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Metabolic scaling, the inverse correlation of metabolic rates to body mass, has been appreciated for more than 80 years. Studies of metabolic scaling have largely been restricted to mathematical modeling of caloric intake and oxygen consumption, and mostly rely on computational modeling. The possibility that other metabolic processes scale with body size has not been comprehensively studied. To address this gap in knowledge, we employed a systems approach including transcriptomics, proteomics, and measurement of in vitro and in vivo metabolic fluxes. Gene expression in livers of five species spanning a 30,000-fold range in mass revealed differential expression according to body mass of genes related to cytosolic and mitochondrial metabolic processes, and to detoxication of oxidative damage. To determine whether flux through key metabolic pathways is ordered inversely to body size, we applied stable isotope tracer methodology to study multiple cellular compartments, tissues, and species. Comparing C57BL/6 J mice with Sprague-Dawley rats, we demonstrate that while ordering of metabolic fluxes is not observed in in vitro cell-autonomous settings, it is present in liver slices and in vivo. Together, these data reveal that metabolic scaling extends beyond oxygen consumption to other aspects of metabolism, and is regulated at the level of gene and protein expression, enzyme activity, and substrate supply.

For a century, since the pioneering work of Otto Warburg, the interwoven relationship between metabolism and cancer has been appreciated. More recently, with obesity rates rising in the U.S. and worldwide, epidemiologic evidence has supported a link between obesity and cancer. A substantial body of work seeks to mechanistically unpack the association between obesity, altered metabolism, and cancer. Without question, these relationships are multifactorial and cannot be distilled to a single obesity- and metabolism-altering hormone, substrate, or factor. However, it is important to understand the hormone-specific associations between metabolism and cancer. Here, we review the links between obesity, metabolic dysregulation, insulin, and cancer, with an emphasis on current investigational metabolic adjuncts to standard-of-care cancer treatment.

SummaryReprogramming metabolism is of great therapeutic interest for reducing morbidity and mortality during sepsis-induced critical illness1. Disappointing results from randomized controlled trials targeting glutamine and antioxidant metabolism in patients with sepsis have begged for both identification of new metabolic targets, and a deeper understanding of the metabolic fate of glutamine at the systemic and tissue-specific manner2–4. In critically ill patients versus elective surgical controls, skeletal muscle transcriptional metabolic reprogramming is comprised of reduced expression of genes involved in mitochondrial metabolism, electron transport, and glutamate transport, with concomitant increases in glutathione cycling, glutamine, branched chain, and aromatic amino acid transport. To analyze putative interorgan communications during sepsis, we performed systemic and tissue specific metabolic phenotyping in a murine polymicrobial sepsis model, cecal ligation and puncture. In the setting of drastically elevated inflammatory cytokines, we observed >10% body weight loss, >50% reductions in oxygen consumption and carbon dioxide production, and near full suppression of voluntary activity for the 48 hours following sepsis as compared to sham-operated controls. We found increased correlations in the metabolome between liver, kidney, and spleen, with drastic loss of correlations between the heart and quadriceps metabolome and all other organs, pointing to a shared metabolic signature within vital abdominal organs, and unique metabolic signatures for skeletal and cardiac muscle during sepsis. A lowered GSH:GSSG and elevated AMP:ATP ratio in the liver underlie the significant upregulation of isotopically labeled glutamine’s contribution to TCA anaplerosis and glutamine-derived glutathione biosynthesis; meanwhile, the skeletal muscle and spleen were the only organs where glutamine’s contribution to the TCA cycle was significantly suppressed. These results highlight tissue-specific mitochondrial reprogramming, rather than global mitochondrial dysfunction, as a mechanistic consequence of sepsis. Using a multi-omic approach, we demonstrate a model by which sepsis-induced proteolysis fuels the liver’s production of anaplerotic substrates and the antioxidant glutathione to sustain tolerance to sepsis.

