Cafeteria Diet Can Affect Bone Microarchitecture in Sedentary and Trained Male Rats.

INTRODUCTION: Poor eating habits and a sedentary lifestyle can impair health. Regular physical activity improves the quality of life and is essential for bone health. Therefore, the present study aimed to evaluate the effects of the cafeteria diet on bone quality of sedentary and exercised rats. METHODS: Sixty young male Wistar rats were divided into six groups (n=10) according to diet composition and activity level, being: SD+CON, standard diet and control; SD+SED, standard diet and sedentary; SD+EX, standard diet and exercised; CD+CON, cafeteria diet and control; CD+SED, cafeteria diet and sedentary; CD+EX, cafeteria diet and exercised. The exercise protocol consisted of 10 ladder-climbing sessions/day, 5 days/week, and the sedentary rats were maintained in individual cages with limited mobility. Body mass and food intake were evaluated weekly. After 10 weeks, the animals were euthanized, and white adipose tissue was collected. The bone structure was evaluated by densitometry, mechanical tests, histomorphometric, and micro-computed tomography analyses. RESULTS: The cafeteria diet increased adipose tissue (p<0.001), decreased bone mineral density (p=0.004), and impaired biomechanical properties (p<0.05) and histomorphometry parameters (p=0.044). The sedentarism decreased bone mineral density (p<0.001) and biomechanical properties (p<0.05), and the exercise did not improve bone properties. CONCLUSION: In this experimental model, it was concluded that the cafeteria diet and a sedentary lifestyle negatively affect bone, and ladder-climbing exercise could not prevent the effects of the unhealthy diet.

In-vivo detection of white adipose tissue browning: a multimodality imaging approach.

Detection and differentiation of brown fat in humans poses several challenges, as this tissue is sparse and often mixed with white adipose tissue. Non-invasive detection of beige fat represents an even greater challenge as this tissue is structurally and functionally more like white fat than brown fat. Here we used positron emission tomography with 18F-fluorodeoxyglucose, computed tomography, xenon-enhanced computed tomography, and dynamic contrast-enhanced ultrasound, to non-invasively detect functional and structural changes associated with the browning process of inguinal white fat, induced in mice by chronic stimulation with the ß3-adrenergic receptor agonist CL-316243. These studies reveal a very heterogeneous increase in baseline tissue radiodensity and xenon-enhanced radiodensity, indicative of both an increase in adipocytes water and protein content as well as tissue perfusion, mostly in regions that showed enhanced norepinephrine-stimulated perfusion before CL-316243 treatment. No statistically significant increase in 18F-fluorodeoxyglucose uptake or norepinephrine-stimulated tissue perfusion were observed in the mice after the CL-316243 treatment. The increase in tissue-water content and perfusion, along with the negligible increase in the tissue glucose uptake and norepinephrine-stimulated perfusion deserve more attention, especially considering the potential metabolic role that this tissue may play in whole body metabolism.

Steroid-Induced Activated White Adipose Tissue Detected on 18F-FDG PET/CT.

White adipose tissue (WAT) usually shows negligible 18F-FDG uptake due to negligible glucose utilization. However, corticosteroids alter the biodistribution of 18F-FDG and increase uptake in WAT. Here, we present a case of diffusely increased 18F-FDG uptake in WAT secondary to high-dose corticosteroid therapy for nephrotic syndrome.

Assessment of Brown and Beige Adipose Tissue Activation in Mice Using PET/CT Imaging.

In response to cold induction, brown adipose tissues (BAT) and emerged brown-like adipocytes (beige adipocytes) in subcutaneous white adipose tissues (WAT browning/beiging) are activated. Thermogenesis is increased during glucose and fatty acid uptake and metabolism in adult humans and mice. This activation of BAT or WAT beiging to generate heat helps to counteract diet-induced obesity. This protocol applies the glucose analog radiotracer 18F-fluorodeoxyglucose (FDG), coupled with positron emission tomography and computed tomography (PET/CT) scanning to evaluate cold-induced thermogenesis in the active BAT (interscapular region) and browned/beiged WAT (subcutaneous adipose region) in mice. The PET/CT scanning technique not only can quantify cold-induced glucose uptake in well-known BAT and beige-fat depots but also helps to visualize the anatomical location of novel uncharacterized mouse BAT and beige fat where cold-induced glucose uptake is high. Histological analysis is further employed to validate signals of delineated anatomical regions in PET/CT images as bona fide mouse BAT or beiged WAT fat depots.

