Publications by authors named "Aaron M Cypess"

65 Publications

The transcriptional co-regulator LDB1 is required for brown adipose function.

Mol Metab 2021 Jun 29;53:101284. Epub 2021 Jun 29.

Comprehensive Diabetes Center and Department of Medicine, USA; Division of Endocrinology, Diabetes and Metabolism, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address:

Objective: Brown adipose tissue (BAT) is critical for thermogenesis and glucose/lipid homeostasis. Exploiting the energy uncoupling capacity of BAT may reveal targets for obesity therapies. This exploitation requires a greater understanding of the transcriptional mechanisms underlying BAT function. One potential regulator of BAT is the transcriptional co-regulator LIM domain-binding protein 1 (LDB1), which acts as a dimerized scaffold, allowing for the assembly of transcriptional complexes. Utilizing a global LDB1 heterozygous mouse model, we recently reported that LDB1 might have novel roles in regulating BAT function. However, direct evidence for the LDB1 regulation of BAT thermogenesis and substrate utilization has not been elucidated. We hypothesize that brown adipocyte-expressed LDB1 is required for BAT function.

Methods: LDB1-deficient primary cells and brown adipocyte cell lines were assessed via qRT-PCR and western blotting for altered mRNA and protein levels to define the brown adipose-specific roles. We conducted chromatin immunoprecipitation with primary BAT tissue and immortalized cell lines. Potential transcriptional partners of LDB1 were revealed by conducting LIM factor surveys via qRT-PCR in mouse and human brown adipocytes. We developed a Ucp1-Cre-driven LDB1-deficiency mouse model, termed Ldb1, to test LDB1 function in vivo. Glucose tolerance and uptake were assessed at thermoneutrality via intraperitoneal glucose challenge and glucose tracer studies. Insulin tolerance was measured at thermoneutrality and after stimulation with cold or the administration of the β3-adrenergic receptor (β3-AR) agonist CL316,243. Additionally, we analyzed plasma insulin via ELISA and insulin signaling via western blotting. Lipid metabolism was evaluated via BAT weight, histology, lipid droplet morphometry, and the examination of lipid-associated mRNA. Finally, energy expenditure and cold tolerance were evaluated via indirect calorimetry and cold challenges.

Results: Reducing Ldb1 in vitro and in vivo resulted in altered BAT-selective mRNA, including Ucp1, Elovl3, and Dio2. In addition, there was reduced Ucp1 induction in vitro. Impacts on gene expression may be due, in part, to LDB1 occupying Ucp1 upstream regulatory domains. We also identified BAT-expressed LIM-domain factors Lmo2, Lmo4, and Lhx8, which may partner with LDB1 to mediate activity in brown adipocytes. Additionally, we observed LDB1 enrichment in human brown adipose. In vivo analysis revealed LDB1 is required for whole-body glucose and insulin tolerance, in part through reduced glucose uptake into BAT. In Ldb1 tissue, we found significant alterations in insulin-signaling effectors. An assessment of brown adipocyte morphology and lipid droplet size revealed larger and more unilocular brown adipocytes in Ldb1 mice, particularly after a cold challenge. Alterations in lipid handling were further supported by reductions in mRNA associated with fatty acid oxidation and mitochondrial respiration. Finally, LDB1 is required for energy expenditure and cold tolerance in both male and female mice.

Conclusions: Our findings support LDB1 as a regulator of BAT function. Furthermore, given LDB1 enrichment in human brown adipose, this co-regulator may have conserved roles in human BAT.
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http://dx.doi.org/10.1016/j.molmet.2021.101284DOI Listing
June 2021

β3-Adrenergic receptors regulate human brown/beige adipocyte lipolysis and thermogenesis.

JCI Insight 2021 Jun 8;6(11). Epub 2021 Jun 8.

Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, Maryland, USA.

β3-Adrenergic receptors (β3-ARs) are the predominant regulators of rodent brown adipose tissue (BAT) thermogenesis. However, in humans, the physiological relevance of BAT and β3-AR remains controversial. Herein, using primary human adipocytes from supraclavicular neck fat and immortalized brown/beige adipocytes from deep neck fat from 2 subjects, we demonstrate that the β3-AR plays a critical role in regulating lipolysis, glycolysis, and thermogenesis. Silencing of the β3-AR compromised genes essential for thermogenesis, fatty acid metabolism, and mitochondrial mass. Functionally, reduction of β3-AR lowered agonist-mediated increases in intracellular cAMP, lipolysis, and lipolysis-activated, uncoupling protein 1-mediated thermogenic capacity. Furthermore, mirabegron, a selective human β3-AR agonist, stimulated BAT lipolysis and thermogenesis, and both processes were lost after silencing β3-AR expression. This study highlights that β3-ARs in human brown/beige adipocytes are required to maintain multiple components of the lipolytic and thermogenic cellular machinery and that β3-AR agonists could be used to achieve metabolic benefit in humans.
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http://dx.doi.org/10.1172/jci.insight.139160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262278PMC
June 2021

Proton MR Spectroscopy Measurements of White and Brown Adipose Tissue in Healthy Humans: Relaxation Parameters and Unsaturated Fatty Acids.

