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BACKGROUND: Mirabegron is a β3-adrenergic receptor (β3-AR) agonist approved only for the treatment of overactive bladder. Encouraging preclinical results suggest that β3-AR agonists could also improve obesity-related metabolic disease by increasing brown adipose tissue (BAT) thermogenesis, white adipose tissue (WAT) lipolysis, and insulin sensitivity. METHODS: We treated 14 healthy women of diverse ethnicities (27.5 ± 1.1 years of age, BMI of 25.4 ± 1.2 kg/m(2)) with 100 mg mirabegron (Myrbetriq extended-release tablet, Astellas Pharma) for 4 weeks in an open-label study. The primary endpoint was the change in BAT metabolic activity as measured by [(18)F]-2-fluoro-d-2-deoxy-d-glucose ((18)F-FDG) PET/CT. Secondary endpoints included resting energy expenditure (REE), plasma metabolites, and glucose and insulin metabolism as assessed by a frequently sampled intravenous glucose tolerance test. RESULTS: Chronic mirabegron therapy increased BAT metabolic activity. Whole-body REE was higher, without changes in body weight or composition. Additionally, there were elevations in plasma levels of the beneficial lipoprotein biomarkers HDL and ApoA1, as well as total bile acids. Adiponectin, a WAT-derived hormone that has antidiabetic and antiinflammatory capabilities, increased with acute treatment and was 35% higher upon completion of the study. Finally, an intravenous glucose tolerance test revealed higher insulin sensitivity, glucose effectiveness, and insulin secretion. CONCLUSION: These findings indicate that human BAT metabolic activity can be increased after chronic pharmacological stimulation with mirabegron and support the investigation of β3-AR agonists as a treatment for metabolic disease. TRIAL REGISTRATION: Clinicaltrials.gov NCT03049462. FUNDING: This work was supported by grants from the Intramural Research Program of the NIDDK, NIH (DK075112, DK075116, DK071013, and DK071014).

The current obesity pandemic results from a physiological imbalance in which energy intake chronically exceeds energy expenditure (EE), and prevention and treatment strategies remain generally ineffective. Approaches designed to increase EE have been informed by decades of experiments in rodent models designed to stimulate adaptive thermogenesis, a long-term increase in metabolism, primarily induced by chronic cold exposure. At the cellular level, thermogenesis is achieved through increased rates of futile cycling, which are observed in several systems, most notably the regulated uncoupling of oxidative phosphorylation from ATP generation by uncoupling protein 1, a tissue-specific protein present in mitochondria of brown adipose tissue (BAT). Physiological activation of BAT and other organ thermogenesis occurs through β-adrenergic receptors (AR), and considerable effort over the past 5 decades has been directed toward developing AR agonists capable of safely achieving a net negative energy balance while avoiding unwanted cardiovascular side effects. Recent discoveries of other BAT futile cycles based on creatine and succinate have provided additional targets. Complicating the current and developing pharmacological-, cold-, and exercise-based methods to increase EE is the emerging evidence for strong physiological drives toward restoring lost weight over the long term. Future studies will need to address technical challenges such as how to accurately measure individual tissue thermogenesis in humans; how to safely activate BAT and other organ thermogenesis; and how to sustain a negative energy balance over many years of treatment.

