Oxidative metabolism and non-invasive characterisation of brown adipose tissue in adult humans

In adult humans, brown adipose tissue (BAT) has been found to be metabolically active. However, the physiological relevance of BAT in adult humans is still imprecise and largely speculative. The study of oxidative metabolism of BAT during different physiological states can unravel the significance of BAT in whole-body energy metabolism; and meanwhile there is also a need to improve the characterisation of BAT using the existing non-invasive medical imaging methods. The aim of the doctoral work was to evaluate whether the oxygen consumption of BAT in adult humans, measured using positron emission tomography, is influenced by cold stress, and with the ingestion of a mixed meal. Cold-induced and meal-induced whole-body thermogenesis was also studied. Additionally, the utility of a non-invasive medical imaging method of x-ray computed tomography to provide metabolic information related to BAT was investigated. The results showed that cold stress, as well as ingestion of a mixed meal,increases the oxygen consumption of BAT. However, the overall capacity of BAT to contribute to cold-induced and meal-induced whole-body thermogenesis is limited. The x-ray computed tomography derived metrics of BAT has the potential to give an insight into underlying tissue composition and substrate metabolism, and this characteristic can be exploited to make a distinction between white adipose tissue and BAT.Ruskean rasvakudoksen oksidatiivinen aineenvaihdunta ja kajoamaton karakterisointi aikuisilla ihmisillä Aikuisilla ihmisillä ruskean rasvakudoksen (BAT) on todettu olevan toiminnallisesti aktiivinen. Ruskean rasvan fysiologinen merkitys on kuitenkin vielä epäselvä ja perustuu suurelta osin oletuksiin. Ruskean rasvan oksidatiivisen aineenvaihdunnan tutkiminen eri fysiologisissa tilanteissa voi selventää ruskean rasvan osuutta koko kehon energia-aineenvaihdunnassa. Samanaikaisesti on tarve kehittää entistä parempia menetelmiä ja kehittää olemassa olevia kajoamattomia lääketieteellisiä kuvantamismenetelmiä ruskean rasvan tarkempaan tunnistamiseen ja karakterisointiin. Väitöskirjatyön tavoitteena oli selvittää, miten ruskean rasvan hapenkulutus eli oksidatiivinen aineenvaihdunta, positroniemissiotomografialla (PET) mitattuna, muuttuu kylmäaltistuksen vaikutuksesta ja toisaalta yksittäisen aterian syömisen jälkeen. Koko kehon energiankulutus mitattiin samoissa tilanteissa epäsuoraa kalorimetriaa käyttäen. Tämän lisäksi selvitettiin kajoamattoman lääketieteellisen tietokonetomografian (TT) käytettävyyttä ruskean rasvan aineenvaihdunnan tutkimuksessa. Kylmäaltistus ja aterian syöminen lisäsivät molemmat ruskean rasvakudoksen hapenkulutusta. Koko kehon tasolla ruskean rasvan osuus kylmästimuloidusta ja ruokailun aiheuttamasta lämmöntuotannosta on kuitenkin rajallinen ja kudoksen pieni koko huomioiden pieni. Tietokonetomografian avulla mitattujen tunnuslukujen avulla on mahdollista saada käsitys ruskea rasvakudoksen koostumuksesta ja aineenvaihdunnasta, ja näitä ominaisuuksia voidaankin hyödyntää erottamaan ruskea rasvakudos valkoisesta rasvakudoksesta

Differentiation of Metabolically Distinct Areas within Head and Neck Region using Dynamic 18F-FDG Positron Emission Tomography Imaging

Positron Emission Tomography (PET) using 18F-FDG is playing a vital role in the diagnosis and treatment planning of cancer. However, the most widely used radiotracer, 18F-FDG, is not specific for tumours and can also accumulate in inflammatory lesions as well as normal physiologically active tissues making diagnosis and treatment planning complicated for the physicians. Malignant, inflammatory and normal tissues are known to have different pathways for glucose metabolism which could possibly be evident from different characteristics of the time activity curves from a dynamic PET acquisition protocol. Therefore, we aimed to develop new image analysis methods, for PET scans of the head and neck region, which could differentiate between inflammation, tumour and normal tissues using this functional information within these radiotracer uptake areas. We developed different dynamic features from the time activity curves of voxels in these areas and compared them with the widely used static parameter, SUV, using Gaussian Mixture Model algorithm as well as K-means algorithm in order to assess their effectiveness in discriminating metabolically different areas. Moreover, we also correlated dynamic features with other clinical metrics obtained independently of PET imaging. The results show that some of the developed features can prove to be useful in differentiating tumour tissues from inflammatory regions and some dynamic features also provide positive correlations with clinical metrics. If these proposed methods are further explored then they can prove to be useful in reducing false positive tumour detections and developing real world applications for tumour diagnosis and contouring.Siirretty Doriast

Brown fat triglyceride content is associated with cardiovascular risk markers in adults from a tropical region

