Determining the fatty acid compositions of human brown and white adipose tissues in vivo using clinical proton magnetic resonance spectroscopy

Brown adipose tissue (BAT) of adult humans is metabolically active tissue which has been shown to have health-benefiting effects, such as preventing from type 2 diabetes and obesity. To develop BAT based treatment methods for obesity or diabetes the metabolism of the BAT tissue has to be well-known. Proton magnetic resonance spectroscopy (1H MRS) is a radiation-free method for studying adipose tissue of living subjects. The method has mostly been used for assessing the fat fraction of the tissue but it also provides values for the fatty acid properties, namely, fractions of saturated (SFA), monounsaturated (MUFA) and polyunsaturated fatty acids (PUFA) as well as their carbon chain length. So far these properties of BAT have not been studied in living human subjects. The subject of this thesis was to first develop a protocol for fatty acid composition measurement and validating it using lipid samples. Next, the protocol was used for determining fatty acid composition of human BAT and white adipose tissue (WAT) in both ambient condition and cold acclimation. The validation study supported the application of the method for human subjects although the determination of one of the parameters, fatty acid chain length, seemed imprecise. The rest of the parameters correlated well with the real values. The human study results indicated that human BAT and WAT have only negligible difference in the fatty acid composition between each other in the ambient condition although BAT has lower fat fraction than WAT. Cold exposure however seemed to change the fatty acid characteristics differently in BAT and WAT. In BAT the fractions of SFA and PUFA decreased in cold exposure while the fraction of MUFA increased. In WAT a decrease of PUFA was detected but the other parameters remained unchanged. The cold exposure did not have an effect on the fat fraction of the tissues. Additionally chain length elongation was observed in BAT although the determined chain length values were considerably shorter than in literature. In conclusion, a cold exposure induced change in fatty acid characteristics can be detected even though no change in fat fraction is detected. Thus determining fatty acid characteristics might be a sensitive method for detecting activation of BAT.Ihmisen ruskean ja valkean rasvakudoksen rasvahappokoostumuksen määrittäminen in vivo kliinisellä protonimagneettispektroskopialla Aikuisten ihmisten ruskea rasva on aineenvaihdunnallisesti aktiivista kudosta, jolla on todettu olevan terveyden kannalta hyödyllisiä vaikutuksia, sillä se suojaa muun muassa tyypin 2 diabetekselta ja lihavuudelta. Ruskean rasvan aktivoitumiseen perustuvien lihavuuden ja diabeteksen hoitomenetelmien kehittäminen edellyttää kudoksen aineenvaihdunnan hyvää tuntemusta. Protonimagneettispektroskopia on ionisoivaa säteilyä käyttämätön menetelmä, jota voidaan käyttää elävien kohteiden rasvakudoksen tutkimiseen. Metodia on käytetty kudosten rasvapitoisuuden määrittämiseen, mutta sillä voidaan määrittää myös rasvahappojen ominaisuudet, kuten tyydyttyneiden, kertatyydyttymättömien ja monityydyttymättömien rasvahappojen osuudet sekä rasvahappojen hiiliketjun pituus. Tähän mennessä menetelmällä ei ole tutkittu elävien ihmisten ruskeaa rasvaa. Tämän tutkielman aiheena oli ensin kehittää rasvahappokoostumuksen mittausprotokolla ja validoida se käyttämällä rasvanäytteitä. Seuraavaksi protokollaa käytettiin ihmisen ruskean ja valkean rasvan koostumuksen mittaamisen huoneenlämpötilassa ja kylmäaltistuksessa. Validaatiotutkimus osoitti, että menetelmää voidaan soveltaa ihmiskohteisiin vaikka yhden muuttujan, rasvahappojen ketjun pituuden, määritys vaikutti epätarkalta. Muut muuttujat korreloivat hyvin todellisten arvojen kanssa. Ihmiskoe osoitti, että ihmisen ruskea ja valkea rasvakudos eroavat rasvahappojen ominaisuuksien osalta häviävässä määrin toisistaan huoneenlämpötilassa, vaikka ruskea rasva on vähemmän rasvapitoista kuin valkea. Kylmäaltistus näytti sen sijaan muuttavan arvoja eri tavalla ruskeassa ja valkeassa rasvassa. Ruskeassa rasvassa tyydyttymättömien ja monityydyttyneiden rasvahappojen osuus väheni kylmäaltistuksessa kun taas kertatyydyttymättömien osuus kasvoi. Myös valkeassa rasvassa havaittiin monityydyttymättömien osuuden väheneminen, mutta muissa parametreissa ei havaittu muutoksia. Kylmäaltistuksella ei ollut vaikutusta kudosten kokonaisrasvapitoisuuteen. Lisäksi ketjun pituuden kasvu havaittiin ruskeassa rasvassa, vaikka määritetyt ketjunpituusarvot olivat huomattavasti lyhempiä kuin kirjallisuudessa raportoidut. Yhteenvetona voidaan todeta, että kylmäaltistuksen aikaansaamat muutokset ruskean rasvan rasvahappojen ominaisuuksissa voidaan havaita, vaikka rasvapitoisuuden muutosta ei havaita. Näin ollen rasvahappojen ominaisuuksien määritys saattaisi olla herkkä menetelmä ruskean rasvan aktivaation havaitsemiseen