Context Pheochromocytomas/paragangliomas (PPGLs) are neuroendocrine tumors that can secrete norepinephrine (NE). Brown adipose tissue (BAT) activation is mediated through the action of NE on β-adrenoceptors (β-ARs). In some malignancies, BAT activation is associated with higher cancer activity. Objective To study the relationship between BAT activation and PPGL clinical outcomes. Design A retrospective case-control study that included 342 patients with PPGLs who underwent 18F-fluoro-2-deoxy-D-glucose positron emission tomography-computed tomography (18F-FDG PET/CT) imaging at the National Institutes of Health (NIH). We excluded all patients with parasympathetic tumors and those who underwent 18F-FDG PET/CT after PPGL resection. Scans of 205 patients were reviewed by 2 blinded nuclear medicine physicians; 16 patients had BAT activation on 18F-FDG PET/CT [7.80%; age 27.50 (15.00–45.50) years; 10 female/6 male; body mass index [BMI] 24.90 [19.60–25.35] kg/m2). From the remaining 189 patients, we selected 36 matched controls (age 34.4 [25.4–45.5] years; 21 female/15 male; BMI 25.0 [22.0–26.0] kg/m2). Primary Outcome Measure Overall survival. Results The presence of active BAT on 18F-FDG PET/CT was associated with decreased overall survival when compared with the control group (HRz 5.80; 95% CI, 1.05–32.05; P = 0.02). This association remained significant after adjusting for the SDHB mutation. Median plasma NE in the BAT group was higher than the control group [4.65 vs 0.55 times above the upper limit of normal; P < 0.01]. There was a significant association between higher plasma NE levels and mortality in PPGLs in both groups. Conclusions Our findings suggest that the detection of BAT activity in PPGL patients is associated with higher mortality. We suggest that BAT activation could either be reflecting or contributing to a state of increased host stress that may predict poor outcome in metastatic PPGL.

Human obesity is an increasing burden worldwide. Lipids stored as metabolic fuel in white adipose tissue (WAT) can be rapidly mobilized through lipolysis. In rodent adipocytes, activation of the β3-adrenergic receptors (β3-ARs) leads to lipolysis. The physiological role of the β3-AR in human adipocytes remains controversial due to its reported low expression and previous access only to partial β3-AR agonists. Mirabegron, an FDA-approved drug for overreactive bladder, is a highly-selective human β3-AR agonist. In clinical trials, mirabegron treatment led to activation of human brown adipose tissue (BAT) thermogenesis and increased plasma NEFA’s. Therefore, we investigated if mirabegron directly mediates lipolysis in human white adipocytes. We found similar gene expression of the three β-ARs in human immortalized and primary white adipocytes, with β2-AR being the most expressed, followed by β1-AR and β3-AR. Next, to assess the functionally of the β3-AR in human adipocytes, we established dose-response curves and found that mirabegron increased the release of glycerol, a lipolytic product, in the picomolar range. To identify the molecular mechanism controlling mirabegron-induced lipolysis, we assessed the regulation of key downstream lipolytic proteins. Mirabegron mediated lipolysis by rapidly phosphorylating hormone sensitive lipase (HSL), as well as the mitogen activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK). Moreover, acute inhibition of either the PKA or MAPK/ERK pathways decreased lipolysis. In summary, we identify a major role played by the β3-AR in the regulation of human WAT lipolysis. Mirabegron acts as a potent pro-lipolytic effector, signaling through the canonical adrenergic receptor pathway as well as the MAPK/ERK pathway. Due to the comparatively minimal effects previously reported of mirabegron on the cardiovascular system, mirabegron may be the optimal choice for targeted lipid mobilization in human WAT. Disclosure C. Cero: None. J.W. Johnson: None. A. O’Mara: None. J.D. Linderman: None. A.M. Cypess: None. Funding National Institutes of Health

Objective This study aimed to quantify and compare the amount, activity, and anatomical distribution of cold-activated brown adipose tissue (BAT) in healthy, young, lean women and men. Methods BAT volume and 18 F-fluorodeoxyglucose uptake were measured by positron emission tomography and computerized tomography in 12 women and 12 men (BMI 18.5-25 kg/m2 , aged 18-35 years) after 5 hours of exposure to their coldest temperature before overt shivering. Results Women had a lower detectable BAT volume than men (P = 0.03), but there was no difference after normalizing to body size. The mean BAT glucose uptake and relative distribution of BAT did not differ by sex. 18 F-fluorodeoxyglucose uptake consistent with BAT was observed in superficial dorsocervical adipose tissue of 6 of 12 women but only 1 of 12 men (P = 0.02). This potential BAT depot would pose fewer biopsy risks than other depots. Conclusions Despite differences in adiposity and total BAT volume, we found that healthy, lean, young women and men do not differ in the relative amount, glucose uptake, and distribution of BAT. Dorsocervical 18 F-fluorodeoxyglucose uptake was more prevalent in women and may be a remnant of interscapular BAT seen in human newborns. Future studies are needed to discern how BAT contributes to whole-body thermal physiology and body weight regulation in women and men.