Radiology 2021 05 16;299(2):396-406. Epub 2021 Mar 16.

From the Biomedical and Metabolic Imaging Branch (R.O., A.H., J.M., K.Z.A., A.M.G.) and Diabetes, Endocrinology, and Obesity Branch (Z.A.S., K.Y.C., A.M.C.), National Institute of Diabetes and Digestive and Kidney Diseases, 10 Center Dr, Bldg 10-CRC, Room 3-5340, Bethesda, MD 20892-1263; and Cancer Imaging Program, National Cancer Institute, Bethesda, Md (J.F.E.).

Background Activation of brown adipose tissue (BAT) in rodents increases lipolysis in white adipose tissue (WAT) and improves glucose tolerance. Adult humans can have metabolically active BAT. Implications for diabetes and obesity in humans require a better characterization of BAT in humans. Purpose To study fat depots with localized proton MR spectroscopy relaxometry and to identify differences between WAT and fluorine 18 fluorodeoxyglucose (FDG) PET/CT proven cold-activated BAT in humans. Materials and Methods Participants were consecutively enrolled in this prospective study (ClinicalTrials.gov identifiers: NCT01568671 and NCT01399385) from August 2016 to May 2019. Supraclavicular potential BAT regions were localized with MRI. Proton densities, T1, and T2 were measured with localized MR spectroscopy in potential BAT and in subcutaneous WAT. FDG PET/CT after cold stimulation was used to retrospectively identify active supraclavicular BAT or supraclavicular quiescent adipose tissue (QAT) regions. MR spectroscopy results from BAT and WAT were compared with grouped and paired tests. Results Of 21 healthy participants (mean age, 36 years ± 16 [standard deviation]; 13 men) FDG PET/CT showed active BAT in 24 MR spectroscopy-targeted regions in 16 participants (eight men). Four men had QAT. The T2 for methylene protons was shorter in BAT (mean, 69 msec ± 6, 24 regions) than in WAT (mean, 83 msec ± 3, 18 regions, < .01) and QAT (mean, 78 msec ± 2, five regions, < .01). A T2 cut-off value of 76 msec enabled the differentiation of BAT from WAT or QAT with a sensitivity of 85% and a specificity of 95%. Densities of protons adjacent and between double bonds were 33% and 24% lower, respectively, in BAT compared with those in WAT ( = .01 and = .03, respectively), indicating a lower content of unsaturated and polyunsaturated fatty acids, respectively, in BAT compared with WAT. Conclusion Proton MR spectroscopy showed shorter T2 and lower unsaturated fatty acids in brown adipose tissue (BAT) than that in white adipose tissue in healthy humans. It was feasible to identify BAT with MR spectroscopy without the use of PET/CT or cold stimulation. © RSNA, 2021 See also the editorial by Barker in this issue.
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http://dx.doi.org/10.1148/radiol.2021202676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108561PMC
May 2021

Reduced brown adipose tissue activity during cold exposure is a metabolic feature of the human thrifty phenotype.

Metabolism 2021 04 18;117:154709. Epub 2021 Jan 18.

Obesity and Diabetes Clinical Research Section, Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, 4212 N 16th Street, Phoenix, AZ 85016, USA; Department of Information Engineering, University of Pisa, Pisa 56122, Italy. Electronic address:

Background: We recently demonstrated that thrifty subjects, characterized by a greater decrease in 24 h energy expenditure (24hEE) during short-term fasting, have less capacity for cold-induced thermogenesis (CIT) during 24 h of mild cold exposure.

Objective: As cold-induced brown adipose tissue activation (CIBA) is a determinant of CIT, we sought to investigate whether thrifty individuals also have reduced CIBA.

Methods: Twenty-four healthy subjects (age: 29.8 ± 9.5y, body fat: 27.3 ± 12.4%, 63% male) were admitted to our clinical research unit and underwent two 24hEE assessments in a whole-room indirect calorimeter during energy balance and fasting conditions at thermoneutrality to quantify their degree of thriftiness. Positron emission tomography/computed tomography scans were performed after exposure to 16 °C for 2 h to quantify peak CIBA.

