The thermoneutral zone in women takes an "arctic" shift compared to men.

Conventionally, women are perceived to feel colder than men, but controlled comparisons are sparse. We measured the response of healthy, lean, young women and men to a range of ambient temperatures typical of the daily environment (17 to 31 °C). The Scholander model of thermoregulation defines the lower critical temperature as threshold of the thermoneutral zone, below which additional heat production is required to defend core body temperature. This parameter can be used to characterize the thermoregulatory phenotypes of endotherms on a spectrum from "arctic" to "tropical." We found that women had a cooler lower critical temperature (mean ± SD: 21.9 ± 1.3 °C vs. 22.9 ± 1.2 °C, P = 0.047), resembling an "arctic" shift compared to men. The more arctic profile of women was predominantly driven by higher insulation associated with more body fat compared to men, countering the lower basal metabolic rate associated with their smaller body size, which typically favors a "tropical" shift. We did not detect sex-based differences in secondary measures of thermoregulation including brown adipose tissue glucose uptake, muscle electrical activity, skin temperatures, cold-induced thermogenesis, or self-reported thermal comfort. In conclusion, the principal contributors to individual differences in human thermoregulation are physical attributes, including body size and composition, which may be partly mediated by sex.

Dichloroacetate as a novel pharmaceutical treatment for cancer-related fatigue in melanoma.

Cancer-related fatigue (CRF) is one of the most common complications in patients with multiple cancer types and severely affects patients' quality of life. However, there have only been single symptom-relieving adjuvant therapies but no effective pharmaceutical treatment for the CRF syndrome. Dichloroacetate (DCA), a small molecule inhibitor of pyruvate dehydrogenase kinase, has been tested 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 rates of tumor growth or the efficacy of standard cancer treatment (immunotherapy and chemotherapy) in two murine cancer models, DCA preserved physical function in mice with late-stage tumors by reducing circulating lactate concentrations. In vivo liquid chromatography-mass spectrometry/mass spectrometry studies suggest that DCA treatment may preserve membrane potential, postpone proteolysis, and relieve oxidative stress in muscles of tumor-bearing mice. In all, this study provides evidence for DCA as a novel pharmaceutical treatment to maintain physical function and motivation in murine models of CRF.NEW & NOTEWORTHY We identify a new metabolic target for cancer-related fatigue, dichloroacetate (DCA). They demonstrate that in mice, DCA preserves physical function and protects against the detrimental effects of cancer treatment by reducing cancer-induced increases in circulating lactate. As DCA is already FDA approved for another indication, these results could be rapidly translated to clinical trials for this condition for which no pharmaceutical therapies exist beyond symptom management.

Tissue-specific reprogramming of glutamine metabolism maintains tolerance to sepsis.

Reprogramming metabolism is of great therapeutic interest for reducing morbidity and mortality during sepsis-induced critical illness. Disappointing results from randomized controlled trials targeting glutamine and antioxidant metabolism in patients with sepsis have begged a deeper understanding of the tissue-specific metabolic response to sepsis. The current study sought to fill this gap. We analyzed skeletal muscle transcriptomics of critically ill patients, versus elective surgical controls, which revealed reduced expression of genes involved in mitochondrial metabolism and electron transport, with increases in glutathione cycling, glutamine, branched chain, and aromatic amino acid transport. We then performed untargeted metabolomics and 13C isotope tracing to analyze systemic and tissue specific metabolic phenotyping in a murine polymicrobial sepsis model. We found an increased number of correlations between the metabolomes of liver, kidney, and spleen, with loss of correlations between the heart and quadriceps and all other organs, pointing to a shared metabolic signature within vital abdominal organs, and unique metabolic signatures for muscles 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 cycle 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 to support liver energetic demands and antioxidant synthesis, rather than global mitochondrial dysfunction, as a metabolic consequence of sepsis.

Gene and protein expression and metabolic flux analysis reveals metabolic scaling in liver ex vivo and in vivo.

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.