Impact of White Adipose Tissue on Brain Structure, Perfusion, and Cognitive Function in Patients With Severe Obesity: The BARICO Study.

BACKGROUND AND OBJECTIVE: While underlying pathophysiology linking obesity to brain health is not completely understood, white adipose tissue (WAT) is considered a key player. In obesity, WAT becomes dysregulated, showing hyperplasia, hypertrophy, and eventually inflammation. This disbalance leads to dysregulated secretion of adipokines influencing both (cardio)vascular and brain health. Within this study, we investigated the association between omental WAT (oWAT) and subcutaneous WAT (scWAT) with brain structure and perfusion and cognition in adults with severe obesity. METHODS: Within the cross-sectional BARICO study, brain structure and perfusion and cognitive function were measured before bariatric surgery (BS) using MRI and cognitive assessments. During BS, oWAT and scWAT depots were collected and analyzed by histopathology. The number and diameter of adipocytes were quantified together with the amount of crown-like structures (CLS) as an indication of inflammation. Blood samples were collected to analyze adipokines and inflammatory markers. Neuroimaging outcomes included brain volumes, cortical thickness, white matter (WM) integrity, WM hyperintensities, cerebral blood flow using arterial spin labeling (ASL), and the ASL spatial coefficient of variation (sCoV), reflecting cerebrovascular health. RESULTS: Seventy-one patients were included (mean age 45.1 ± 5.8 years; 83.1% women; mean body mass index 40.8 ± 3.8 kg/m2). scWAT showed more CLS (z = -2.72, p < 0.01, r = -0.24) and hypertrophy compared with oWAT (F(1,64) = 3.99, p < 0.05, η2 = 0.06). Adiponectin levels were inversely associated with the average diameter of scWAT (ß = -0.31, 95% CI -0.54 to -0.08) and oWAT (ß = -0.33, 95% CI -0.55 to -0.09). Furthermore, the adipocyte diameter in oWAT was positively associated with the sCoV in the parietal cortex (ß = 0.33, 95% CI 0.10-0.60), and the number of adipocytes (per mm2) was positively associated with sCoV in the nucleus accumbens (NAcc) (ß = 0.34, 95% CI 0.09-0.61). Cognitive function did not correlate with any WAT parameter or plasma marker. These associations were highly influenced by age and sex. sCoV in the NAcc was positively associated with fasting plasma glucose (ß = 0.35, 95% CI 0.10-0.56). DISCUSSION: scWAT and oWAT are different in morphology and in their relationship with plasma markers and cerebrovascular health. Although scWAT showed more CLS and hypertrophy, scWAT was not associated with brain readouts. This study showed, however, important relationships between oWAT morphology and cerebrovascular health in obesity. TRIAL REGISTRATION INFORMATION: Trial Registration Number NTR7288 (trialregister.nl/trial/7090).

Macrophages in epididymal adipose tissue secrete osteopontin to regulate bone homeostasis.

Epididymal white adipose tissue (eWAT) secretes an array of cytokines to regulate the metabolism of organs and tissues in high-fat diet (HFD)-induced obesity, but its effects on bone metabolism are not well understood. Here, we report that macrophages in eWAT are a main source of osteopontin, which selectively circulates to the bone marrow and promotes the degradation of the bone matrix by activating osteoclasts, as well as modulating bone marrow-derived macrophages (BMDMs) to engulf the lipid droplets released from adipocytes in the bone marrow of mice. However, the lactate accumulation induced by osteopontin regulation blocks both lipolysis and osteoclastogenesis in BMDMs by limiting the energy regeneration by ATP6V0d2 in lysosomes. Both surgical removal of eWAT and local injection of either clodronate liposomes (for depleting macrophages) or osteopontin-neutralizing antibody show comparable amelioration of HFD-induced bone loss in mice. These results provide an avenue for developing therapeutic strategies to mitigate obesity-related bone disorders.