Results: A greater decrease in 24hEE during fasting was associated with lower peak CIBA (r = 0.50, p = 0.01), such that a 100 kcal/day greater reduction in 24hEE related to an average 3.2 g/mL lower peak CIBA.

Conclusion: Our results indicate that reduced CIBA is a metabolic trait of the thrifty phenotype which might explain reduced CIT capacity and greater predisposition towards weight gain in individuals with a thrifty metabolism.
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http://dx.doi.org/10.1016/j.metabol.2021.154709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956243PMC
April 2021

Identification and characterization of distinct brown adipocyte subtypes in C57BL/6J mice.

Life Sci Alliance 2021 01 30;4(1). Epub 2020 Nov 30.

Research Group Adipocytes and Metabolism, Institute for Diabetes and Obesity, Helmholtz Zentrum München, Neuherberg, Germany

Brown adipose tissue (BAT) plays an important role in the regulation of body weight and glucose homeostasis. Although increasing evidence supports white adipose tissue heterogeneity, little is known about heterogeneity within murine BAT. Recently, UCP1 high and low expressing brown adipocytes were identified, but a developmental origin of these subtypes has not been studied. To obtain more insights into brown preadipocyte heterogeneity, we use single-cell RNA sequencing of the BAT stromal vascular fraction of C57/BL6 mice and characterize brown preadipocyte and adipocyte clonal cell lines. Statistical analysis of gene expression profiles from brown preadipocyte and adipocyte clones identify markers distinguishing brown adipocyte subtypes. We confirm the presence of distinct brown adipocyte populations in vivo using the markers EIF5, TCF25, and BIN1. We also demonstrate that loss of enhances UCP1 expression and mitochondrial respiration, suggesting that BIN1 marks dormant brown adipocytes. The existence of multiple brown adipocyte subtypes suggests distinct functional properties of BAT depending on its cellular composition, with potentially distinct functions in thermogenesis and the regulation of whole body energy homeostasis.
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http://dx.doi.org/10.26508/lsa.202000924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723269PMC
January 2021

Sexual Dimorphisms in Adult Human Brown Adipose Tissue.

Obesity (Silver Spring) 2020 02;28(2):241-246

Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.

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 F-fluorodeoxyglucose uptake were measured by positron emission tomography and computerized tomography in 12 women and 12 men (BMI 18.5-25 kg/m , 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. 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 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.
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http://dx.doi.org/10.1002/oby.22698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986330PMC
February 2020

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

J Clin Invest 2020 05;130(5):2209-2219

Diabetes, Endocrinology, and Obesity Branch, Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, Maryland, USA.

BACKGROUNDMirabegron 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.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 β3-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).
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http://dx.doi.org/10.1172/JCI131126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190915PMC
May 2020

Opportunities and challenges in the therapeutic activation of human energy expenditure and thermogenesis to manage obesity.

J Biol Chem 2020 02 30;295(7):1926-1942. Epub 2019 Dec 30.

Diabetes, Endocrinology, and Obesity Branch, Intramural Research Program, NIDDK, National Institutes of Health, Bethesda, Maryland 20892. Electronic address:

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.
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http://dx.doi.org/10.1074/jbc.REV119.007363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029124PMC
February 2020

Pheochromocytoma and Paraganglioma Patients With Poor Survival Often Show Brown Adipose Tissue Activation.

J Clin Endocrinol Metab 2020 04;105(4)

National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.

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.
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http://dx.doi.org/10.1210/clinem/dgz314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059996PMC
April 2020

Brief Report: Adipogenic Expression of Brown Fat Genes in HIV and HIV-Related Parameters.

J Acquir Immune Defic Syndr 2019 12;82(5):491-495

Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA.

Context: Persons with HIV are at increased risk for adipose dysfunction, which could mediate metabolic complications such as cardiovascular disease, fatty liver disease, and diabetes. We have previously reported reduced browning and beiging capacity of the subcutaneous adipose depot in HIV.

Objective: We sought to evaluate how HIV-related parameters are related to the expression of brown and beige fat genes in the abdominal subcutaneous adipose tissue.

Design: Eighteen persons with HIV underwent punch biopsy of abdominal subcutaneous fat to determine mRNA expression of adipose-related genes using quantitative reverse transcriptase-polymerase chain reaction.

Results: Duration of antiretroviral therapy use, particularly related to protease inhibitor use, was significantly related to reduced expression of multiple brown and beige fat genes (including UCP1, PGC1α, PRDM16 and others, all P ≤ 0.04) in the abdominal subcutaneous fat. In addition, duration of HIV and CD4 T-cell count were significantly correlated with reduced expression of multiple brown and beige fat genes in the abdominal subcutaneous fat (PGC1α, P2XR5, TMEM26, CD137, all P ≤ 0.05 for duration of HIV; and PGC1α, ZIC1, PRDM16, PAT2, P2RX5, TMEM26, CD137, all P ≤ 0.04). In contrast, HIV viral load did not correlate with any brown or beige fat genes.