Diclofenac does not reduce the risk of acute pancreatitis in patients with primary sclerosing cholangitis after endoscopic retrograde cholangiography

Background The European Society of Gastrointestinal Endoscopy recommends rectal indomethacin or diclofenac before endoscopic retrograde cholangiopancreatography (ERCP) to prevent post-ERCP pancreatitis. However, data on the prophylactic effect in patients with primary sclerosing cholangitis (PSC) are lacking. Methods This was a retrospective case-control study. In 2009-2018, a total of 2000 ERCPs were performed in 931 patients with PSC. Case procedures (N = 1000 after November 2013) were performed after administration of rectal diclofenac. Control procedures (N = 1000 before November 2013) were performed with the same indication but without diclofenac. Acute post-ERCP pancreatitis and other ERCP-related adverse events (AEs) were evaluated. Results Post-ERCP pancreatitis developed in 49 (4.9%) procedures in the diclofenac group and 62 (6.2%) procedures in the control group (p = 0.241). No difference existed between the groups in terms of the severity of pancreatitis or any other acute AEs. The risk of pancreatitis was elevated in patients with native papilla: 11.4% in the diclofenac group and 8.7% in the control group (p = 0.294). In adjusted logistic regression, diclofenac did not reduce the risk of pancreatitis (odds ratio (OR) = 1.074, 95% confidence interval 0.708-1.629, p = 0.737). However, in generalised estimation equations with the advanced model, diclofenac seemed to diminish the risk of pancreatitis (OR = 0.503) but not significantly (p = 0.110). Conclusion In this large patient cohort in a low-risk unit, diclofenac does not seem to reduce the risk of post-ERCP pancreatitis in patients with PSC. The trend in the pancreatitis rate after ERCP is decreasing. The evaluation of the benefits of diclofenac among PSC patients warrants a randomised controlled study targeted to high-risk patients and procedures.Peer reviewe

Study of the Effect of Reconstruction Parameters for Myocardial Perfusion Imaging in PET With a Novel Flow Phantom