In this study, we identified a potential practice-changing approach, dichloroacetate (DCA), to harness metabolic adjuvant therapy to treat cancer-related fatigue (CRF). CRF is one of the most common complications in patients with multiple cancer types. Although CRF severely affects patients’ quality of life and adherence to potentially curative treatment, there have only been single symptom-relieving adjuvant therapies but no effective pharmaceutical treatment for CRF. In this study, we used YUMMER1.7 murine melanoma as the model to study CRF. Mice with late-stage YUMMER1.7 melanoma (3 weeks after tumor xenograft) have significant decreases in muscle performance, including decrease forelimb grip strength, maximum running speed, maximum oxygen consumption and motivation for movement. Dichloroacetate (DCA) has been considered as a potential therapy to slow tumor growth, based largely on its effects in vitro to halt cell division. We found that although DCA did not affect tumor growth, DCA unexpectedly preserved muscle performance in mice with late-stage compared with early-stage tumors. DCA-treated mice had significantly preserved grip strength (9.5% decrease in DCA-treated late-stage mice vs. 29% in non-treated mice), maximum running speed (13% decrease in DCA-treated mice vs. 31% in non-treated mice) and VO2 peak (no significant reduction in DCA-treated mice whereas non-treated mice decreased by 26%). The daily running distance was also significantly higher in DCA-treated mice compared with non-treated mice during the third week after tumor xenograft. Meanwhile, motivation for movement was fully reserved. Moreover, we found that DCA could relieve treatment-worsened CRF in murine YUMMER1.7 melanoma (treated with anti-PD1 immunotherapy) and MC38 colon cancer (treated with 5-fluorouracil chemotherapy) without affecting the efficacy of these treatments. An in vivo liquid chromatography-mass spectrometry/mass spectrometry-based isotope tracer study suggests that DCA treatment may postpone proteolysis in muscle of tumor-bearing mice. Concentrations of 6 free amino acids (arginine, asparagine, leucine, lysine, methionine and threonine) were increased in muscle from late-stage non-treated mice, consistent with increased proteolysis and/or less amino acid utilization in muscle tissue during advanced-stage tumor progression. Such elevation was reversed by DCA treatment. We also discovered lower concentration of serine and glycine in DCA-treated muscle tissue, which provide precursors for antioxidants to adapt to oxidative stress. The abnormal increase of muscle mitochondrial membrane potential, which may enhance reactive oxygen species production, was also reversed in DCA-treaded mice. In all, this study provides evidence for DCA as the first potential adjuvant pharmaceutical treatment to maintain physical function and motivation in cancer patients experiencing CRF. Citation Format: xinyi zhang, Won D. Lee, Brooks P. Leitner, Wanling Zhu, Zongyu Li, Rafael C. Gaspar, Alexandra A. Halberstam, Briana Robles, Joshua D. Rabinowitz, Rachel J. Perry. Dichloroacetate as a novel pharmaceutical treatment for cancer-related fatigue in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 285.

Objective Diversity and equity in medicine remain pivotal to care delivery. Data analysis on sex and racial diversity of pain medicine fellowship trainees and faculty in the United States are scant. We sought to characterize demographic and retention patterns among pain medicine fellows and faculty, who represent the emerging chronic pain management workforce. Design cross-sectional retrospective analysis. Method We conducted an analysis of data from the American Association of Medical Colleges (AAMC) and the United States Accreditation Council on Graduate Medical Education (ACGME)-approved residency and fellowship training-programs for each year from 2009 through 2019, inclusively. We compared changes in sex, racial/ethnicity composition and retention rates of fellows and faculty in the United States by practice setting. Results From 2009 to 2019, there was a 14% increase in the number of ACGME pain fellowship programs. From 2009 to 2019, the ratio of men to women pain fellows ranged from 5:1 to 3.7:1. Compared with their self-identified White peers, Asian (OR 0.44; 95% CI: 0.34–0.58), Black (OR 0.46; 95% CI: 0.30–0.72), and Native American/Alaskan Native (OR 0.26; 95% CI: 0.08–0.80) identifying individuals had significantly lower odds of being a pain fellow, P Conclusions The demographics of pain medicine training programs reflect a persistent male vs. female gap with underrepresentation of racial minorities. Further research is needed to elucidate reasons underlying these disparities.

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).

Metabolic scaling, the inverse correlation of metabolic rates to body mass, has been appreciated for more than 80 years. Studies of metabolic scaling have almost exclusively been restricted to mathematical modeling of oxygen consumption. The possibility that other metabolic processes scale with body size has not been studied. To address this gap in knowledge, we employed a systems approach spanning from transcriptomics to in vitro and in vivo tracer-based flux. Gene expression in livers of five species spanning a 30,000-fold range in mass revealed differential expression of genes related to cytosolic and mitochondrial metabolic processes, in addition to detoxication of oxidative damage. This suggests that transcriptional scaling of damage control mechanisms accommodates increased oxidative metabolism in smaller species. To determine whether flux through key implicated metabolic pathways scaled, we applied stable isotope tracer methodology to study multiple cellular compartments, tissues, and species. Comparing mice and rats, we demonstrate that while scaling of metabolic fluxes is not observed in the cell-autonomous setting, it is present in liver slices and in vivo. Together, these data reveal that metabolic scaling extends beyond oxygen consumption to numerous other metabolic pathways, and is likely regulated at the level of gene expression and substrate supply.

