Increasing energy expenditure through activation of endogenous brown adipose tissue (BAT) is a potential approach to treat obesity and diabetes. The class of β3-adrenergic receptor (AR) agonists ...stimulates rodent BAT, but this activity has never been demonstrated in humans. Here we determined the ability of 200 mg oral mirabegron (Myrbetriq, Astellas Pharma, Inc.), a β3-AR agonist currently approved to treat overactive bladder, to stimulate BAT as compared to placebo. Mirabegron led to higher BAT metabolic activity as measured via 18F-fluorodeoxyglucose (18F-FDG) using positron emission tomography (PET) combined with computed tomography (CT) in all twelve healthy male subjects (p = 0.001), and it increased resting metabolic rate (RMR) by 203 ± 40 kcal/day (+13%; p = 0.001). BAT metabolic activity was also a significant predictor of the changes in RMR (p = 0.006). Therefore, a β3-AR agonist can stimulate human BAT thermogenesis and may be a promising treatment for metabolic disease.
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•The β3-AR agonist mirabegron acutely activates human BAT glucose uptake•The β3-AR agonist mirabegron acutely activates human WAT lipolysis•Mirabegron stimulates brown/beige fat in multiple depots.•Mirabegron-induced BAT activity is a predictor of whole-body thermogenesis
Preclinical models indicate that activation of brown adipose tissue (BAT) can improve obesity and diabetes. Cypess et al. show that the β3-adrenergic receptor agonist mirabegron, currently approved for overactive bladder, stimulates human BAT thermogenesis and energy expenditure, suggesting that this pharmacological approach may be a promising treatment for metabolic disease.
Brown fat as a therapy for obesity and diabetes Cypess, Aaron M; Kahn, C Ronald
Current opinion in endocrinology, diabetes and obesity./Current opinion in endocrinology, diabetes and obesity
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Journal Article
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Human fat consists of white and brown adipose tissue (WAT and BAT). Though most fat is energy-storing WAT, the thermogenic capacity of even small amounts of BAT makes it an attractive therapeutic ...target for inducing weight loss through energy expenditure. This review evaluates the recent discoveries regarding the identification of functional BAT in adult humans and its potential as a therapy for obesity and diabetes.
Over the past year, several independent research teams used a combination of positron-emission tomography and computed tomography (PET/CT) imaging, immunohistochemistry, and gene and protein expression assays to prove conclusively that adult humans have functional BAT. This has occurred against a backdrop of basic studies defining the origins of BAT, new components of its transcriptional regulation, and the role of hormones in stimulation of BAT growth and differentiation.
Adult humans have functional BAT, a new target for antiobesity and antidiabetes therapies focusing on increasing energy expenditure. Future studies will refine the methodologies used to measure BAT mass and activity, expand our knowledge of critical-control points in BAT regulation, and focus on testing pharmacological agents that increase BAT thermogenesis and help achieve long-lasting weight loss and an improved metabolic profile.
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.
As potential activators of brown adipose tissue (BAT), mild cold exposure and sympathomimetic drugs have been considered as treatments for obesity and diabetes, but whether they activate the same ...pathways is unknown. In 10 healthy human volunteers, we found that the sympathomimetic ephedrine raised blood pressure, heart rate, and energy expenditure, and increased multiple circulating metabolites, including glucose, insulin, and thyroid hormones. Cold exposure also increased blood pressure and energy expenditure, but decreased heart rate and had little effect on metabolites. Importantly, cold increased BAT activity as measured by ¹⁸F-fluorodeoxyglucose PET-CT in every volunteer, whereas ephedrine failed to stimulate BAT. Thus, at doses leading to broad activation of the sympathetic nervous system, ephedrine does not stimulate BAT in humans. In contrast, mild cold exposure stimulates BAT energy expenditure with fewer other systemic effects, suggesting that cold activates specific sympathetic pathways. Agents that mimic cold activation of BAT could provide a promising approach to treating obesity while minimizing systemic effects.
Obesity develops when energy intake exceeds energy expenditure. Although most current obesity therapies are focused on reducing calorific intake, recent data suggest that increasing cellular energy ...expenditure (bioenergetics) may be an attractive alternative approach. This is especially true for adaptive thermogenesis - the physiological process whereby energy is dissipated in mitochondria of brown fat and skeletal muscle in the form of heat in response to external stimuli. There have been significant recent advances in identifying the factors that control the development and function of these tissues, and in techniques to measure brown fat in human adults. In this article, we integrate these developments in relation to the classical understandings of cellular bioenergetics to explore the potential for developing novel anti-obesity therapies that target cellular energy expenditure.