Conclusions: Key HIV-related parameters reflective of nonacute infection (increased duration of HIV and duration of antiretroviral therapy use) or relatively reduced immunologic function (lower CD4 count) were linked to reduced expression of brown and beige fat gene in the abdominal subcutaneous adipose depot.

Clinical Trial Registration: NCT01098045.
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http://dx.doi.org/10.1097/QAI.0000000000002180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857717PMC
December 2019

Reply to Letter to the Editor: "No insulating effect of obesity, neither in mice nor in humans".

Am J Physiol Endocrinol Metab 2019 11;317(5):E954-E956

Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.

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http://dx.doi.org/10.1152/ajpendo.00363.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879861PMC
November 2019

Thyroid Hormone Effects on Glucose Disposal in Patients With Insulin Receptor Mutations.

J Clin Endocrinol Metab 2020 03;105(3)

National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.

Context: Patients with mutations of the insulin receptor gene (INSR) have extreme insulin resistance and are at risk for early morbidity and mortality from diabetes complications. A case report suggested that thyroid hormone could improve glycemia in INSR mutation in part by increasing brown adipose tissue (BAT) activity and volume.

Objective: To determine if thyroid hormone increases tissue glucose uptake and improves hyperglycemia in INSR mutation.

Design: Single-arm, open-label study of liothyronine.

Setting: National Institutes of Health.

Participants: Patients with homozygous (n = 5) or heterozygous (n = 2) INSR mutation.

Intervention: Liothyronine every 8 hours for 2 weeks (n = 7); additional 6 months' treatment in those with hemoglobin A1c (HbA1c) > 7% (n = 4).

Outcomes: Whole-body glucose uptake by isotopic tracers; tissue glucose uptake in muscle, white adipose tissue (WAT) and BAT by dynamic [18F] fluorodeoxyglucose positron emission tomography/computed tomography; HbA1c.

Results: There was no change in whole-body, muscle, or WAT glucose uptake from baseline to 2 weeks of liothyronine. After 6 months, there was no change in HbA1c (8.3 ± 1.2 vs 9.1 ± 3.0%, P = 0.27), but there was increased whole-body glucose disposal (22.8 ± 4.9 vs 30.1 ± 10.0 µmol/kg lean body mass/min, P = 0.02), and muscle (0.7 ± 0.1 vs 2.0 ± 0.2 µmol/min/100 mL, P < 0.0001) and WAT glucose uptake (1.2 ± 0.2 vs 2.2 ± 0.3 µmol/min/100 mL, P < 0.0001). BAT glucose uptake could not be quantified because of small volume. There were no signs or symptoms of hyperthyroidism.

Conclusion: Liothyronine administered at well-tolerated doses did not improve HbA1c. However, the observed increases in muscle and WAT glucose uptake support the proposed mechanism that liothyronine increases tissue glucose uptake. More selective agents may be effective at increasing tissue glucose uptake without thyroid hormone-related systemic toxicity.Clinical Trial Registration Number: NCT02457897; https://clinicaltrials.gov/ct2/show/NCT02457897.
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http://dx.doi.org/10.1210/clinem/dgz079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093053PMC
March 2020

12-Lipoxygenase Regulates Cold Adaptation and Glucose Metabolism by Producing the Omega-3 Lipid 12-HEPE from Brown Fat.

Cell Metab 2019 10 25;30(4):768-783.e7. Epub 2019 Jul 25.

Joslin Diabetes Center, Section on Integrative Physiology and Metabolism, Harvard Medical School, Boston, MA, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA. Electronic address:

Distinct oxygenases and their oxylipin products have been shown to participate in thermogenesis by mediating physiological adaptations required to sustain body temperature. Since the role of the lipoxygenase (LOX) family in cold adaptation remains elusive, we aimed to investigate whether, and how, LOX activity is required for cold adaptation and to identify LOX-derived lipid mediators that could serve as putative cold mimetics with therapeutic potential to combat diabetes. By utilizing mass-spectrometry-based lipidomics in mice and humans, we demonstrated that cold and β3-adrenergic stimulation could promote the biosynthesis and release of 12-LOX metabolites from brown adipose tissue (BAT). Moreover, 12-LOX ablation in mouse brown adipocytes impaired glucose uptake and metabolism, resulting in blunted adaptation to the cold in vivo. The cold-induced 12-LOX product 12-HEPE was found to be a batokine that improves glucose metabolism by promoting glucose uptake into adipocytes and skeletal muscle through activation of an insulin-like intracellular signaling pathway.
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http://dx.doi.org/10.1016/j.cmet.2019.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774888PMC
October 2019

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

J Clin Endocrinol Metab 2019 10;104(10):4865-4878

Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.