Key Points Question How does representation of American Indian and Alaska Native individuals at specific stages of academic medical training compare with representation of their White counterparts? Findings This cross-sectional study including 1.35 million American Indian and Alaska Native and White individuals in each stage of the 2018-2019 academic medical training continuum found that, compared with their White peers, American Indian and Alaska Native individuals had 63% lower odds of applying to medical school compared with the general US population and 48% lower odds of holding a full-time faculty position postresidency. Meaning These findings suggest there are distinct stages in academic medical training for targeted policy and program changes to increase the representation of American Indian and Alaska Native individuals., Importance Identifying gaps in inclusivity of Indigenous individuals is key to diversifying academic medical programs, increasing American Indian and Alaska Native representation, and improving disparate morbidity and mortality outcomes in American Indian and Alaska Native populations. Objective To examine representation of American Indian and Alaska Native individuals at different stages in the 2018-2019 academic medical training continuum and trends (2011-2020) of American Indian and Alaska Native representation in residency specialties. Design, Setting, and Participants A cross-sectional, population-based analysis was conducted using self-reported race and ethnicity data on trainees from the Association of American Medical Colleges (2018), the Accreditation Council for Graduate Medical Education (2011-2018), and the US Census (2018). Data were analyzed between February 18, 2020, and March 4, 2021. Exposures Enrolled trainees at specific stages of medical training. Main Outcomes and Measures The primary outcome was the odds of representation of American Indian and Alaska Native individuals at successive academic medical stages in 2018-2019 compared with White individuals. Secondary outcomes comprised specialty-specific proportions of American Indian and Alaska Native residents from 2011 to 2020 and medical specialty–specific proportions of American Indian and Alaska Native physicians in 2018. Fisher exact tests were performed to calculate the odds of American Indian and Alaska Native representation at successive stages of medical training. Simple linear regressions were performed to assess trends across residency specialties. Results The study data contained a total of 238 974 607 White and American Indian and Alaska Native US citizens, 24 795 US medical school applicants, 11 242 US medical school acceptees, 10 822 US medical school matriculants, 10 917 US medical school graduates, 59 635 residents, 518 874 active physicians, and 113 168 US medical school faculty. American Indian and Alaska Native individuals had a 63% lower odds of applying to medical school (odds ratio [OR], 0.37; 95% CI, 0.31-0.45) and 48% lower odds of holding a full-time faculty position (OR, 0.52; 95% CI, 0.44-0.62) compared with their White counterparts, yet had 54% higher odds of working in a residency specialty deemed as a priority by the Indian Health Service (OR, 1.54; 95% CI, 1.09-2.16). Of the 33 physician specialties analyzed, family medicine (0.55%) and pain medicine (0.46%) had more than an average proportion (0.41%) of American Indian and Alaska Native physicians compared with their representation across all specialties. Conclusions and Relevance This cross-sectional study noted 2 distinct stages in medical training with significantly lower representation of American Indian and Alaska Native compared with White individuals. An actionable framework to guide academic medical institutions on their Indigenous diversification and inclusivity efforts is proposed., This cross-sectional study examines the representation of American Indian and Alaska Native individuals through the academic stages of medical training and proposes a framework that may be used to enhance diversification efforts.

BackgroundObesity confers an increased risk and accelerates the progression of multiple tumor types in rodents and humans, including both breast and colon cancer. Because sustained weight loss is rarely achieved, therapeutic approaches to slow or prevent obesity-associated cancer development have been limited, and mechanistic insights as to the obesity-cancer connection have been lacking.MethodsE0771 breast tumors and MC38 colon tumors were treated in vivo in mice and in vitro with two mechanistically different insulin-lowering agents, a controlled-release mitochondrial protonophore (CRMP) and sodium-glucose cotransporter-2 (SGLT2) inhibitors, and tumor growth and glucose metabolism were assessed. Groups were compared by ANOVA with Bonferroni’s multiple comparisons test.ResultsDapagliflozin slows tumor growth in two mouse models (E0771 breast cancer and MC38 colon adenocarcinoma) of obesity-associated cancers in vivo, and a mechanistically different insulin-lowering agent, CRMP, also slowed breast tumor growth through its effect to reverse hyperinsulinemia. In both models and with both agents, tumor glucose uptake and oxidation were not constitutively high, but were hormone-responsive. Restoration of hyperinsulinemia by subcutaneous insulin infusion abrogated the effects of both dapagliflozin and CRMP to slow tumor growth.ConclusionsTaken together, these data demonstrate that hyperinsulinemia per se promotes both breast and colon cancer progression in obese mice, and highlight SGLT2 inhibitors as a clinically available means of slowing obesity-associated tumor growth due to their glucose- and insulin-lowering effects.