In endothermic animals, brown adipose tissue (BAT) is activated to produce heat for defending body temperature in response to cold. BAT's ability to expend energy has made it a potential target for novel therapies to ameliorate obesity and associated metabolic disorders in humans. Though this tissue has been well studied in small animals, BAT's thermogenic capacity in humans remains largely unknown due to the difficulties of measuring its volume, activity, and distribution. Identifying and quantifying active human BAT is commonly performed using

In endothermic animals, brown adipose tissue (BAT) is activated to produce heat for defending body temperature in response to cold. BAT's ability to expend energy has made it a potential target for novel therapies to ameliorate obesity and associated metabolic disorders in humans. Though this tissue has been well studied in small animals, BAT's thermogenic capacity in humans remains largely unknown due to the difficulties of measuring its volume, activity, and distribution. Identifying and quantifying active human BAT is commonly performed using 18F-Fluorodeoxyglucose (18F-FDG) positron emission tomography and computed tomography (PET/CT) scans following cold-exposure or pharmacological activation. Here we describe a detailed image-analysis approach to quantify total-body human BAT from 18F-FDG PET/CT scans using an open-source software. We demonstrate the drawing of user-specified regions of interest to identify metabolically active adipose tissue while avoiding common non-BAT tissues, to measure BAT volume and activity, and to further characterize its anatomical distribution. Although this rigorous approach is time-consuming, we believe it will ultimately provide a foundation to develop future automated BAT quantification algorithms.

Background: Brown Adipose Tissue (BAT) in adult humans has become increasingly recognized to contribute to energy consumption and modulate metabolism. To date, BAT stimulation has predominately relied on cold exposure. However, long-term cold exposure is impractical as a treatment option for obesity and diabetes. Thus, we investigated if a chronic pharmacotherapeutic approach could stimulate BAT and contribute to metabolic health. Methods: In an ongoing study, 6 healthy female volunteers received 4 weeks of daily mirabegron (Myrbetriq, Astellas Pharma) 100 mg, a β3 adrenergic receptor (AR) agonist. Acute responses were determined by comparing effects before and then five hours after dosing. Chronic changes were assessed after 4 weeks of treatment. The primary endpoint was the change in BAT metabolic activity measured by 18F-FDG PET/CT. Secondary endpoints included resting energy expenditure (REE), insulin and glucose sensitivity, liver steatosis, and cardiovascular stimulation. Results: Acute effects of mirabegron included consistent increases in rate pressure product (RPP), REE, and serum non-esterified fatty acids (NEFA) (p Conclusions: Acute treatment with mirabegron in women successfully activates BAT thermogenesis. Preliminary data show chronic treatment resulted in a blunting of several responses, consistent with physiological attenuation of β-AR signaling. The increases in sleeping EE and improved insulin sensitivity suggest chronic mirabegron treatment may help alleviate metabolic disease. Disclosure A. O'Mara: None. A. Cypess: None. C. Cero: None. J.W. Johnson: None. J.D. Linderman: None. B. Leitner: None. L. Fletcher: None. R. Brychta: None. D. Kapuria: None. S. McGehee: None. Y. Rotman: None.