White, beige, and brown adipocytes are developmentally and functionally distinct but often occur mixed together within individual depots. To target white, beige, and brown adipocytes for diagnostic ...or therapeutic purposes, a better understanding of the cell surface properties of these cell types is essential. Using a combination of in silico, in vitro, and in vivo methods, we have identified three new cell surface markers of adipose cell types. The amino acid transporter ASC-1 is a white adipocyte-specific cell surface protein, with little or no expression in brown adipocytes, whereas the amino acid transporter PAT2 and the purinergic receptor P2RX5 are cell surface markers expressed in classical brown and beige adipocytes in mice. These markers also selectively mark brown/beige and white adipocytes in human tissue. Thus, ASC-1, PAT2, and P2RX5 are membrane surface proteins that may serve as tools to identify and target white and brown/beige adipocytes for therapeutic purposes.
Acral melanoma, the most common melanoma subtype among non-White individuals, is associated with poor prognosis. However, its key molecular drivers remain obscure. Here, we perform integrative ...genomic and clinical profiling of acral melanomas from 104 patients treated in North America (n = 37) or China (n = 67). We find that recurrent, late-arising focal amplifications of cytoband 22q11.21 are a leading determinant of inferior survival, strongly associated with metastasis, and linked to downregulation of immunomodulatory genes associated with response to immune checkpoint blockade. Unexpectedly, LZTR1 - a known tumor suppressor in other cancers - is a key candidate oncogene in this cytoband. Silencing of LZTR1 in melanoma cell lines causes apoptotic cell death independent of major hotspot mutations or melanoma subtypes. Conversely, overexpression of LZTR1 in normal human melanocytes initiates processes associated with metastasis, including anchorage-independent growth, formation of spheroids, and an increase in MAPK and SRC activities. Our results provide insights into the etiology of acral melanoma and implicate LZTR1 as a key tumor promoter and therapeutic target.
OBJECTIVE Over the last 2 decades, sport-related concussion (SRC) has garnered significant attention. Even with increased awareness and athlete education, sideline recognition and real-time diagnosis ...remain crucial. The need for an objective and standardized assessment of concussion led to the eventual development of the Sport Concussion Assessment Tool (SCAT) during the Second International Conference on Concussion in Sport in 2004, which is now in its third iteration (SCAT3). In an effort to update our understanding of the most well-known sideline concussion assessment, the authors conducted a systematic review of the SCAT and the evidence supporting its use to date. METHODS English-language titles and abstracts published between 1995 and October 2015 were searched systematically across 4 electronic databases and a review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines adapted for the review of a heterogeneous collection of study designs. Peer-reviewed journal articles were included if they reported quantitative data on any iteration of the SCAT, Standardized Assessment of Concussion (SAC), or modified Balance Error Scoring System (mBESS) data at baseline or following concussion in an exclusively athlete population with any portion older than 13 years of age. Studies that included nonathletes, only children less than 13 years old, exclusively BESS data, exclusively symptom scale data, or a non-SCAT-related assessment were excluded. RESULTS The database search process yielded 549 abstracts, and 105 full-text articles were reviewed with 36 meeting criteria for inclusion. Nineteen studies were associated with the SAC, 1 was associated with the mBESS exclusively, and 16 studies were associated with a full iteration of the SCAT. The majority of these studies (56%) were prospective cohort studies. Male football players were the most common athletes studied. An analysis of the studies focused on baseline differences associated with age, sex, concussion history, and the ability to detect an SRC. CONCLUSIONS Looking toward the upcoming Concussion in Sport Group meeting in fall 2016, one may expect further revision to the SCAT3. However, based on this systematic review, the authors propose further, in-depth study of an already comprehensive concussion test, with acute, diagnostic, as well as long-term use.
Primary brain tumors diagnosed during infancy present several challenges for the pediatric neurosurgeon including the management of tumor-related hydrocephalus. Infant tumor-related hydrocephalus ...(iTRH) is present in over 70% of new diagnoses overall and in over 90% of infants with infratentorial neoplasms. iTRH may be related to direct obstruction of cerebrospinal fluid (CSF) pathways, shedding of protein and/or cells leading to dysfunctional subarachnoid, tumor-related CSF production, or, most frequently, a combination of these mechanisms. Treatment plans must consider the acuity of presentation, the mechanism of iTRH, and the additional neoadjuvant or adjuvant therapies required to treat the neoplasm. This narrative review provides a broad reference on the epidemiology, pathophysiology, and treatment of iTRH.
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