Evaluation of brown adipose tissue with intermolecular double-quantum coherence magnetic resonance spectroscopy at 3.0 T.

In the current study, we propose a single-voxel (SV) magnetic resonance spectroscopy (MRS) pulse sequence, based on intermolecular double-quantum coherence (iDQC), for in vivo specific assessment of brown adipose tissue (BAT) at 3 T. The multilocular adipocyte, present in BAT, typically contains a large number of small lipid droplets surrounded by abundant intracellular water, while the monolocular adipocyte, present in white adipose tissue (WAT), accommodates only a single large lipid droplet with much less water content. The SV-iDQC sequence probes the spatial correlation between water and fat spins at a distance of about the size of an adipocyte, thus can be used for assessment of BAT, even when mixed with WAT and/or muscle tissues. This sequence for measurement of water-to-fat (water-fat) iDQC signals was tested on phantoms and mouse BAT and WAT tissues. It was then used to differentiate adipose tissues in the supraclavicular and subcutaneous regions of healthy youth human volunteers (n = 6). Phantom results with water-fat emulsions demonstrated enhanced water-fat iDQC signal with increased voxel size, increased energy level of emulsification, or increased distribution balance of water and fat spins. The animal tissue experiments resulted in obvious water-fat iDQC signal in mouse BAT, while this signal was almost absent in the WAT spectrum. The optimal choice of the dipolar coupling distance for the observation was approximately 100 µm, as tested on both emulsion phantom and animal tissue. The water-fat iDQC signals observed in the supraclavicular adipose tissues were higher than in the subcutaneous adipose tissues in healthy young volunteers (0.43 ± 0.36 vs. 0.10 ± 0.06, p = 0.06). It was concluded that the iDQC-based sequence has potential for assessment of mouse and human BAT at 3 T, which is of interest for clinical research and the diagnosis of obesity and associated diseases.

Molecular Imaging of Brown Adipose Tissue Mass.

Brown adipose tissue (BAT), a uniquely thermogenic tissue that plays an important role in metabolism and energy expenditure, has recently become a revived target in the fight against metabolic diseases, such as obesity, diabetes, and non-alcoholic fatty liver disease (NAFLD). Different from white adipose tissue (WAT), the brown adipocytes have distinctive features including multilocular lipid droplets, a large number of mitochondria, and a high expression of uncoupling protein-1 (UCP-1), as well as abundant capillarity. These histologic characteristics provide an opportunity to differentiate BAT from WAT using imaging modalities, such as PET/CT, SPECT/CT, MRI, NIRF and Ultrasound. However, most of the reported imaging methods were BAT activation dependent, and the imaging signals could be affected by many factors, including environmental temperatures and the states of the sympathetic nervous system. Accurate BAT mass detection methods that are independent of temperature and hormone levels have the capacity to track the development and changes of BAT throughout the lifetime of mammals, and such methods could be very useful for the investigation of potential BAT-related therapies. In this review, we focus on molecular imaging modalities that can detect and quantify BAT mass. In addition, their detection mechanism and limitations will be discussed as well.

Role of Brown and Beige Adipose Tissues in Seasonal Adaptation in the Raccoon Dog (Nyctereutes procyonoides).