Obesity results from the accumulation of excess white adipose tissue, and its increasing rates worldwide pose a significant risk to overall health due to its multiple comorbidities, like type 2 diabetes. A novel treatment strategy is to increase energy expenditure through activation of brown and beige adipocytes, which can use uncoupling protein 1 (UCP1) for thermogenesis. In addition to having different developmental lineages, brown and beige adipocytes differ functionally regarding the additional mechanisms by which they generate heat. Most human fat depots are not easily accessible, so little is known about their developmental and functional characteristics. In this study, we collected adipose tissue from 11 patients (age 16-84, 4 female/7 male) who had undergone autopsy. We sampled from 7 anatomically distinct fat depots: subcutaneous (sc), omental (om), retroperitoneal (rp), pericardial (pc), periadrenal (pa), paraspinal (ps), and supraclavicular (sv). We measured mRNA levels of lineage and functional genes associated with brown, beige, and white adipocytes. Energy storing white adipocytes were defined by high leptin expression, while energy expending brown and beige cells were defined by high UCP1; these were further distinguished as having a brown lineage using Zic1 and beige via Tbx1. Principal component analysis showed three different clusters of genes consistent with the brown, beige, and white lineages. Functionally, based on expression of leptin and UCP1 for white and brown fat, respectively, the sc and om were white (P In summary, human adipose tissue is not merely white or brown but instead is composed of many depots with distinct developmental lineages and functional capacities. These differences will be important when trying to use brown and beige adipocyte thermogenesis to treat obesity and diabetes. Disclosure J.W. Johnson: None. C. Cero: None. A. O'Mara: None. J.D. Linderman: None. A.S. Baskin: None. A. Cypess: None.

In rodent models, the β3-adrenergic receptor (AR) is responsible for thermogenesis in brown adipose tissue (BAT) and lipolysis in white adipose tissue (WAT). In contrast, the contribution of β3-AR in human adipocytes is controversial due to the low expression of the β3-AR in WAT and access only to partial β3-AR agonists. Mirabegron, an FDA-approved drug for overreactive bladder, is a selective human β3-AR agonist. In a recent clinical trial, mirabegron activated human BAT thermogenesis and WAT lipolysis. Therefore, we investigated the distribution and relative contribution of β1/2/3-AR in (i) whole white (hWAT) and brown (hBAT) adipose tissue from human autopsies and (ii) immortalized human white (hWA) and brown (hBA) adipocytes. Among the three β-ARs, β1-AR and β2-AR are similarly expressed in brown and white adipose tissue, whereas β3-AR has the highest expression in hBAT. In immortalized differentiated cells, hBA have a significantly higher expression of β3-AR compared to hWA. To assess the functionally of these receptors in adipocytes, dose-response curves of agonist-stimulated lipolysis were investigated in differentiated human and mouse adipocytes. We observed that stimulation of any one of the three β-ARs in human adipocytes induces a significant increase in glycerol release, a lipolytic byproduct. However, the effective dose of mirabegron to activate β3-AR-mediated lipolysis in white and brown adipocytes via mirabegron was significantly lower (hWA: EC50 2.55E-09; hBA: EC50 6.31E-09) compared to specific activators of β1-AR or β2-AR. In summary, we identify a major role played by the β3-AR in the regulation of human BAT thermogenesis and WAT lipolysis, both in vivo and in vitro. Due to the comparatively minimal effects of mirabegron treatment on the cardiovascular system, selective β3-AR agonists may be the optimal choice for targeted stimulation of human WAT and BAT. Disclosure C. Cero: None. A. O'Mara: None. J.W. Johnson: None. A.S. Baskin: None. J.D. Linderman: None. A. Cypess: None.

β3-adrenergic receptor (AR) agonists are approved to treat only overactive bladder. However, rodent studies suggest that these drugs could have other beneficial effects on human metabolism. We performed tissue receptor profiling and showed that the human β3-AR mRNA is also highly expressed in gallbladder and brown adipose tissue (BAT). We next studied the clinical implications of this distribution in 12 healthy men given one-time randomized doses of placebo, the approved dose of 50 mg, and 200 mg of the β3-AR agonist mirabegron. There was a more-than-dose-proportional increase in BAT metabolic activity as measured by [18F]-2-fluoro-D-2-deoxy-d-glucose positron emission tomography/computed tomography (medians 0.0 vs. 18.2 vs. 305.6 mL ⋅ mean standardized uptake value [SUVmean] ⋅ g/mL). Only the 200-mg dose elevated both nonesterified fatty acids (68%) and resting energy expenditure (5.8%). Previously undescribed increases in gallbladder size (35%) and reductions in conjugated bile acids were also discovered. Therefore, besides urinary bladder relaxation, the human β3-AR contributes to white adipose tissue lipolysis, BAT thermogenesis, gallbladder relaxation, and bile acid metabolism. This physiology should be considered in the development of more selective β3-AR agonists to treat obesity-related complications.