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.
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http://dx.doi.org/10.1210/jc.2019-00728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6733495PMC
October 2019

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

J Vis Exp 2019 04 1(146). Epub 2019 Apr 1.

Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health;

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 F-Fluorodeoxyglucose (F-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 F-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.
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http://dx.doi.org/10.3791/58469DOI Listing
April 2019

TGF-β receptor 1 regulates progenitors that promote browning of white fat.

Mol Metab 2018 10 27;16:160-171. Epub 2018 Jul 27.

Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes & Digestive & Kidney Diseases, USA. Electronic address:

Objective: Beige/brite adipose tissue displays morphological characteristics and beneficial metabolic traits of brown adipose tissue. Previously, we showed that TGF-β signaling regulates the browning of white adipose tissue. Here, we inquired whether TGF-β signals regulated presumptive beige progenitors in white fat and investigated the TGF-β regulated mechanisms involved in beige adipogenesis.

Methods: We deleted TGF-β receptor 1 (TβRI) in adipose tissue (TβRI mice) and, using flow-cytometry based assays, identified and isolated presumptive beige progenitors located in the stromal vascular cells of white fat. These cells were molecularly characterized to examine beige/brown marker expression and to investigate TGF-β dependent mechanisms. Further, the cells were transplanted into athymic nude mice to examine their adipogenesis potential.

Results: Deletion of TβRI promotes beige adipogenesis while reducing the detrimental effects of high fat diet feeding. Interaction of TGF-β signaling with the prostaglandin pathway regulated the appearance of beige adipocytes in white fat. Using flow cytometry techniques and stromal vascular fraction from white fat, we isolated presumptive beige stem/progenitor cells (iBSCs). Upon genetic or pharmacologic inhibition of TGF-β signaling, these cells express high levels of predominantly beige markers. Transplantation of TβRI-deficient stromal vascular cells or iBSCs into athymic nude mice followed by high fat diet feeding and stimulation of β-adrenergic signaling via CL316,243 injection or cold exposure promoted robust beige adipogenesis in vivo.

Conclusions: TβRI signals target the prostaglandin network to regulate presumptive beige progenitors in white fat capable of developing into beige adipocytes with functional attributes. Controlled inhibition of TβRI signaling and concomitant PGE2 stimulation has the potential to promote beige adipogenesis and improve metabolism.
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http://dx.doi.org/10.1016/j.molmet.2018.07.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6158128PMC
October 2018

Cold-Activated Lipid Dynamics in Adipose Tissue Highlights a Role for Cardiolipin in Thermogenic Metabolism.

Cell Rep 2018 07;24(3):781-790

Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA. Electronic address:

Thermogenic fat expends energy during cold for temperature homeostasis, and its activity regulates nutrient metabolism and insulin sensitivity. We measured cold-activated lipid landscapes in circulation and in adipose tissue by MS/MS shotgun lipidomics. We created an interactive online viewer to visualize the changes of specific lipid species in response to cold. In adipose tissue, among the approximately 1,600 lipid species profiled, we identified the biosynthetic pathway of the mitochondrial phospholipid cardiolipin as coordinately activated in brown and beige fat by cold in wild-type and transgenic mice with enhanced browning of white fat. Together, these data provide a comprehensive lipid bio-signature of thermogenic fat activation in circulation and tissue and suggest pathways regulated by cold exposure.
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http://dx.doi.org/10.1016/j.celrep.2018.06.073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117118PMC
July 2018

Regulation of Human Adipose Tissue Activation, Gallbladder Size, and Bile Acid Metabolism by a β3-Adrenergic Receptor Agonist.

Diabetes 2018 10 6;67(10):2113-2125. Epub 2018 Jul 6.

Diabetes, Endocrinology, and Obesity Branch, Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD

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 [F]-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 [SUV] ⋅ 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.
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http://dx.doi.org/10.2337/db18-0462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6152342PMC
October 2018

Kinetics of human brown adipose tissue activation and deactivation.

Int J Obes (Lond) 2019 03 24;43(3):633-637. Epub 2018 May 24.

Diabetes, Endocrinology, and Obesity Branch, Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.

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/m, 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 F-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.
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http://dx.doi.org/10.1038/s41366-018-0104-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6252171PMC
March 2019

Impaired insulin signaling in unaffected siblings and patients with first-episode psychosis.

Mol Psychiatry 2019 10 9;24(10):1513-1522. Epub 2018 Mar 9.