Myocardial perfusion imaging (MPI) with positron emission tomography (PET) allows quantitative temporal measurements of the radioactive tracer distribution in tissue. The quantification for myocardial blood flow (MBF) is conducted with kinetic modeling of the image-derived time-activity curves (TACs) allowing derivation for MBF in units of mL/min per gram of tissue. The ordered-subset expectation maximization (OSEM) reconstruction algorithm with time-of-flight (TOF) and point spread function (PSF) modeling is now routinely employed in cardiac imaging. However, the varying counting statistics of the MPI measurements conducted with short-lived tracers present a challenge for the PET image reconstruction methods. Thus, the effect of the reconstruction methods on the flow quantification needs to be evaluated in a standardized manner. Recently, a novel PET flow phantom modeling the MBF has been developed for investigation of the standardization of the MBF measurements. In this study, the effect of the reconstruction parameters on the image-derived flow values against a known reference flow of the flow phantom was studied with [O-15]H2O. The effects were studied by comparison of TACs and relative errors of the image-derived flow values with respect to the phantom-derived reference flow value using 5 repeated PET scans with fixed acquisition parameters using a digital Discovery MI PET/CT system. The reconstruction methods applied were OSEM using both TOF and PSF (OSEM-TOF-PSF) with several matrix sizes (128 x 128, 192 x 192, 256 x 256, 384 x 384), Gaussian filter sizes (4, 8 mm) and OSEM without TOF and PSF (OSEM), with TOF (OSEM-TOF) and with PSF (OSEM-PSF) in addition to recently introduced regularized reconstruction method based on Bayesian-penalized maximum likelihood (Q.Clear). Between repeated measurements, the image-derived flow values showed high repeatability with a SD less than 2 mL/min as well as high accuracy with the maximum error of 7% with respect to the reference flow for all reconstructions. Overall, reconstruction settings had only a small impact on the resulting flow values. In conclusion, due to the small differences detected, any of the implemented reconstruction algorithms on the system can be applied in MPI studies for accurate flow quantification

Assessment of a digital and an analog PET/CT system for accurate myocardial perfusion imaging with a flow phantom

In Myocardial Perfusion Imaging (MPI) with Positron Emission Tomography/Computed Tomography (PET/CT) systems, accurate quantification is essential. We assessed flow quantification accuracy over various injected activities using a flow phantom.Methods The study was performed on the digital 4-ring Discovery MI (DMI-20) and analog Discovery 690 (D690) PET/CT systems, using 325-1257 MBq of [O-15]H2O. PET performance and flow quantification accuracy were assessed in terms of count-rates, dead-time factors (DTF), scatter fractions (SF), time-activity curves (TACs), areas-under-the-curves (AUCs) and flow values.Results On DMI-20, prompts of 12.8 Mcps, DTF of 2.06 and SF of 46.1% were measured with 1257 MBq of activity. On the D690, prompts of 6.85 Mcps, DTF of 1.57 and SF of 32.5% were measured with 1230 MBq of activity. AUC values were linear over all activities. Mean wash-in flow error was - 9% for both systems whereas wash-out flow error was - 5% and - 6% for DMI-20 and D690. With the highest activity, wash-out flow error was - 12% and - 7% for the DMI-20 and D690.Conclusion DMI-20 and D690 preserved accurate flow quantification over all injected activities, with maximum error of - 12%. In the future, flow quantification accuracy over the activities and count-rates evaluated in this study should be assessed

Femoral Bone Marrow Insulin Sensitivity Is Increased by Resistance Training in Elderly Female Offspring of Overweight and Obese Mothers

Abstract-Bone marrow insulin sensitivity may be an important factor for bone health in addition to bone mineral density especially in insulin resistant conditions. First we aimed to study if prenatal maternal obesity plays a role in determining bone marrow insulin sensitivity in elderly female offspring. Secondly we studied if a four-month individualized resistance training intervention increases bone marrow insulin sensitivity in elderly female offspring and whether this possible positive outcome is regulated by the offspring’s mother’s obesity status. 37 frail elderly females (mean age 71.9 ± 3.1 years) of which 20 were offspring of lean/normal-weight mothers (OLM, maternal BMI ≤ 26.3 kg/m2) and 17 were offspring of obese/overweight mothers (OOM, maternal BMI ≥ 28.1 kg/m2) were studied before and after a four-month individualized resistance training intervention. Nine age- and sex-matched non-frail controls (maternal BMI ≤ 26.3 kg/m2) were studied at baseline. Femoral bone marrow (FBM) and vertebral bone marrow (VBM) insulin sensitivity were measured using [18F]fluoro-2-deoxy-D-glucose positron emission tomography with computer tomography under hyperinsulinemic euglycemic clamp. We found that bone marrow insulin sensitivity was not related to maternal obesity status but FBM insulin sensitivity correlated with whole body insulin sensitivity (R = 0.487, p = 0.001). A four-month resistance training intervention increased FBM insulin sensitivity by 47% (p = 0.006) only in OOM, while VBM insulin sensitivity remained unchanged regardless of the maternal obesity status. In conclusion, FBM and VBM glucose metabolism reacts differently to a four-month resistance training intervention in elderly women according to their maternal obesity status.</p