Increases in intramyocellular lipids (IMCL) are strongly associated with muscle insulin resistance. An important exception to this observation occurs in athletes, who manifest increased IMCL content despite increased muscle insulin sensitivity. This phenomenon has been coined the “Athlete’s Paradox” and is not well understood. Here, we examined the hypothesis that the Athlete’s Paradox can be explained by lower plasma membrane (PM) associated sn-1,2-diacylglycerol (DAG) content leading to lower PKCε and PKCθ translocation in skeletal muscle despite increased muscle triglyceride (TAG) content. To address this hypothesis we studied 3 groups of male C57BL/6J mice following 6 weeks of: 1) Regular chow feeding (RC), 2) High-fat diet feeding (HFD); 3) RC-feeding and running wheel exercise (EX). DAG stereoisomers were assessed in five subcellular compartments [PM, endoplasmic reticulum (ER), mitochondria (Mito), and lipid droplet (LD)] using a novel liquid chromatography-tandem mass spectrometry/cellular fractionation method. Consistent with the Athlete’s Paradox we found that EX mice manifested improved glucose tolerance and muscle insulin sensitivity compared to HFD mice, as assessed by glucose tolerance and hyperinsulinemic-euglycemic clamp studies, despite similar increases in muscle TAG content (RC=5.7 ± 3.2 µg/mg; HFD=17.8 ± 6.0 µg/mg; EX=13.7 ± 5.2 µg/mg) compared to RC mice (RC vs. HFD P Conclusion: Lower PM sn-1,2-DAG content and PKCε/PKCθ activity provides an explanation for the preserved insulin sensitivity in EX mice and thus the Athlete’s Paradox. Disclosure R. C. Gaspar: None. M. Kahn: None. G. Cline: None. J. R. Pauli: None. R. J. Perry: None. K. Petersen: Advisory Panel; Spouse/Partner; AstraZeneca, iMetabolic Biopharma Corporation, Janssen Research & Development, LLC, Merck & Co., Inc., Consultant; Spouse/Partner; Aegerion Pharmaceuticals Inc., Novo Nordisk, Research Support; Self; Gilead Sciences, Inc., Merck & Co., Inc. G. I. Shulman: Consultant; Self; 89bio, Inc., BridgeBio, Ionis Pharmaceuticals, Maze Therapeutics, Novo Nordisk, Other Relationship; Self; AstraZeneca, Esperion Therapeutics, Inc, Generian Pharmaceuticals, Inc., Gilead Sciences, Inc., iMetabolic Biopharma Corporation, Janssen Research & Development, LLC, Merck & Co., Inc., The Liver Company. K. Lyu: None. B. T. Hubbard: None. B. Leitner: None. P. Luukkonen: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Research Support; Self; Novo Nordisk Foundation. S. Hirabara: None. I. Sakuma: None. A. Nasiri: Employee; Spouse/Partner; Medtronic. D. Zhang: None. Funding São Paulo Research Foundation (2019/11338-9, 2017/20542-3); National Institutes of Health (R01DK116774, P30DK045735)

BackgroundThe relationship between systemic metabolism, immune function, and lung cancer is complex and remains poorly defined. Seemingly paradoxically, overweight and obesity confer an improved response to immune checkpoint inhibition in non-small cell lung cancer (NSCLC); however, it is not known whether excess body weight or adiposity impacts the immunometabolic tumor microenvironment.MethodsUtilizing three complementary National Cancer Institute-funded open-source databases containing 18F-fluorodeoxyglucose positron-emission tomography/computed tomography (PET-CT) images for tumor and tissue glucose uptake, adipose tissue and skeletal muscle mass, histology annotated with tumor infiltrating leukocytes, and tumor RNA sequencing, we performed a retrospective cross-sectional analysis to examine phenotypic, metabolic, and genomic intersections of adiposity and tumor immune-metabolism in patients with lung adenocarcinoma (LUAD) versus squamous cell carcinoma (LUSC).ResultsOur data reveal distinct immunometabolomic features of LUSC as compared to LUAD: visceral fat content was negatively correlated with both tumor glucose uptake and leukocyte infiltration. Subcutaneous and visceral adiposity conferred different effects on the tumor genetic landscapes in both tumor types. LUSC tumors showed greater gene expression pathways related to pyruvate, glucose, amino acid, and lipid metabolism, in addition to significantly greater 18F-FDG uptake compared with LUAD, suggesting deeper metabolic regulation within the LUSC tumor microenvironment.ConclusionsSeveral immunometabolomic characteristics of LUSC and LUAD differ, including tumor glucose uptake and the associated metabolic pathways in the tumor, as well as the impact of visceral adiposity on tumor metabolism. These data may highlight opportunities to advance mechanistically targeted precision medicine approaches by better understanding the interplay between metabolic, immunologic, and genomic factors in lung cancer treatment.