Psychotic Disorders Division, McLean Hospital, Belmont, MA, USA.

Patients with psychotic disorders are at high risk for type 2 diabetes mellitus, and there is increasing evidence that patients display glucose metabolism abnormalities before significant antipsychotic medication exposure. In the present study, we examined insulin action by quantifying insulin sensitivity in first-episode psychosis (FEP) patients and unaffected siblings, compared to healthy individuals, using a physiological-based model and comprehensive assessment battery. Twenty-two unaffected siblings, 18 FEP patients, and 15 healthy unrelated controls were evaluated using a 2-h oral glucose tolerance test (OGTT), with 7 samples of plasma glucose and serum insulin concentration measurements. Insulin sensitivity was quantified using the oral minimal model method. Lipid, leptin, free fatty acids, and inflammatory marker levels were also measured. Anthropometric, nutrient, and activity assessments were conducted; total body composition and fat distribution were determined using whole-body dual-energy X-ray absorptiometry. Insulin sensitivity significantly differed among groups (F = 6.01 and 0.004), with patients and siblings showing lower insulin sensitivity, compared to controls (P = 0.006 and 0.002, respectively). Body mass index, visceral adipose tissue area (cm), lipids, leptin, free fatty acids, inflammatory markers, and activity ratings were not significantly different among groups. There was a significant difference in nutrient intake with lower total kilocalories/kilogram body weight in patients, compared to siblings and controls. Overall, the findings suggest that familial abnormal glucose metabolism or a primary insulin signaling pathway abnormality is related to risk for psychosis, independent of disease expression and treatment effects. Future studies should examine underlying biological mechanisms of insulin signaling abnormalities in psychotic disorders.
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http://dx.doi.org/10.1038/s41380-018-0045-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6129440PMC
October 2019

PET Imaging of Human Brown Adipose Tissue with the TSPO Tracer [C]PBR28.

Mol Imaging Biol 2018 04;20(2):188-193

Molecular Imaging Laboratory, Athinoula. A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02129, USA.

Purpose: Brown adipose tissue (BAT) in adult humans has been recently rediscovered and intensively investigated as a new potential therapeutic target for obesity and type 2 diabetes (T2D). However, reliable assessment of BAT mass in vivo represents a considerable challenge. The purpose of this investigation is to demonstrate for the first time that human BAT depots can be imaged with a translocator protein (TSPO)-specific positron emission tomography (PET) tracer [C]PBR28 under thermoneutral conditions.

Procedures: In this retrospective analysis, we analyzed the images of three healthy volunteers who underwent PET/magnetic resonance (MR) imaging after injection of 14 m Ci of [C]PBR28 at room temperature. Thirty-minute static PET images were reconstructed from the data obtained 60-90 min after the injection of the tracer.

Results: [C]PBR28 uptake in the neck/supraclavicular regions was identified, which was parallel to the known distribution pattern of human BAT depots. These areas co-localized with the areas of hyperintensity and corresponded to fat on T1-weighted MR images. Standardized uptake value (SUV) was used to quantify [C]PBR28 signal in BAT depots. The average (± SD) SUV and SUV for BAT depots was 2.13 (± 0.33) and 3.19 (± 0.34), respectively, while the average SUV for muscle and subcutaneous adipose tissue was 0.79 (± 0.1) and 0.18 (± 0.04), respectively.

Conclusions: In this brief article, we provide the first evidence suggesting that [C]PBR28, a widely available TSPO-specific PET tracer, can be used for imaging human BAT mass under thermoneutral conditions.
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http://dx.doi.org/10.1007/s11307-017-1129-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6394407PMC
April 2018

NFIA co-localizes with PPARγ and transcriptionally controls the brown fat gene program.

Nat Cell Biol 2017 Sep 14;19(9):1081-1092. Epub 2017 Aug 14.

Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.

Brown fat dissipates energy as heat and protects against obesity. Here, we identified nuclear factor I-A (NFIA) as a transcriptional regulator of brown fat by a genome-wide open chromatin analysis of murine brown and white fat followed by motif analysis of brown-fat-specific open chromatin regions. NFIA and the master transcriptional regulator of adipogenesis, PPARγ, co-localize at the brown-fat-specific enhancers. Moreover, the binding of NFIA precedes and facilitates the binding of PPARγ, leading to increased chromatin accessibility and active transcription. Introduction of NFIA into myoblasts results in brown adipocyte differentiation. Conversely, the brown fat of NFIA-knockout mice displays impaired expression of the brown-fat-specific genes and reciprocal elevation of muscle genes. Finally, expression of NFIA and the brown-fat-specific genes is positively correlated in human brown fat. These results indicate that NFIA activates the cell-type-specific enhancers and facilitates the binding of PPARγ to control the brown fat gene program.
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http://dx.doi.org/10.1038/ncb3590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885759PMC
September 2017

Mapping of human brown adipose tissue in lean and obese young men.