Brown adipose tissue (BAT) expresses uncoupling protein-1 (UCP1), which enables energy to be exerted towards needed thermogenesis. Beige adipocytes are precursor cells interspersed among white adipose tissue (WAT) that possess similar UCP1 activity and capacity for thermogenesis. The raccoon dog (Nyctereutes procyonoides) is a canid species that utilizes seasonal obesity to survive periods of food shortage in climate zones with cold winters. The potential to recruit a part of the abundant WAT storages as beige adipocytes for UCP1-dependent thermogenesis was investigated in vitro by treating raccoon dog adipocytes with different browning inducing factors. In vivo positron emission tomography/computed tomography (PET/CT) imaging with the glucose analog 18F-FDG showed that BAT was not detected in the adult raccoon dog during the winter season. In addition, UCP1 expression was not changed in response to chronic treatments with browning inducing factors in adipocyte cultures. Our results demonstrated that most likely the raccoon dog endures cold weather without the induction of BAT or recruitment of beige adipocytes for heat production. Its thick fur coat, insulating fat, and muscle shivering seem to provide the adequate heat needed for surviving the winter.

Obesity protects against sepsis-induced and norepinephrine-induced white adipose tissue browning.

Sepsis is a dysregulated systemic response to infection and can lead to organ damage and death. Obesity is a significant problem worldwide and affects outcomes from sepsis. Our laboratory demonstrated that white adipose tissue (WAT) undergoes browning during sepsis, a process whereby WAT adopts a brown adipose tissue phenotype. However, this browning process was not observed in obese mice during sepsis. White adipose tissue browning is detrimental in patients with burn injury and cancer. We hypothesize that norepinephrine (NE) induces WAT browning in nonobese mice but not in obese mice similarly to sepsis-induced WAT browning. Six-week-old C57BL/6 male mice were randomized to a high-fat diet or normal diet. After 6-7 wk of feeding, polymicrobial sepsis was induced by cecal ligation and puncture (CLP). Norepinephrine was administered intraperitoneally via osmotic minipumps for 18 h or 72 h (no CLP) at which time tissue and plasma were harvested. Controls were mice that underwent CLP (no NE) with 18-h harvest. A separate group of mice underwent pretreatment with NE or vehicle infusion for 72 h, CLP was performed, and at 18 h had tissue and plasma harvested. Sepsis resulted in significant weight loss in both nonobese and obese mice. NE treatment alone caused weight loss in obese mice. Septic nonobese mice had higher uncoupling protein-1 (UCP1) expression compared with control and obese septic mice. NE treatment increased UCP1 expression in nonobese, but not obese mice. NE-treated obese septic mice had lower lung myeloperoxidase (MPO) activity, alanine aminotransferase (ALT), aspartate aminotransferase (AST), TNFα, and IL-6 levels compared with NE-treated nonobese septic mice. Obesity protects mice from septic-induced and NE-induced WAT browning.NEW & NOTEWORTHY White adipose tissue browning is detrimental in patients with burn injury and cancer. WAT browning occurs in nonobese mice and can be induced by ß receptor norepinephrine infusion, but obese mice are resistant to sepsis-induced and norepinephrine-induced WAT browning. We propose that the lack of WAT browning and unchanged inflammatory cytokine response may contribute to the protection of obese mice from sepsis.

Irisin induces white adipose tissue browning in mice as assessed by magnetic resonance imaging.

This study aimed to track and evaluate the effect of low-dose irisin on the browning of white adipose tissue (WAT) in mice using magnetic resonance imaging (MRI) noninvasively in vivo. Mature white adipocytes extracted from mice were cultured, induced and characterized before being treated by irisin. The volume and fat fraction of WAT were quantified using MRI in normal chow diet and high fat mice after injection of irisin. The browning of cultured white adipocytes and WAT in mice were validated by immunohistochemistry and western blotting for uncoupling protein 1 (UCP1) and deiodinase type II (DIO2). The serum indexes were examined with high fat diet after irisin intervention. UCP1 and DIO2 in adipocytes showed increases responding to the irisin treatment. The size of white adipocytes in mice receiving irisin intervention was reduced. MRI measured volumes and fat fraction of WAT were significantly lower after Irisin treatment. Blood glucose and cholesterol levels were reduced in high fat diet mice after irisin treatment. Irisin intervention exerted browning of WAT, resulting reduction of volume and fat fraction of WAT as measured by MRI. Furthermore, it improved the condition of mice with diet-induced obesity and related metabolic disorders.