Racial health disparities persist despite increased public awareness of systemic racism. Due to the inherent subjectivity of pain perception, assessment and management, physician-patient bias in pain medicine remains widespread. It is broadly accepted that increasing racial diversity in the field of medicine is a critical step towards addressing persistent inequities in patient care. To assess the current racial demographics of the pain medicine pipeline, we conducted a cross-sectional analysis of medical school matriculants and graduates, residents, and pain fellows in 2018. Our results show that the 2018 anesthesiology residency ERAS applicant pool consisted of 46.2% non-Hispanic White, 7.0% non-Hispanic Black and 5.8% Hispanic students. The population of 2018 anesthesiology residents included 63% non-Hispanic White, 6.8% non-Hispanic Black and 5.4% Hispanic persons. Of the total eligible resident pool for pain fellowships (n = 30,415) drawn from core specialties, 44% were non-Hispanic White, 4.9% non-Hispanic Black and 5.1% Hispanic. Similar proportions were observed for pain medicine and regional anesthesia fellows. We briefly discuss the implications of the shortage of non-Hispanic Black and Hispanic representation in pain medicine as it relates to the COVID-19 pandemic and suggest approaches to improving these disparities.

Design and rationale: Obesity results from energy intake exceeding energy expenditure (EE) over a prolonged period. Many anti-obesity drugs are designed to decrease energy intake. However, their potential impact on EE is not well documented. We designed a placebo-controlled, double-blind, randomized cross-over study to determine the acute effects of several FDA-approved anti-obesity drugs on basal metabolic rate (BMR) under well-controlled conditions. Protocol and inclusion criteria: This ongoing study is limited to healthy males of all ethnicities aged 18–35 years with a BMI of 18.5 to 25.0 kg/m2. Following an overnight stay in the Metabolic Clinical Research Unit, fasting subjects were measured from 8:00am to 12:00pm in a whole-room indirect calorimeter, which was maintained at a thermoneutral temperature (26.7±0.9°C) to prevent non-shivering thermogenesis. The six treatments include placebo, caffeine as the positive control (300 mg), phentermine (37.5 mg), topiramate (200 mg), Qsymia (phentermine 15 mg / topiramate 92 mg), and naltrexone (100 mg), with a 1-week outpatient washout period after each treatment. Drug-naïve subjects received a single dose of each drug to minimize potential metabolic adaptations that may occur with weight-loss or chronic use. The prespecified primary outcome was a ≥5% increase in BMR vs. placebo for each drug. This difference can be detected for 16 subjects with 0.83 power at α=0.05 allowing for ≤25% dropout. Secondary outcomes include respiratory quotient (RQ), heart rate (HR), mean arterial pressure (MAP), and self-reported hunger. Preliminary data: To date, 7 subjects were recruited and 6 have completed the study (26.1±4.3 years, BMI 23.1±1.4 kg/m2, body fat percentage 18.4±4.1%). Interim analysis using paired t-tests shows, compared to placebo, caffeine trended towards increasing EE (1.17±0.07 vs. 1.27±0.12 kcal/min; p=0.07) and increased MAP by 5.5±4.2% (88±2 vs. 93±4; p Summary and future directions: Anti-obesity drugs may increase energy expenditure by upregulating sympathetic nervous system activity. Combined with appetite suppression, the impact on energy balance can lead to weight loss. We aim to complete our study to determine whether these drugs can acutely increase EE with minimal cardiovascular side-effects and compare our findings with long-term interventions.

Obesity confers an increased incidence and poorer clinical prognosis in more than 10 cancer types. Paradoxically, obesity may provide protection from poor outcomes in lung cancer. Mechanisms for the obesity-cancer links are not fully elucidated, with altered glucose metabolism being a promising candidate. Using 18F-fluorodeoxyglucose positron-emission-tomography/computed tomography images from The Cancer Imaging Archive, we explored the relationship between body mass index (BMI) and glucose metabolism in several cancers. In 188 patients (BMI mean [SD] = 27.7 [5.1], range = 17.4–49.3 kg/m2), higher BMI was associated with greater tumor glucose uptake in breast cancer (r = 0.36; P = .02) and with lower tumor glucose uptake in non-small cell lung cancer (r = -0.26; P = .048) using two-sided Pearson correlations. No relationship was observed in soft tissue sarcoma or squamous cell carcinoma. Harnessing the National Cancer Institute’s open-access database, we demonstrate altered tumor glucose metabolism as a potential mechanism for the detrimental and protective effects of obesity on breast and lung cancer, respectively.