Proc Natl Acad Sci U S A 2017 08 24;114(32):8649-8654. Epub 2017 Jul 24.

Diabetes, Endocrinology, and Obesity Branch, Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892;

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/m; 8 obese, BMI 34.8 ± 3.3 kg/m] after 5 h of tolerable cold exposure, we measured BAT volume and activity by F-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.
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http://dx.doi.org/10.1073/pnas.1705287114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559032PMC
August 2017

Optical visualisation of thermogenesis in stimulated single-cell brown adipocytes.

Sci Rep 2017 05 3;7(1):1383. Epub 2017 May 3.

Department of Biomedical Engineering, National University of Singapore, 117583, Singapore, Singapore.

The identification of brown adipose deposits in adults has led to significant interest in targeting this metabolically active tissue for treatment of obesity and diabetes. Improved methods for the direct measurement of heat production as the signature function of brown adipocytes (BAs), particularly at the single cell level, would be of substantial benefit to these ongoing efforts. Here, we report the first application of a small molecule-type thermosensitive fluorescent dye, ERthermAC, to monitor thermogenesis in BAs derived from murine brown fat precursors and in human brown fat cells differentiated from human neck brown preadipocytes. ERthermAC accumulated in the endoplasmic reticulum of BAs and displayed a marked change in fluorescence intensity in response to adrenergic stimulation of cells, which corresponded to temperature change. ERthermAC fluorescence intensity profiles were congruent with mitochondrial depolarisation events visualised by the JC-1 probe. Moreover, the averaged fluorescence intensity changes across a population of cells correlated well with dynamic changes such as thermal power, oxygen consumption, and extracellular acidification rates. These findings suggest ERthermAC as a promising new tool for studying thermogenic function in brown adipocytes of both murine and human origins.
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http://dx.doi.org/10.1038/s41598-017-00291-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5431191PMC
May 2017

The cold-induced lipokine 12,13-diHOME promotes fatty acid transport into brown adipose tissue.

Nat Med 2017 May 27;23(5):631-637. Epub 2017 Mar 27.

Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.

Brown adipose tissue (BAT) and beige adipose tissue combust fuels for heat production in adult humans, and so constitute an appealing target for the treatment of metabolic disorders such as obesity, diabetes and hyperlipidemia. Cold exposure can enhance energy expenditure by activating BAT, and it has been shown to improve nutrient metabolism. These therapies, however, are time consuming and uncomfortable, demonstrating the need for pharmacological interventions. Recently, lipids have been identified that are released from tissues and act locally or systemically to promote insulin sensitivity and glucose tolerance; as a class, these lipids are referred to as 'lipokines'. Because BAT is a specialized metabolic tissue that takes up and burns lipids and is linked to systemic metabolic homeostasis, we hypothesized that there might be thermogenic lipokines that activate BAT in response to cold. Here we show that the lipid 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) is a stimulator of BAT activity, and that its levels are negatively correlated with body-mass index and insulin sensitivity. Using a global lipidomic analysis, we found that 12,13-diHOME was increased in the circulation of humans and mice exposed to cold. Furthermore, we found that the enzymes that produce 12,13-diHOME were uniquely induced in BAT by cold stimulation. The injection of 12,13-diHOME acutely activated BAT fuel uptake and enhanced cold tolerance, which resulted in decreased levels of serum triglycerides. Mechanistically, 12,13-diHOME increased fatty acid (FA) uptake into brown adipocytes by promoting the translocation of the FA transporters FATP1 and CD36 to the cell membrane. These data suggest that 12,13-diHOME, or a functional analog, could be developed as a treatment for metabolic disorders.
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http://dx.doi.org/10.1038/nm.4297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5699924PMC
May 2017

Variable Cold-Induced Brown Adipose Tissue Response to Thyroid Hormone Status.

Thyroid 2017 01 29;27(1):1-10. Epub 2016 Nov 29.

1 Department of Medicine, Beth Israel Deaconess Medical Center , Boston, Massachusetts.

Background: In addition to its role in adaptive thermogenesis, brown adipose tissue (BAT) may protect from weight gain, insulin resistance/diabetes, and metabolic syndrome. Prior studies have shown contradictory results regarding the influence of thyroid hormone (TH) levels on BAT volume and activity. The aim of this pilot study was to gain further insights regarding the effect of TH treatment on BAT function in adult humans by evaluating the BAT mass and activity prospectively in six patients, first in the hypothyroid and then in the thyrotoxic phase.