Brown adipose tissue (BAT) is regarded as an interesting potential target for the treatment of obesity, diabetes, and cardiovascular diseases, and the detailed characterization of its structural and functional phenotype could enable an advance in these fields. Most studies evaluating BAT structure and function were performed in temperate climate regions, and we are yet to know how these findings apply to the 40% of the world’s population living in tropical areas. Here, we used 18F-fluorodeoxyglucose positron emission tomography – magnetic resonance imaging to evaluate BAT in 45 lean, overweight, and obese volunteers living in a tropical area in Southeast Brazil. We aimed at investigating the associations between BAT activity, volume, metabolic activity, and BAT content of triglycerides with adiposity and cardiovascular risk markers in a sample of adults living in a tropical area and we showed that BAT glucose uptake is not correlated with leanness; instead, BAT triglyceride content is correlated with visceral adiposity and markers of cardiovascular risk. This study expands knowledge regarding the structure and function of BAT in people living in tropical areas. In addition, we provide evidence that BAT triglyceride content could be an interesting marker of cardiovascular risk

Regulation of human brown adipose tissue by adenosine and A2A receptors – studies with [15O]H2O and [11C]TMSX PET/CT

PurposeBrown adipose tissue (BAT) has emerged as a potential target to combat obesity and diabetes, but novel strategies to activate BAT are needed. Adenosine and A2A receptor (A2AR) agonism activate BAT in rodents, and endogenous adenosine is released locally in BAT as a by-product of noradrenaline, but physiological data from humans is lacking. The purpose of this pilot study was to investigate the effects of exogenous adenosine on human BAT perfusion, and to determine the density of A2ARs in human BAT in vivo for the first time, using PET/CT imaging.MethodsHealthy, lean men (n = 10) participated in PET/CT imaging with two radioligands. Perfusion of BAT, white adipose tissue (WAT) and muscle was quantified with [15O]H2O at baseline, during cold exposure and during intravenous administration of adenosine. A2AR density of the tissues was quantified with [11C]TMSX at baseline and during cold exposure.ResultsAdenosine increased the perfusion of BAT even more than cold exposure (baseline 8.3 ± 4.5, cold 19.6 ± 9.3, adenosine 28.6 ± 7.9 ml/100 g/min, p 11C]TMSX in BAT was significantly lower during cold exposure compared to baseline. In cold, low [11C]TMSX binding coincided with high concentrations of noradrenaline.ConclusionsAdenosine administration caused a maximal perfusion effect in human supraclavicular BAT, indicating increased oxidative metabolism. Cold exposure increased noradrenaline concentrations and decreased the density of A2AR available for radioligand binding in BAT, suggesting augmented release of endogenous adenosine. Our results show that adenosine and A2AR are relevant for activation of human BAT, and A2AR provides a future target for enhancing BAT metabolism.</div

Human Brown Fat Radiodensity Indicates Underlying Tissue Composition and Systemic Metabolic Health

Context: Metabolic imaging studying brown adipose tissue (BAT) physiology has increased, in which computed tomography (CT) is commonly used as an anatomical reference for metabolic positron emission tomography (PET) imaging. However, the capacity of CT to provide metabolic information has been underexploited.Objective: To evaluate whether CT radiodensity of BAT could noninvasively estimate underlying tissue morphology, regarding amount of stored triglycerides. Furthermore, could the alteration in tissue characteristics due to cold stimulus, as a marker for active BAT, be detected with radiodensity? Can BAT be differentiated from white adipose tissue (WAT) solely using CT-based measurements?Design, Setting, and Participants: A cross-sectional study evaluating 66 healthy human subjects with CT, PET, and H-1-magnetic resonance spectroscopy (H-1-MRS).Main Outcome Measures: BAT radiodensity was measured with CT. BAT-stored triglyceride content was measured with H-1-MRS. Arterial blood volume in BAT, as a marker of tissue vascularity, was measured with [O-15]H2O, along with glucose or fatty acid uptake using [F-18]2-fluoro-2-deoxy-D-glucose or 14(R,S)-[F-18]fluoro-6-thia-heptadecanoic acid PET imaging, respectively.Results: BAT radiodensity was found to be correlating with tissue-retained blood and triglyceride content. Cold stimulus induced an increase in BAT radiodensity. Active BAT depots had higher radiodensity than both nonactive BAT and WAT. BAT radiodensity associated with systemic metabolic health parameters.Conclusion: BAT radiodensity can be used as a marker of underlying tissue morphology. Active BAT can be identified using CT, exploiting tissue composition information. Moreover, BAT radiodensity provides an insight into whole-body systemic metabolic health

Obesity associated blunted subcutaneous adipose tissue blood flow after meal is improved after bariatric surgery

