cold exposure. The PET scans for two representative subjects from this dataset are shown in Fig 1. The resulting PET and CT values (mean ± 95% CI) from the clavicular BAT depots for these two subjects are listed in Table 1.The results of this study show the ability to measure the presence of brown adipose tissue in healthy adults with a variety of ages and BMI levels. Although it is likely this method does not capture the entire volume of BAT or the full degree of activation for a specific subject, this method can detect activated BAT in adult humans in an automated fashion. One advantage of this research over existing studies is that the same subjects are scanned after exposure to both thermoneutral and cold conditions, which enables a comparison of the images between temperatures.Funding1R21DK096282 from NIDDK/NIH &amp; UL1 TR000445 from NCATS/NIHimage Cold Exposure BAT Values Thermoneutral Exposure BAT Values PET Standardized Uptake Value [SUV] CT Hounsfield Units [HU] PET Standardized Uptake Value [SUV] CT Hounsfield Units [HU] BAT Volume [cm3] Subject 1 5.2 ± 0.1 ‐49.5 ± 0.9 0.6 ± 0.0 ‐71.1 ± 1.3 23.7 Subject 2 3.4 ± 0.1 ‐64.1 ± 1.7 0.4 ± 0.0 ‐93.2 ± 2.4 8.5

Oxygen deprivation and the cellular response to hypoxia in adipocytes - perspectives on white and brown adipose tissues in obesity.

Relative hypoxia has been shown to develop in white adipose tissue depots of different types of obese mouse (genetic, dietary), and this leads to substantial changes in white adipocyte function. These changes include increased production of inflammation-related adipokines (such as IL-6, leptin, Angptl4, and VEGF), an increase in glucose utilization and lactate production, and the induction of fibrosis and insulin resistance. Whether hypoxia also occurs in brown adipose tissue depots in obesity has been little considered. However, a recent study has reported low pO2 in brown fat of obese mice, this involving mitochondrial loss and dysfunction. We suggest that obesity-linked hypoxia may lead to similar alterations in brown adipocytes as in white fat cells – particularly changes in adipokine production, increased glucose uptake and lactate release, and insulin resistance. This would be expected to compromise thermogenic activity and the role of brown fat in glucose homeostasis and triglyceride clearance, underpinning the development of the metabolic syndrome. Hypoxia-induced augmentation of lactate production may also stimulate the “browning” of white fat depots through recruitment of UCP1 and the development of brite adipocytes.

Human Brown Adipose Tissue Depots Automatically Segmented by Positron Emission Tomography/Computed Tomography and Registered Magnetic Resonance Images

Human Brown Adipose Tissue Depots Automatically Segmented by Positron Emission Tomography/Computed Tomography and Registered Magnetic Resonance Images

Human brown adipose tissue depots automatically segmented by positron emission tomography/computed tomography and registered magnetic resonance images.

Reliably differentiating brown adipose tissue (BAT) from other tissues using a non-invasive imaging method is an important step toward studying BAT in humans. Detecting BAT is typically confirmed by the uptake of the injected radioactive tracer 18F-Fluorodeoxyglucose (18F-FDG) into adipose tissue depots, as measured by positron emission tomography/computed tomography (PET-CT) scans after exposing the subject to cold stimulus. Fat-water separated magnetic resonance imaging (MRI) has the ability to distinguish BAT without the use of a radioactive tracer. To date, MRI of BAT in adult humans has not been co-registered with cold-activated PET-CT. Therefore, this protocol uses 18F-FDG PET-CT scans to automatically generate a BAT mask, which is then applied to co-registered MRI scans of the same subject. This approach enables measurement of quantitative MRI properties of BAT without manual segmentation. BAT masks are created from two PET-CT scans: after exposure for 2 hr to either thermoneutral (TN) (24 °C) or cold-activated (CA) (17 °C) conditions. The TN and CA PET-CT scans are registered, and the PET standardized uptake and CT Hounsfield values are used to create a mask containing only BAT. CA and TN MRI scans are also acquired on the same subject and registered to the PET-CT scans in order to establish quantitative MRI properties within the automatically defined BAT mask. An advantage of this approach is that the segmentation is completely automated and is based on widely accepted methods for identification of activated BAT (PET-CT). The quantitative MRI properties of BAT established using this protocol can serve as the basis for an MRI-only BAT examination that avoids the radiation associated with PET-CT.

Brown and beige fat in humans: thermogenic adipocytes that control energy and glucose homeostasis.