Renal Sinus Fat Is Expanded in Patients with Obesity and/or Hypertension and Reduced by Bariatric Surgery Associated with Hypertension Remission

Renal sinus fat is a fat depot at the renal hilum. Because of its location around the renal artery, vein, and lymphatic vessels, an expanded renal sinus fat mass may have hemodynamic and renal implications. We studied whether renal sinus fat area (RSF) associates with hypertension and whether following bariatric surgery a decrease in RSF associates with improvement of hypertension. A total of 74 severely obese and 46 lean controls were studied with whole-body magnetic resonance imaging (MRI). A total of 42 obese subjects were re-studied six months after bariatric surgery. RSF was assessed by two independent researchers using sliceOmatic. Glomerular filtration rate (eGFR) was estimated according to the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). Patients with obesity accumulated more RSF compared to lean controls (2.3 [1.7-3.1] vs. 1.8 [1.4-2.5] cm(2), p = 0.03). Patients with hypertension (N = 36) had a larger RSF depot compared to normotensive subjects (2.6 [2.0-3.3] vs. 2.0 [1.4-2.5] cm(2), p = 0.0007) also after accounting for body mass index (BMI). In the pooled data, RSF was negatively associated with eGFR (r = -0.20, p = 0.03), whereas there was no association with systolic or diastolic blood pressure. Following bariatric surgery, RSF was reduced (1.6 [1.3-2.3] vs. 2.3 [1.7-3.1] cm(2), p = 0.03) along with other markers of adiposity. A total of 9/27 of patients achieved remission from hypertension. The remission was associated with a larger decrease in RSF, compared to patients who remained hypertensive (-0.68 [ -0.74 to -0.44] vs. -0.28 [ -0.59 to 0] cm(2), p = 0.009). The accumulation of RSF seems to be involved in the pathogenesis of hypertension in obesity. Following bariatric surgery, loss of RSF was associated with remission from hypertension

Femoral Bone Marrow Insulin Sensitivity Is Increased by Resistance Training in Elderly Female Offspring of Overweight and Obese Mothers

Bone marrow insulin sensitivity may be an important factor for bone health in addition to bone mineral density especially in insulin resistant conditions. First we aimed to study if prenatal maternal obesity plays a role in determining bone marrow insulin sensitivity in elderly female offspring. Secondly we studied if a four-month individualized resistance training intervention increases bone marrow insulin sensitivity in elderly female offspring and whether this possible positive outcome is regulated by the offspring's mother's obesity status. 37 frail elderly females (mean age 71.9 +/- 3.1 years) of which 20 were offspring of lean/normal-weight mothers (OLM, maternal BMI = 28.1 kg/m(2)) were studied before and after a four-month individualized resistance training intervention. Nine age-and sex-matched non-frail controls (maternal BMIPeer reviewe

Systemic cross-talk between brain, gut, and peripheral tissues in glucose homeostasis : effects of exercise training (CROSSYS). Exercise training intervention in monozygotic twins discordant for body weight