It has become increasingly evident that the diversity of adipose tissue types may play distinct and potentially important roles in human physiology. White adipose tissue (WAT), the primary energy storage tissue, is important in homeostasis but when found in excess can predispose individuals to severe insulin resistance and diabetes. Human life is compatible with WAT composing between 4 and 60% of total body mass, pointing to its incredible adaptability. In contrast, brown adipose tissue (BAT), typically thought to occur only in hibernating animals and babies, is becoming recognized for its role in human energy expenditure, hormone production, immune regulation, among others. BAT usually comprises around 0–2% of total body mass; however, recent scientific advances in noninvasive imaging and molecular biology have allowed to explore unknown functions of this dynamic tissue. We discuss here the anatomy and physiology of WAT and BAT in the lean and obese human, and potential mechanisms regarding the interplay within obesity and Type 2 diabetes. Later, we review the current methodology for measuring and detecting WAT and BAT, how to experimentally modulate BAT activity, as well as future investigations to yield greater insight into BAT’s functional role in human health.

Despite interest in exercise as a treatment for anxiety disorders the mechanism behind the anxiolytic effects of exercise is unclear. Two observations motivate the present work. First, engagement of attention control during increased working memory (WM) load can decrease anxiety. Second, exercise can improve attention control. Therefore, exercise could boost the anxiolytic effects of increased WM load via its strengthening of attention control. Anxiety was induced by threat of shock and was quantified with anxiety-potentiated startle (APS). Thirty-five healthy volunteers (19 male, age M = 26.11, SD = 5.52) participated in two types of activity, exercise (biking at 60-70% of heart rate reserve) and control-activity (biking at 10-20% of heart rate reserve). After each activity, participants completed a WM task (n-back) at low- and high-load during safe and threat. Results were not consistent with the hypothesis: exercise vs. control-activity increased APS in high-load (p = .03). However, this increased APS was not accompanied with threat-induced impairment in WM performance (p = .37). Facilitation of both task-relevant stimulus processing and task-irrelevant threat processing, concurrent with prevention of threat interference on cognition, suggests that exercise increases cognitive ability. Future studies should explore how exercise affects the interplay of cognition and anxiety in patients with anxiety disorders.

Background Research supports the anxiolytic effect of exercise, but the mechanism underlying this effect is unclear. This study examines the influence of exercise in healthy controls on two distinct defensive states implicated in anxiety disorders: fear, a phasic response to a predictable threat, and anxiety, a sustained response to an unpredictable threat. Methods Thirty-four healthy volunteers (17 male, age M = 26.18, SD = 5.6) participated in sessions of exercise (biking at 60-70% of heart rate reserve) and control (biking at 10-20% of heart rate reserve) activity for 30 min, separated by 1 week. Threat responses were measured by eyeblink startle and assessed with the "Neutral-Predictable-Unpredictable threat test," which includes a neutral (N) and two threat conditions, one with predictable (P) and one with unpredictable (U) shock. Results Results show that exercise versus control activity reduces startle potentiation during unpredictable threat (P = .031), but has no effect on startle potentiation during predictable threat (P = .609). Conclusions These results suggest that exercise reduces defensive response to unpredictable, but not predictable, threat, a dissociation that may help inform clinical indications for this behavioral intervention, as well as provide clues to its underlying neurobehavioral mechanisms.

To develop a safe and noninvasive in vivo assay of hepatic propionate oxidative capacity. A modified 1-13C-propionate breath test was administered to 57 methylmalonic acidemia (MMA) subjects, including 19 transplant recipients, and 16 healthy volunteers. Isotopomer enrichment (13CO2/12CO2) was measured in exhaled breath after an enteral bolus of sodium-1-13C-propionate, and normalized for CO2 production. 1-13C-propionate oxidation was then correlated with clinical, laboratory, and imaging parameters collected via a dedicated natural history protocol. Lower propionate oxidation was observed in patients with the severe mut0 and cblB subtypes of MMA, but was near normal in those with the cblA and mut− forms of the disorder. Liver transplant recipients demonstrated complete restoration of 1-13C-propionate oxidation to control levels. 1-13C-propionate oxidation correlated with cognitive test result, growth indices, bone mineral density, renal function, and serum biomarkers. Test repeatability was robust in controls and in MMA subjects (mean coefficient of variation 6.9% and 12.8%, respectively), despite widely variable serum methylmalonic acid concentrations in the patients. Propionate oxidative capacity, as measured with 1-13C-propionate breath testing, predicts disease severity and clinical outcomes, and could be used to assess the therapeutic effects of liver-targeted genomic therapies for MMA and related disorders of propionate metabolism. This clinical study is registered in www.clinicaltrials.gov with the ID: NCT00078078. Study URL: http://clinicaltrials.gov/ct2/show/NCT00078078

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.