Prognostic impacts of glucocorticoid treatment in patients with polymyalgia rheumatica and giant cell arteritis.

Identifying comorbidities in polymyalgia rheumatica/giant cell arteritis (PMR/GCA) is crucial for patients' outcomes. The present study aimed to evaluate the impact of the inflammatory process and glucocorticoid treatment on aortic arterial stiffness and body composition in PMR/GCA. 77 patients with newly diagnosed PMR/GCA were treated with oral glucocorticoids and followed for 40 weeks. Aortic pulse wave velocity (PWV) was measured at baseline and during the follow-up period and compared to the results of temporal artery biopsy (TAB) and 18F-FDG PET/CT. Body composition was assessed by total body DXA at baseline and the end of the study. Of 77 patients (49 (63.6%) female, mean of age: (71.8 ± 8.0)), 64 (83.1%) had pure PMR, 10 (13.0%) concomitant PMR and GCA, and 3 (3.9%) pure GCA. Compared to baseline values, aortic PWV was initially decreased at week 16 (p = 0.010) and remained lower than baseline at week 28 (p = 0.002) and week 40 (p < 0.001), with no association with results of TAB and 18F-FDG PET/CT. Aortic PWV was significantly associated with age, male gender, left systolic and diastolic blood pressure, right diastolic blood pressure, and CRP. Total bone mineral content (BMC) was decreased in both genders (p < 0.001), while fat mass (FM) was significantly increased (p < 0.001). However, lean body mass did not significantly change during the study. Changes in FM were correlated with cumulative prednisolone dose (rho: 0.26, p = 0.031). Glucocorticoid treatment of patients with PMR/GCA had several prognostic impacts. Arterial stiffness was decreased due either to the treatment or a reduction in the inflammatory load. Additionally, treatment led to changes in body composition, including a decrease in BMC and FM excess.

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

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, P < .01) and QAT (mean, 78 msec ± 2, five regions, P < .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 (P = .01 and P = .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. Online supplemental material is available for this article.

Photoacoustic molecular imaging-escorted adipose photodynamic-browning synergy for fighting obesity with virus-like complexes.

Photodynamic therapy and adipose browning induction are two promising approaches to reverse obesity. The former strategy acts rapidly and locally, whereas the latter has a more gradual and widespread effect. Despite their complementarity, they have rarely been combined and imaged non-invasively in vivo. Here we introduce an adipose-targeting hepatitis B core protein complex that contains a traceable photosensitizer (ZnPcS4 (zinc phthalocyanine tetrasulfonate)) and a browning agent (rosiglitazone) that allows simultaneous photodynamic and browning treatments, with photoacoustic molecular imaging. After intravenous injection in obese mice, the complex binds specifically to white adipose tissues, especially those rich in blood supply, and drives adipose reduction thanks to the synergy of ZnPcS4 photodynamics and rosiglitazone browning. Using photoacoustic molecular imaging, we could monitor the changes induced by the treatment, which included complex activity, lipid catabolism and angiogenesis. Our findings demonstrate the anti-obesity potential of our feedback-based synergic regimen orchestrated by the targeted hepatitis B core complex.

Overexpression of Adiponectin Receptor 1 Inhibits Brown and Beige Adipose Tissue Activity in Mice.