Methods: The study subjects underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) scanning after cold exposure to measure BAT mass and activity while undergoing treatment for differentiated thyroid cancer, first while hypothyroid following TH withdrawal at the time of the radioactive iodine treatment and then three to six months after starting TH suppressive treatment when they were iatrogenically thyrotoxic. Thermogenic and metabolic parameters were measured in both phases.

Results: All study subjects had detectable BAT under cold stimulation in both the hypothyroid and thyrotoxic state. The majority but not all (4/6) subjects showed an increase in detectable BAT volume and activity under cold stimulation between the hypothyroid and thyrotoxic phase (total BAT volume: 72.0 ± 21.0 vs. 87.7 ± 16.5 mL, p = 0.25; total BAT activity 158.1 ± 72.8 vs. 189.0 ± 55.5 SUV*g/mL, p = 0.34). Importantly, circulating triiodothyronine was a stronger predictor of energy expenditure changes compared with cold-induced BAT activity.

Conclusions: Iatrogenic hypothyroidism lasting two to four weeks does not prevent cold-induced BAT activation, while the use of TH to induce thyrotoxicosis does not consistently increase cold-induced BAT activity. It remains to be determined which physiological factors besides TH play a role in regulating BAT function.
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http://dx.doi.org/10.1089/thy.2015.0646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5206686PMC
January 2017

Humans with Type-2 Diabetes Show Abnormal Long-Term Potentiation-Like Cortical Plasticity Associated with Verbal Learning Deficits.

J Alzheimers Dis 2017 ;55(1):89-100

Berenson-Allen Center for Noninvasive Brain Stimulation, Division of Interventional Cognitive Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

Background: Type-2 diabetes mellitus (T2DM) accelerates cognitive aging and increases risk of Alzheimer's disease. Rodent models of T2DM show altered synaptic plasticity associated with reduced learning and memory. Humans with T2DM also show cognitive deficits, including reduced learning and memory, but the relationship of these impairments to the efficacy of neuroplastic mechanisms has never been assessed.

Objective: Our primary objective was to compare mechanisms of cortical plasticity in humans with and without T2DM. Our secondary objective was to relate plasticity measures to standard measures of cognition.

Methods: A prospective cross-sectional cohort study was conducted on 21 adults with T2DM and 15 demographically-similar non-diabetic controls. Long-term potentiation-like plasticity was assessed in primary motor cortex by comparing the amplitude of motor evoked potentials (MEPs) from single-pulse transcranial magnetic stimulation before and after intermittent theta-burst stimulation (iTBS). Plasticity measures were compared between groups and related to neuropsychological scores.

Results: In T2DM, iTBS-induced modulation of MEPs was significantly less than controls, even after controlling for potential confounds. Furthermore, in T2DM, modulation of MEPs 10-min post-iTBS was significantly correlated with Rey Auditory Verbal Learning Task (RAVLT) performance.

Conclusion: Humans with T2DM show abnormal cortico-motor plasticity that is correlated with reduced verbal learning. Since iTBS after-effects and the RAVLT are both NMDA receptor-dependent measures, their relationship in T2DM may reflect brain-wide alterations in the efficacy of NMDA receptors. These findings offer novel mechanistic insights into the brain consequences of T2DM and provide a reliable means to monitor brain health and evaluate the efficacy of clinical interventions.
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http://dx.doi.org/10.3233/JAD-160505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5193103PMC
February 2018

Connexin 43 Mediates White Adipose Tissue Beiging by Facilitating the Propagation of Sympathetic Neuronal Signals.

Cell Metab 2016 09;24(3):420-433

Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address:

"Beige" adipocytes reside in white adipose tissue (WAT) and dissipate energy as heat. Several studies have shown that cold temperature can activate pro-opiomelanocortin-expressing (POMC) neurons and increase sympathetic neuronal tone to regulate WAT beiging. WAT, however, is traditionally known to be sparsely innervated. Details regarding the neuronal innervation and, more importantly, the propagation of the signal within the population of "beige" adipocytes are sparse. Here, we demonstrate that beige adipocytes display an increased cell-to-cell coupling via connexin 43 (Cx43) gap junction channels. Blocking of Cx43 channels by 18α-glycyrrhetinic acid decreases POMC-activation-induced adipose tissue beiging. Adipocyte-specific deletion of Cx43 reduces WAT beiging to a level similar to that observed in denervated fat pads. In contrast, overexpression of Cx43 is sufficient to promote beiging even with mild cold stimuli. These data reveal the importance of cell-to-cell communication, effective in cold-induced WAT beiging, for the propagation of limited neuronal inputs in adipose tissue.
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http://dx.doi.org/10.1016/j.cmet.2016.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5024720PMC
September 2016
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