Proteomic profiling demonstrates inflammatory and endotheliopathy signatures associated with impaired cardiopulmonary exercise hemodynamic profile in Post Acute Sequelae of SARS-CoV-2 infection (PASC) syndrome.

Approximately 50% of patients who recover from the acute SARS-CoV-2 experience Post Acute Sequelae of SARS-CoV-2 infection (PASC) syndrome. The pathophysiological hallmark of PASC is characterized by impaired system oxygen extraction (EO2) on invasive cardiopulmonary exercise test (iCPET). However, the mechanistic insights into impaired EO2 remain unclear. We studied 21 consecutive iCPET in PASC patients with unexplained exertional intolerance. PASC patients were dichotomized into mildly reduced (EO2peak-mild) and severely reduced (EO2peak-severe) EO2 groups according to the median peak EO2 value. Proteomic profiling was performed on mixed venous blood plasma obtained at peak exercise during iCPET. PASC patients as a group exhibited depressed peak exercise aerobic capacity (peak VO2; 85 ± 18 vs. 131 ± 45% predicted; p = 0.0002) with normal systemic oxygen delivery, DO2 (37 ± 9 vs. 42 ± 15 mL/kg/min; p = 0.43) and reduced EO2 (0.4 ± 0.1 vs. 0.8 ± 0.1; p < 0.0001). PASC patients with EO2peak-mild exhibited greater DO2 compared to those with EO2peak-severe [42.9 (34.2-41.2) vs. 32.1 (26.8-38.0) mL/kg/min; p = 0.01]. The proteins with increased expression in the EO2peak-severe group were involved in inflammatory and fibrotic processes. In the EO2peak-mild group, proteins associated with oxidative phosphorylation and glycogen metabolism were elevated. In PASC patients with impaired EO2, there exist a spectrum of PASC phenotype related to differential aberrant protein expression and cardio-pulmonary physiologic response. PASC patients with EO2peak-severe exhibit a maladaptive physiologic and proteomic signature consistent with persistent inflammatory state and endothelial dysfunction, while in the EO2peak-mild group, there is enhanced expression of proteins involved in oxidative phosphorylation-mediated ATP synthesis along with an enhanced cardiopulmonary physiological response.

Distinct subcellular localisation of intramyocellular lipids and reduced PKCε/PKCθ activity preserve muscle insulin sensitivity in exercise-trained mice.

AIMS/HYPOTHESIS: Athletes exhibit increased muscle insulin sensitivity, despite increased intramuscular triacylglycerol content. This phenomenon has been coined the 'athlete's paradox' and is poorly understood. Recent findings suggest that the subcellular distribution of sn-1,2-diacylglycerols (DAGs) in the plasma membrane leading to activation of novel protein kinase Cs (PKCs) is a crucial pathway to inducing insulin resistance. Here, we hypothesised that regular aerobic exercise would preserve muscle insulin sensitivity by preventing increases in plasma membrane sn-1,2-DAGs and activation of PKCε and PKCθ despite promoting increases in muscle triacylglycerol content. METHODS: C57BL/6J mice were allocated to three groups (regular chow feeding [RC]; high-fat diet feeding [HFD]; RC feeding and running wheel exercise [RC-EXE]). We used a novel LC-MS/MS/cellular fractionation method to assess DAG stereoisomers in five subcellular compartments (plasma membrane [PM], endoplasmic reticulum, mitochondria, lipid droplets and cytosol) in the skeletal muscle. RESULTS: We found that the HFD group had a greater content of sn-DAGs and ceramides in multiple subcellular compartments compared with the RC mice, which was associated with an increase in PKCε and PKCθ translocation. However, the RC-EXE mice showed, of particular note, a reduction in PM sn-1,2-DAG and ceramide content when compared with HFD mice. Consistent with the PM sn-1,2-DAG-novel PKC hypothesis, we observed an increase in phosphorylation of threonine1150 on the insulin receptor kinase (IRKT1150), and reductions in insulin-stimulated IRKY1162 phosphorylation and IRS-1-associated phosphoinositide 3-kinase activity in HFD compared with RC and RC-EXE mice, which are sites of PKCε and PKCθ action, respectively. CONCLUSIONS/INTERPRETATION: These results demonstrate that lower PKCθ/PKCε activity and sn-1,2-DAG content, especially in the PM compartment, can explain the preserved muscle insulin sensitivity in RC-EXE mice.