Brown adipose tissue (BAT), a specialized fat that dissipates energy to produce heat, plays an important role in the regulation of energy balance. Two types of thermogenic adipocytes with distinct developmental and anatomical features exist in rodents and humans: classical brown adipocytes and beige (also referred to as brite) adipocytes. While classical brown adipocytes are located mainly in dedicated BAT depots of rodents and infants, beige adipocytes sporadically reside with white adipocytes and emerge in response to certain environmental cues, such as chronic cold exposure, a process often referred to as "browning" of white adipose tissue. Recent studies indicate the existence of beige adipocytes in adult humans, making this cell type an attractive therapeutic target for obesity and obesity-related diseases, including type 2 diabetes. This Review aims to cover recent progress in our understanding of the anatomical, developmental, and functional characteristics of brown and beige adipocytes and discuss emerging questions, with a special emphasis on adult human BAT.

Engineering Fat Cell Fate to Fight Obesity and Metabolic Diseases.

All mammals harbor two types of adipose tissues that serve distinct physiological functions: white adipose tissue (WAT) and brown adipose tissue (BAT). WAT functions mainly in the storage of excess energy, while BAT specializes in dissipating energy in the form of heat and functions as a defense against hypothermia and obesity. Since adult humans possess significant amounts of active BAT depots and it's mass inversely correlates with adiposity, BAT plays an important role in human obesity and energy homeostasis.New evidence suggests two types of thermogenic adipocytes with distinct developmental and anatomical features: classical brown adipocytes and beige adipocytes. Classical brown adipocytes are located mainly in dedicated BAT depots of rodents and infants. Beige adipocytes, on the other hand, reside mainly in subcutaneous WAT where they arise postnatally in response to certain external cues, such as chronic cold exposure and long-term treatment with PPAR- agonists, a process often referred to as the "browning" of WAT. Importantly, adult human BAT appears to be mainly composed of beige-like adipocytes, making this cell type an attractive therapeutic target for obesity and obesity-related diseases, such as insulin resistance and type2 diabetes. I will review recent progress in the molecular control of brown and beige adipocyte development and discuss emerging questions.(Presented at the 1912th Meeting, December 21, 2015).

18F-FDG PET/CT monitoring of β3 agonist-stimulated brown adipocyte recruitment in white adipose tissue.

There is rising interest in recruitment of brown adipocytes into white adipose tissue (WAT) as a means to augment energy expenditure for weight reduction. We thus investigated the potential of (18)F-FDG uptake as an imaging biomarker that can monitor the process of WAT browning. C57BL/6 mice were treated daily with the β3 agonist CL316,243 (5-[(2R)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,3-benzodioxole-2,2-dicarboxylic acid disodium salt), whereas controls received saline. (18)F-FDG small-animal PET/CT was serially performed at 1 h after CL316,243 injection. After sacrifice, interscapular brown adipose tissue (BAT) and WAT depots were extracted, weighed, and measured for (18)F-FDG uptake. Tissues underwent immunostaining, and UCP1 content was quantified by Western blotting. PET/CT showed low (18)F-FDG uptake in both BAT and inguinal WAT at baseline. BAT uptake was substantially increased by a single stimulation with CL316,243. Uptake in inguinal WAT was only modestly elevated by the first stimulation uptake but gradually increased to BAT level by prolonged stimulation. Ex vivo measurements recapitulated the PET findings, and measured (18)F-FDG uptake in other WAT depots was similar to inguinal WAT. WAT browning by prolonged stimulation was confirmed by a substantial increase in uncoupling protein 1 (UCP1), cytochrome-c oxidase 4 (COX4), and PR domain containing 16 (PRDM16) staining as markers of brown adipocytes. UCP1 content, which served as a measure for extent of browning, was low in baseline inguinal WAT but linearly increased over 10 d of CL316,243 injection. Finally, image-based and ex vivo-measured (18)F-FDG uptake in inguinal WAT correlated well with UCP1 content. (18)F-FDG PET/CT has the capacity to monitor brown adipocyte recruitment into WAT depots in vivo and may thus be useful for screening the efficacy of strategies to promote WAT browning.