ObjectiveCold exposure increases energy expenditure (EE) and could have a role in combating obesity. To understand this potential, we determined the capacity for cold-induced thermogenesis (CIT), the EE increase above the basal metabolic rate at the individualized coldest tolerable temperature before overt shivering.DesignDuring a 13-day inpatient protocol, we quantitated the EE of 12 lean men and 9 men with obesity at various randomly ordered ambient temperatures in a room calorimeter. Subjects underwent brown fat imaging after exposure to their coldest tolerable temperature.ResultsCIT capacity was 300 ± 218 kcal/d (mean ± SD) or 17 ± 11% in lean men and 125 ± 146 kcal/d or 6 ± 7% in men with obesity (P = 0.01). The temperature below which EE increased, lower critical temperature (Tlc), was warmer in lean men than men with obesity (22.9 ± 1.2 vs 21.1 ± 1.7°C, P = 0.03), but both had similar skin temperature (Tskin) changes and coldest tolerable temperatures. Whereas lean subjects had higher brown fat activity, skeletal muscle activity increased synchronously with CIT beginning at the Tlc in both groups, indicating that muscle is recruited for CIT in parallel with brown fat, not sequentially after nonshivering thermogenesis is maximal.ConclusionsDespite greater insulation from fat, men with obesity had a narrower range of tolerable cool temperatures available for increasing EE and less capacity for CIT than lean men, likely as a result of greater basal heat production and similar perception to Tskin cooling. Further study of the reduced CIT capacity in men with obesity may inform treatment opportunities for obesity.

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.

We previously investigated 16 men with overweight or class I obesity who were admitted to a metabolic ward and engaged in 90 minutes of daily cycle ergometry at a fixed resistance. Subjects resided in a respiratory chamber for 2 days per week. The remaining days were spent in their inpatient rooms. Total expenditure was measured over 2 weeks via doubly labeled water (DLW). We found a surprisingly large (∼500 kcal/day) decrease in expenditure when subjects resided in the respiratory chamber as compared to the days spent in their rooms. Here, we attempted to reproduce this finding in non-exercising healthy volunteers. Purpose: To measure differences in daily energy expenditure between days spent on a metabolic ward vs. days spent in a respiratory chamber. Methods: 10 adults (2 M, 8 F) aged (mean ± SE) 34 ± 3.5 years with BMI 27.9 ± 2.3 kg/m2 completed a 7-day inpatient stay on the metabolic ward at the NIH Clinical Center. Two days were spent residing in a respiratory chamber. Study participants received a controlled diet and refrained from exercise. Temperature and clothing were kept constant. Energy expenditure on days spent on the ward was calculated using DLW over 6 days after accounting for the energy expended during the 2 respiratory chamber days. Results: Average energy expenditure on the ward was 2122 ± 155 kcal/day, with an average of 1996±130 kcal/day expended during the two respiratory chamber days. Therefore, energy expenditure on the metabolic ward was 126 ± 55 kcal/day (p= 0.048) greater than in the respiratory chamber. Conclusion: Participants expended ∼126 kcal/day more on the metabolic ward than in the respiratory chamber. This was a much smaller discrepancy than previously found in exercising men. Failure to reproduce our previous results may have been due to the lack of exercise, the inclusion of women, or the wider range of BMIs in the current study. Further studies are needed to investigate the determinants of energy expenditure differences between ward and respiratory chamber days. Disclosure M.S. Zhou: None. R.E. Howard: None. A. Rabel: None. C. Sedmak: None. H. Cai: None. P.J. Walter: None. R. Brychta: None. L. Fletcher: None. B. Leitner: None. J. Guo: None. S. Sikder: None. A.B. Courville: None. S. Bernstein: None. S. Grewal: None. R. Muniyappa: None. K.Y. Chen: None. K. Hall: None.

Background: Cold stimulation of human brown adipose tissue (BAT) can increase its glucose uptake and energy expenditure, making it a potential target for treating obesity and metabolic disease. BAT is commonly found in deeper fascial layers of specific depots. We observed a distinct sexual dimorphism in the dorsal side of the cervical BAT depot. Methods: Twenty-one healthy, lean, young subjects (12 men, mean BMI 23 ± 2.1 kg/m2), were exposed to five hours of tolerable cold exposure. BAT was measured via by 18F-FDG PET/CT. Results: Men and women had similar total BAT metabolic activity. We classified the cervical BAT depot into two distinct anatomically continuous areas: a deeper, intermuscular region, and a superficial, dorsocervical region (sdBAT, Figure A-B), sdBAT was present in 6 women, but only in one man (Figure C). Women had less lean mass than men (p Conclusions: We believe that sdBAT in women is likely part of the same fascial layer as the classical cervical depot. But based on its location, the sdBAT depot could be a remnant of interscapular BAT seen in rodents and human newborns. These findings are consistent with a model in which the dominant source of thermogenesis is lean tissue, which is lower in women, and when insufficient leads to BAT activation. Disclosure L. Fletcher: None. B. Leitner: None. K.I. Kim: None. S. McGehee: None. R. Brychta: None. A. Cypess: None. K.Y. Chen: 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.