Isotope tracing reveals distinct substrate preference in murine melanoma subtypes with differing anti-tumor immunity.

BACKGROUND: Research about tumor "metabolic flexibility"-the ability of cells to toggle between preferred nutrients depending on the metabolic context-has largely focused on obesity-associated cancers. However, increasing evidence for a key role for nutrient competition in the tumor microenvironment, as well as for substrate regulation of immune function, suggests that substrate metabolism deserves reconsideration in immunogenic tumors that are not strongly associated with obesity. METHODS: We compare two murine models: immunologically cold YUMM1.7 and immunologically-hot YUMMER1.7. We utilize stable isotope and radioisotope tracer-based metabolic flux studies as well as gas and liquid chromatography-based metabolomics analyses to comprehensively probe substrate preference in YUMM1.7 and YUMMER1.7 cells, with a subset of studies on the impact of available metabolites across a panel of five additional melanoma cell lines. We analyze bulk RNA-seq data and identify increased expression of amino acid and glucose metabolism genes in YUMMER1.7. Finally, we analyze melanoma patient RNA-seq data to identify potential prognostic predictors rooted in metabolism. RESULTS: We demonstrate using stable isotope tracer-based metabolic flux studies as well as gas and liquid chromatography-based metabolomics that immunologically-hot melanoma utilizes more glutamine than immunologically-cold melanoma in vivo and in vitro. Analyses of human melanoma RNA-seq data demonstrate that glutamine transporter and other anaplerotic gene expression positively correlates with lymphocyte infiltration and function. CONCLUSIONS: Here, we highlight the importance of understanding metabolism in non-obesity-associated cancers, such as melanoma. This work advances the understanding of the correlation between metabolism and immunogenicity in the tumor microenvironment and provides evidence supporting metabolic gene expression as potential prognostic factors of melanoma progression and may inform investigations of adjunctive metabolic therapy in melanoma. TRIAL REGISTRATION: Deidentified data from The Cancer Genome Atlas were analyzed.

Insulin and cancer: a tangled web.

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.

An optimized method for tissue glycogen quantification.

Mobilization of glycogen, the short-term storage form of glucose, is the body's first defense against hypoglycemia and is critical for energy provision during high intensity exercise. Therefore, to advance metabolic research, it is critical to be able to accurately measure glycogen concentrations, including during a prolonged fast and other glycogen-modulating interventions. Unfortunately, prior enzymatic methods of glycogen detection have been plagued by poor detection in the lower range, high sample mass requirements, and complicated and/or expensive protocols which introduce substantial technical variability into the measured glycogen concentrations. To address these limitations, here we report a streamlined and versatile glycogen extraction protocol coupled with an optimized phenol-sulfuric acid quantification protocol. With this method, we demonstrate how glycogen can be extracted from only 20 mg of tissue with one centrifugation step and quantified with a highly precise (Intra-assay %CV ranges from 5-10%) and sensitive (proportionality constant for glycogen = 0.07279 A.U./µg) assay. The cost of all materials equates to ~10 cents per sample. Therefore, this method represents an attractive means of assessing ex vivo tissue glycogen content including at the extremes of glycogen concentrations.

Representation of American Indian and Alaska Native Individuals in Academic Medical Training.

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.

Multimodal analysis suggests differential immuno-metabolic crosstalk in lung squamous cell carcinoma and adenocarcinoma.