Background: Obesity and physical inactivity are major global public health concerns, both of which increase the risk of insulin resistance and type 2 diabetes. Regulation of glucose homeostasis involves cross-talk between the central nervous system, peripheral tissues, and gut microbiota, and is affected by genetics. Systemic cross-talk between brain, gut, and peripheral tissues in glucose homeostasis: effects of exercise training (CROSSYS) aims to gain new systems-level understanding of the central metabolism in human body, and how exercise training affects this cross-talk. Methods: CROSSYS is an exercise training intervention, in which participants are monozygotic twins from pairs discordant for body mass index (BMI) and within a pair at least the other is overweight. Twins are recruited from three population-based longitudinal Finnish twin studies, including twins born in 1983-1987, 1975-1979, and 1945-1958. The participants undergo 6-month-long exercise intervention period, exercising four times a week (including endurance, strength, and high-intensity training). Before and after the exercise intervention, comprehensive measurements are performed in Turku PET Centre, Turku, Finland. The measurements include: two positron emission tomography studies (insulin-stimulated whole-body and tissue-specific glucose uptake and neuroinflammation), magnetic resonance imaging (brain morphology and function, quantification of body fat masses and organ volumes), magnetic resonance spectroscopy (quantification of fat within heart, pancreas, liver and tibialis anterior muscle), echocardiography, skeletal muscle and adipose tissue biopsies, a neuropsychological test battery as well as biosamples from blood, urine and stool. The participants also perform a maximal exercise capacity test and tests of muscular strength. Discussion: This study addresses the major public health problems related to modern lifestyle, obesity, and physical inactivity. An eminent strength of this project is the possibility to study monozygotic twin pairs that share the genome at the sequence level but are discordant for BMI that is a risk factor for metabolic impairments such as insulin resistance. Thus, this exercise training intervention elucidates the effects of obesity on metabolism and whether regular exercise training is able to reverse obesity-related impairments in metabolism in the absence of the confounding effects of genetic factors.Peer reviewe

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

Systemic cross-talk between brain, gut, and peripheral tissues in glucose homeostasis: effects of exercise training (CROSSYS). Exercise training intervention in monozygotic twins discordant for body weight

Background: Obesity and physical inactivity are major global public health concerns, both of which increase the risk of insulin resistance and type 2 diabetes. Regulation of glucose homeostasis involves cross-talk between the central nervous system, peripheral tissues, and gut microbiota, and is affected by genetics. Systemic cross-talk between brain, gut, and peripheral tissues in glucose homeostasis: effects of exercise training (CROSSYS) aims to gain new systems-level understanding of the central metabolism in human body, and how exercise training affects this cross-talk.Methods: CROSSYS is an exercise training intervention, in which participants are monozygotic twins from pairs discordant for body mass index (BMI) and within a pair at least the other is overweight. Twins are recruited from three population-based longitudinal Finnish twin studies, including twins born in 1983-1987, 1975-1979, and 1945-1958. The participants undergo 6-month-long exercise intervention period, exercising four times a week (including endurance, strength, and high-intensity training). Before and after the exercise intervention, comprehensive measurements are performed in Turku PET Centre, Turku, Finland. The measurements include: two positron emission tomography studies (insulin-stimulated whole-body and tissue-specific glucose uptake and neuroinflammation), magnetic resonance imaging (brain morphology and function, quantification of body fat masses and organ volumes), magnetic resonance spectroscopy (quantification of fat within heart, pancreas, liver and tibialis anterior muscle), echocardiography, skeletal muscle and adipose tissue biopsies, a neuropsychological test battery as well as biosamples from blood, urine and stool. The participants also perform a maximal exercise capacity test and tests of muscular strength.Discussion: This study addresses the major public health problems related to modern lifestyle, obesity, and physical inactivity. An eminent strength of this project is the possibility to study monozygotic twin pairs that share the genome at the sequence level but are discordant for BMI that is a risk factor for metabolic impairments such as insulin resistance. Thus, this exercise training intervention elucidates the effects of obesity on metabolism and whether regular exercise training is able to reverse obesity-related impairments in metabolism in the absence of the confounding effects of genetic factors