Adult humans and mice possess significant classical brown adipose tissues (BAT) and, upon cold-induction, acquire brown-like adipocytes in certain depots of white adipose tissues (WAT), known as beige adipose tissues or WAT browning/beiging. Activating thermogenic classical BAT or WAT beiging to generate heat limits diet-induced obesity or type-2 diabetes in mice. Adiponectin is a beneficial adipokine resisting diabetes, and causing "healthy obese" by increasing WAT expansion to limit lipotoxicity in other metabolic tissues during high-fat feeding. However, the role of its receptors, especially adiponectin receptor 1 (AdipoR1), on cold-induced thermogenesis in vivo in BAT and in WAT beiging is still elusive. Here, we established a cold-induction procedure in transgenic mice over-expressing AdipoR1 and applied a live 3-D [18F] fluorodeoxyglucose-PET/CT (18F-FDG PET/CT) scanning to measure BAT activity by determining glucose uptake in cold-acclimated transgenic mice. Results showed that cold-acclimated mice over-expressing AdipoR1 had diminished cold-induced glucose uptake, enlarged adipocyte size in BAT and in browned WAT, and reduced surface BAT/body temperature in vivo. Furthermore, decreased gene expression, related to thermogenic Ucp1, BAT-specific markers, BAT-enriched mitochondrial markers, lipolysis and fatty acid oxidation, and increased expression of whitening genes in BAT or in browned subcutaneous inguinal WAT of AdipoR1 mice are congruent with results of PET/CT scanning and surface body temperature in vivo. Moreover, differentiated brown-like beige adipocytes isolated from pre-adipocytes in subcutaneous WAT of transgenic AdipoR1 mice also had similar effects of lowered expression of thermogenic Ucp1, BAT selective markers, and BAT mitochondrial markers. Therefore, this study combines in vitro and in vivo results with live 3-D scanning and reveals one of the many facets of the adiponectin receptors in regulating energy homeostasis, especially in the involvement of cold-induced thermogenesis.

Altered FDG Biodistribution in Subcutaneous White Fat on PET/CT Following l-Asparaginase Chemotherapy.

ABSTRACT: A 13-year-old boy with mediastinal T-cell lymphoblastic lymphoma demonstrated an altered biodistribution with diffuse activity in subcutaneous white adipose tissue and decreased visceral activity on interim posttreatment FDG PET/CT. This altered biodistribution was attributed to administration of the chemotherapeutic enzyme l-asparaginase 3 hours preceding the PET/CT, altering adipocytes amino acid and glucose metabolism. Treatment response assessment was adversely affected by the altered biodistribution, emphasizing the importance of maximizing the time between chemotherapy and PET/CT during successive oncologic treatment cycles. Because adipocytes protect leukemic cells in culture from l-asparaginase, we hypothesize that white adipose tissue-altered biodistribution may be related to l-asparaginase resistance.

Effects of Hyperthyroidism on Adipose Tissue Activity and Distribution in Adults.

Background: Positron emission tomography (PET) has provided evidence that adult humans retain metabolically active brown adipose tissue (BAT) depots. Thyroid hormones (TH) stimulate BAT thermogenesis by central and peripheral mechanisms. However, the effect of hyperthyroidism on BAT activity and BAT volume in humans is yet not fully understood. The aim of this study was to investigate the effect of TH on (i) the metabolic activity of brown and white adipose tissue (WAT) depots, (ii) on abdominal visceral and subcutaneous adipose tissue area, and (iii) on serum levels of metabolically active cytokines. Methods: Nineteen patients with overt hyperthyroidism were investigated through repeated 2-[18F]fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography (2-[18F]FDG PET/CT) in the hyperthyroid and in the euthyroid state. The 2-[18F]FDG uptake was calculated as standard uptake ratio with blood pool as reference. Fat areas were quantified by means of CT segmentation. Serum levels of fetuin A and B, fibroblast growth factor 21, adipocyte fatty acid-binding protein (AFABP), retinol-binding protein 4, pro-enkephalin, pro-neurotensin, and neuregulin 4 were determined in the hyperthyroid and in the euthyroid state for each subject. Results: 2-[18F]FDG uptake was increased in the hyperthyroid state in BAT in comparison with the euthyroid phase (p = 0.001). There was no correlation between serum free triiodothyronine (fT3) and free thyroxine (fT4) levels and 2-[18F]FDG uptake in BAT or WAT. In the hyperthyroid state, fT3 levels were positively associated with skeletal muscle standardized uptake value ratios. Areas of visceral adipose tissue and skeletal muscle were significantly decreased in hyperthyroidism. AFABP levels correlated positively with fT3 (p = 0.031, ß = 0.28) and fT4 (p = 0.037, ß = 0.27) in the hyperthyroid state. Conclusions: Our results suggest that the contribution of increased TH levels to the glucose uptake of BAT and WAT is low compared with that of the skeletal muscle. Hyperthyroid subjects have reduced areas of visceral adipose tissue and increased AFABP levels.