Immunometabolism within the tumor microenvironment is an appealing target for precision therapy approaches in lung cancer. Interestingly, obesity confers an improved response to immune checkpoint inhibition in non-small cell lung cancer (NSCLC), suggesting intriguing relationships between systemic metabolism and the immunometabolic environment in lung tumors. We hypothesized that visceral fat and 18F-Fluorodeoxyglucose uptake influenced the tumor immunometabolic environment and that these bidirectional relationships differ in NSCLC subtypes, lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). By integrating 18F-FDG PET/CT imaging, bulk and single-cell RNA-sequencing, and histology, we observed that LUSC had a greater dependence on glucose than LUAD. In LUAD tumors with high glucose uptake, glutaminase was downregulated, suggesting a tradeoff between glucose and glutamine metabolism, while in LUSC tumors with high glucose uptake, genes related to fatty acid and amino acid metabolism were also increased. We found that tumor-infiltrating T cells had the highest expression of glutaminase, ribosomal protein 37, and cystathionine gamma-lyase in NSCLC, highlighting the metabolic flexibility of this cell type. Further, we demonstrate that visceral adiposity, but not body mass index (BMI), was positively associated with tumor glucose uptake in LUAD and that patients with high BMI had favorable prognostic transcriptional profiles, while tumors of patients with high visceral fat had poor prognostic gene expression. We posit that metabolic adjunct therapy may be more successful in LUSC rather than LUAD due to LUAD's metabolic flexibility and that visceral adiposity, not BMI alone, should be considered when developing precision medicine approaches for the treatment of NSCLC.

1-13C-propionate breath testing as a surrogate endpoint to assess efficacy of liver-directed therapies in methylmalonic acidemia (MMA).

PURPOSE: To develop a safe and noninvasive in vivo assay of hepatic propionate oxidative capacity. METHODS: 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. RESULTS: 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. CONCLUSION: 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. TRIAL REGISTRATION: This clinical study is registered in www.clinicaltrials.gov with the ID: NCT00078078. Study URL: http://clinicaltrials.gov/ct2/show/NCT00078078.

The Impact of Obesity on Tumor Glucose Uptake in Breast and Lung Cancer.

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.

Sexual Dimorphisms in Adult Human Brown Adipose Tissue.

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.

Chronic mirabegron treatment increases human brown fat, HDL cholesterol, and insulin sensitivity.

BACKGROUNDMirabegron is a ß3-adrenergic receptor (ß3-AR) agonist approved only for the treatment of overactive bladder. Encouraging preclinical results suggest that ß3-AR agonists could also improve obesity-related metabolic disease by increasing brown adipose tissue (BAT) thermogenesis, white adipose tissue (WAT) lipolysis, and insulin sensitivity.METHODSWe treated 14 healthy women of diverse ethnicities (27.5 ± 1.1 years of age, BMI of 25.4 ± 1.2 kg/m2) 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 [18F]-2-fluoro-d-2-deoxy-d-glucose (18F-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.RESULTSChronic 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.CONCLUSIONThese findings indicate that human BAT metabolic activity can be increased after chronic pharmacological stimulation with mirabegron and support the investigation of ß3-AR agonists as a treatment for metabolic disease.TRIAL REGISTRATIONClinicaltrials.gov NCT03049462.FUNDINGThis work was supported by grants from the Intramural Research Program of the NIDDK, NIH (DK075112, DK075116, DK071013, and DK071014).

SGLT2 inhibition slows tumor growth in mice by reversing hyperinsulinemia.

BACKGROUND: Obesity 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. METHODS: E0771 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. RESULTS: Dapagliflozin 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. CONCLUSIONS: Taken 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.

Quantification of the Capacity for Cold-Induced Thermogenesis in Young Men With and Without Obesity.

OBJECTIVE: Cold 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. DESIGN: During 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. RESULTS: CIT 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. CONCLUSIONS: Despite 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.

Whole Body and Regional Quantification of Active Human Brown Adipose Tissue Using 18F-FDG PET/CT.

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.

Kinetics of human brown adipose tissue activation and deactivation.

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.