Brown adipose tissue (BAT) has been identified as a potential target in the treatment and prevention of obesity and metabolic disease. The precise kinetics of BAT activation and the duration of stimulus required to recruit metabolically active BAT, and its subsequent deactivation, are not well-understood. In this clinical trial, 19 healthy adults (BMI: 23.7 ± 0.7 kg/m2, Age: 31.2 ± 2.8 year, 12 female) underwent three different cooling procedures to stimulate BAT glucose uptake, and active BAT volume was determined using 18F-Fluorodeoxyglucose (FDG) PET/CT imaging. We found that 20 min of pre-injection cooling produces activation similar to the standard 60 min (39.9 mL vs. 44.2 mL, p = 0.52), indicating that BAT activity approaches its peak function soon after the initiation of cooling. Furthermore, upon removal of cold exposure, active BAT volume declines (13.6 mL vs. 44.2 mL, p = 0.002), but the deactivation process persists even hours following cessation of cooling. Thus, the kinetics of human BAT thermogenesis are characterized by a rapid increase soon after cold stimulation but a more gradual decline after rewarming. These characteristics reinforce the feasibility of developing mild, short-duration cold exposure to activate BAT and treat obesity and metabolic disease.

Human brown adipose tissue (BAT) can be activated to increase glucose uptake and energy expenditure, making it a potential target for treating obesity and metabolic disease. Data on the functional and anatomic characteristics of BAT are limited, however. In 20 healthy young men [12 lean, mean body mass index (BMI) 23.2 ± 1.9 kg/m2; 8 obese, BMI 34.8 ± 3.3 kg/m2] after 5 h of tolerable cold exposure, we measured BAT volume and activity by 18F-labeled fluorodeoxyglucose positron emission tomography/computerized tomography (PET/CT). Obese men had less activated BAT than lean men (mean, 130 vs. 334 mL) but more fat in BAT-containing depots (mean, 1,646 vs. 855 mL) with a wide range (0.1–71%) in the ratio of activated BAT to inactive fat between individuals. Six anatomic regions had activated BAT—cervical, supraclavicular, axillary, mediastinal, paraspinal, and abdominal—with 67 ± 20% of all activated BAT concentrated in a continuous fascial layer comprising the first three depots in the upper torso. These nonsubcutaneous fat depots amounted to 1.5% of total body mass (4.3% of total fat mass), and up to 90% of each depot could be activated BAT. The amount and activity of BAT was significantly influenced by region of interest selection methods, PET threshold criteria, and PET resolutions. The present study suggests that active BAT can be found in specific adipose depots in adult humans, but less than one-half of the fat in these depots is stimulated by acute cold exposure, demonstrating a previously underappreciated thermogenic potential.

Funding for Open Access provided by the UMD Libraries Open Access Publishing Fund., While endurance exercise training improves cerebrovascular health and has neurotrophic effects within the hippocampus, the effects of stopping this exercise on the brain remain unclear. Our aim was to measure the effects of 10 days of detraining on resting cerebral bloodflow (rCBF) in gray matter and the hippocampus in healthy and physically fit older adults. We hypothesized that rCBF would decrease in the hippocampus after a 10-day cessation of exercise training. Twelve master athletes, defined as older adults (age ≥ 50 years) with long-term endurance training histories (≥ 15 years), were recruited from local running clubs. After screening, eligible participants were asked to cease all training and vigorous physical activity for 10 consecutive days. Before and immediately after the exercise cessation period, rCBF was measured with perfusion-weighted MRI. A voxel-wise analysis was used in gray matter, and the hippocampus was selected a priori as a structurally defined region of interest (ROI), to detect rCBF changes overtime. Resting CBF significantly decreased in eight gray matter brain regions. These regions included: (L) inferior temporal gyrus, fusiform gyrus, inferior parietal lobule, (R) cerebellar tonsil, lingual gyrus, precuneus, and bilateral cerebellum (FEW p < 0.05). Additionally, rCBF within the left and right hippocampus significantly decreased after 10 days of no exercise training. These findings suggest that the cerebrovascular system, including the regulation of resting hippocampal blood flow, is responsive to short-term decreases in exercise training among master athletes. Cessation of exercise training among physically fit individuals may provide a novel method to assess the effects of acute exercise and exercise training on brain function in older adults.