The scaffold protein p62 regulates adaptive thermogenesis through ATF2 nuclear target activation.

During ß-adrenergic stimulation of brown adipose tissue (BAT), p38 phosphorylates the activating transcription factor 2 (ATF2) which then translocates to the nucleus to activate the expression of Ucp1 and Pgc-1α. The mechanisms underlying ATF2 target activation are unknown. Here we demonstrate that p62 (Sqstm1) binds to ATF2 to orchestrate activation of the Ucp1 enhancer and Pgc-1α promoter. P62Δ69-251 mice show reduced expression of Ucp1 and Pgc-1α with impaired ATF2 genomic binding. Modulation of Ucp1 and Pgc-1α expression through p62 regulation of ATF2 signaling is demonstrated in vitro and in vivo in p62Δ69-251 mice, global p62-/- and Ucp1-Cre p62flx/flx mice. BAT dysfunction resulting from p62 deficiency is manifest after birth and obesity subsequently develops despite normal food intake, intestinal nutrient absorption and locomotor activity. In summary, our data identify p62 as a master regulator of BAT function in that it controls the Ucp1 pathway through regulation of ATF2 genomic binding.

Quantification of Fat Concentration and Vascular Response in Brown and White Adipose Tissue of Rats by Spectral CT Imaging.

OBJECTIVE: The purpose of the study was to non-invasively characterize and discriminate brown adipose tissue (BAT) from white adipose tissue (WAT) in rats using spectral computed tomography (CT) with histological validation. MATERIALS AND METHODS: A lipid-containing phantom (lipid fractions from 0% to 100%) was imaged with spectral CT. An in vivo, non-enhanced spectral CT scan was performed on 24 rats, and fat concentrations of BAT and WAT were measured. The rats were randomized to receive intraperitoneal treatment with norepinephrine (NE) (n = 12) or saline (n = 12). Non-enhanced and enhanced spectral CT scans were performed after treatment to measure the elevation of iodine in BAT and WAT. The BAT/aorta and WAT/aorta ratios were calculated and compared, after which isolated BAT and WAT samples were subjected to histological and uncoupling protein 1 (UCP1) analyses. RESULTS: The ex-vivo phantom study showed excellent linear fit between measured fat concentration and the known gravimetric reference standard (r² = 0.996). In vivo, BAT had significantly lower fat concentration than WAT (p < 0.001). Compared to the saline group, the iodine concentration of BAT increased significantly (p < 0.001) after injection of NE, while the iodine concentration of WAT only changed slightly. The BAT/aorta ratio also increased significantly after exposure to NE compared to the saline group (p < 0.001). Histological and UCP1 expression analyses supported the spectral CT imaging results. CONCLUSION: The study consolidates spectral CT as a new approach for non-invasive imaging of BAT and WAT. Quantitative analyses of BAT and WAT by spectral CT revealed different characteristics and pharmacologic activations in the two types of adipose tissue.

Correlation among body composition and metabolic regulation in a male mouse model of Cushing's syndrome.

Glucocorticoids play a critical role in the regulation of homeostasis, including metabolism. In patients with Cushing's syndrome, chronic glucocorticoid excess disrupts physiological internal milieu, resulting in central obesity, muscle atrophy, fatty liver, and insulin resistance. However, the relationship among various metabolic effects of glucocorticoids remains unknown. In the present study, we studied a male mouse model of Cushing's syndrome and indicated that glucocorticoid excess alters metabolic phenotype and body composition involving possible communication among skeletal muscle, liver, and adipose tissue.