Background and aims: GIP and meal ingestion increase subcutaneous adipose tissue (SAT) perfusion in healthy subjects. Effects of GIP and meal on visceral adipose tissue (VAT) perfusion is unclear. Our aim was to investigate the effects of meal and GIP on VAT and SAT perfusion in obese subjects with type 2 diabetes (T2DM) before and after bariatric surgery.Materials and methods: We recruited 10 obese subjects with T2DM scheduled for bariatric surgery and 10 control subjects. Subjects were studied under two stimulations: meal ingestion and GIP infusion. SAT and VAT perfusion was measured using 15O-H2O PET-MRI at three time points: baseline, 20min and 50min after start of stimulation. Obese subjects were studied before and after bariatric surgery.Results: Before bariatric surgery the responses of SAT perfusion to meal (p=0.04) and GIP-infusion (p=0.002) were blunted in the obese subjects compared to the controls. VAT perfusion response did not differ between obese and control subjects after meal or GIP-infusion.After bariatric surgery SAT perfusion response to meal was similar to that of control subjects. SAT perfusion response to GIP administration remained lower in operated than control subjects. There was no change in VAT perfusion response after bariatric surgery.Conclusions: The vasodilating effects of GIP and meal are blunted in SAT but not in VAT in obese subjects with T2DM. Bariatric surgery improves the effects of meal on SAT perfusion, but not the effects of GIP. Postprandial increase in SAT perfusion after bariatric surgery seems to be regulated in a GIP independent manner.</p

Novel effects of the gastrointestinal hormone secretin on cardiac metabolism and renal function

The cardiac benefits of gastrointestinal hormones have been of interest in recent years. The aim of this study was to explore the myocardial and renal effects of the gastrointestinal hormone secretin in the GUTBAT trial (NCT03290846). A placebo-controlled crossover study was conducted on 15 healthy males in fasting conditions, where subjects were blinded to the intervention. Myocardial glucose uptake was measured with [F-18]2-fluoro-2-deoxy-o-glucose ([F-18]FDG) positron emission tomography. Kidney function was measured with [F-18]FDG renal clearance and estimated glomerular filtration rate (eGFR). Secretin increased myocardial glucose uptake compared with placebo (secretin vs. placebo, means +/- SD, 15.5 +/- 7.4 vs. 9.7 +/- 4.9 gmol/100 g/min, 95% confidence interval (CI) [2.2, 9.4], P = 0.004). Secretin also increased [F-18]FDG renal clearance (44.5 +/- 5.4 vs. 39.5 8.5 mL/min, 95%CI [1.9, 8.1], P = 0.004), and eGFR was significantly increased from baseline after secretin, compared with placebo (17.8 +/- 9.8 vs. 6.0 +/- 5.2 Delta mL/min/1.73 m(2),( ) 95%CI [6.0, 17.6], P = 0.001). Our results implicate that secretin increases heart work and renal filtration, making it an interesting drug candidate for future studies in heart and kidney failure. NEW & NOTEWORTHY Secretin increases myocardial glucose uptake compared with placebo, supporting a previously proposed inotropic effect. Secretin also increased renal filtration rate.Peer reviewe

Brown fat triglyceride content is associated with cardiovascular risk markers in adults from a tropical region

Brown adipose tissue (BAT) is regarded as an interesting potential target for the treatment of obesity, diabetes, and cardiovascular diseases, and the detailed characterization of its structural and functional phenotype could enable an advance in these fields. Most studies evaluating BAT structure and function were performed in temperate climate regions, and we are yet to know how these findings apply to the 40% of the world's population living in tropical areas. Here, we used F-18-fluorodeoxyglucose positron emission tomography - magnetic resonance imaging to evaluate BAT in 45 lean, overweight, and obese volunteers living in a tropical area in Southeast Brazil. We aimed at investigating the associations between BAT activity, volume, metabolic activity, and BAT content of triglycerides with adiposity and cardiovascular risk markers in a sample of adults living in a tropical area and we showed that BAT glucose uptake is not correlated with leanness; instead, BAT triglyceride content is correlated with visceral adiposity and markers of cardiovascular risk. This study expands knowledge regarding the structure and function of BAT in people living in tropical areas. In addition, we provide evidence that BAT triglyceride content could be an interesting marker of cardiovascular risk

Cannabinoid Type 1 Receptors Are Upregulated During Acute Activation of Brown Adipose Tissue

Activating brown adipose tissue (BAT) could provide a potential approach for the treatment of obesity and metabolic disease in humans. Obesity is associated with upregulation of the endocannabinoid system, and blocking the cannabinoid type 1 receptor (CB1R) has been shown to cause weight loss and to decrease cardiometabolic risk factors. These effects may be mediated partly via increased BAT metabolism, since there is evidence that CB1R antagonism activates BAT in rodents. To investigate the significance of CB1R in BAT function, we quantified the density of CB1R in human and rodent BAT using the positron emission tomography radioligand [F-18]FMPEP-d(2) and measured BAT activation in parallel with the glucose analog [F-18]fluorodeoxyglucose. Activation by cold exposure markedly increased CB1R density and glucose uptake in the BAT of lean men. Similarly, 3-receptor agonism increased CB1R density in the BAT of rats. In contrast, overweight men with reduced BAT activity exhibited decreased CB1R in BAT, reflecting impaired endocannabinoid regulation. Image-guided biopsies confirmed CB1R mRNA expression in human BAT. Furthermore, CB1R blockade increased glucose uptake and lipolysis of brown adipocytes. Our results highlight that CB1Rs are significant for human BAT activity, and the CB1Rs provide a novel therapeutic target for BAT activation in humans