Engineering fat cell fate to fight obesity and metabolic diseases

All mammals harbor two types of adipose tissues that serve distinct physiological functions: white adipose tissue (WAT) and brown adipose tissue (BAT). WAT functions mainly in the storage of excess energy, while BAT specializes in dissipating energy in the form of heat and functions as a defense against hypothermia and obesity. Since adult humans possess significant amounts of active BAT depots and it's mass inversely correlates with adiposity, BAT plays an important role in human obesity and energy homeostasis.New evidence suggests two types of thermogenic adipocytes with distinct developmental and anatomical features: classical brown adipocytes and beige adipocytes. Classical brown adipocytes are located mainly in dedicated BAT depots of rodents and infants. Beige adipocytes, on the other hand, reside mainly in subcutaneous WAT where they arise postnatally in response to certain external cues, such as chronic cold exposure and long-term treatment with PPAR- agonists, a process often referred to as the browning of WAT. Importantly, adult human BAT appears to be mainly composed of beige-like adipocytes, making this cell type an attractive therapeutic target for obesity and obesity-related diseases, such as insulin resistance and type2 diabetes. I will review recent progress in the molecular control of brown and beige adipocyte development and discuss emerging questions.(Presented at the 1912th Meeting, December 21, 2015).

The "Skinny" on brown fat, obesity, and bone.

The discovery that metabolically active brown fat is present in humans throughout ontogeny raises new questions about the interactions between thermoregulatory, metabolic, and skeletal homeostasis. Brown adipose tissue (BAT) is distinct from white adipose tissue (WAT) for its ability to burn, rather than store, energy. BAT uniquely expresses uncoupling protein-1 (abbreviated as UCP1), which diverts the energy produced by cellular respiration to generate heat. While BAT is found in small mammals, hibernators, and newborns, this depot was thought to regress in humans during early postnatal life. Recent studies revealed that human BAT remains metabolically active throughout childhood and even in adulthood, particularly in response to cold exposure. In addition to the constitutive BAT depots present at birth, BAT cells can be induced within WAT depots under specific metabolic and climatic conditions. These cells, called inducible brown fat, "brite," or beige fat, are currently the focus of intense investigation as a possible treatment for obesity. Inducible brown fat is associated with higher bone mineral density, suggesting that brown fat interacts with bone growth in previously unrecognized ways. Finally, BAT may have contributed to climatic adaptation in hominins. Here, I review current findings on the role of BAT in thermoregulation, bone growth, and metabolism, describe the potential role of BAT in moderating the obesity epidemic, and outline possible functions of BAT across hominin evolutionary history.

A gain-of-function mutation in adenylate cyclase 3 protects mice from diet-induced obesity.

In a screen for genes that affect the metabolic response to high-fat diet (HFD), we selected one line of N-ethyl-N-nitrosourea (ENU)-mutagenized mice, Jll, with dominantly inherited resistance to diet-induced obesity (DIO). Mutant animals had dramatically reduced body weight and fat mass, and low basal insulin and glucose levels relative to unaffected controls. Both white adipose tissue (WAT) and brown adipose tissue (BAT) depots were smaller in mutant animals. Mutant animals fed a HFD gained only slightly more weight than animals fed regular chow, and were protected from hepatic lipid accumulation. The phenotype was genetically linked to a 5.7-Mb interval on chromosome 12, and sequencing of the entire interval identified a single coding mutation, predicted to cause a methionine-to-isoleucine substitution at position 279 of the Adcy3 protein (Adcy3M279I, henceforth referred to as Adcy3Jll). The mutant protein is hyperactive, possibly constitutively so, producing elevated levels of cyclic AMP in a cell-based assay. These mice demonstrate that increased Adcy3 activity robustly protect animals from diet-induced metabolic derangements.

Cerenkov Luminescence Imaging of Interscapular Brown Adipose Tissue

Brown adipose tissue (BAT), widely known as a “good fat” plays pivotal roles for thermogenesis in mammals. This special tissue is closely related to metabolism and energy expenditure, and its dysfunction is one important contributor for obesity and diabetes. Contrary to previous belief, recent PET/CT imaging studies indicated the BAT depots are still present in human adults. PET imaging clearly shows that BAT has considerably high uptake of 18F-FDG under certain conditions. In this video report, we demonstrate that Cerenkov luminescence imaging (CLI) with 18F-FDG can be used to optically image BAT in small animals. BAT activation is observed after intraperitoneal injection of norepinephrine (NE) and cold treatment, and depression of BAT is induced by long anesthesia. Using multiple-filter Cerenkov luminescence imaging, spectral unmixing and 3D imaging reconstruction are demonstrated. Our results suggest that CLI with 18F-FDG is a practical technique for imaging BAT in small animals, and this technique can be used as a cheap, fast, and alternative imaging tool for BAT research.