Adrenergic pathway activation enhances brown adipose tissue metabolism: A [18F]FDG PET/CT study in mice

Abstract

Objective Pharmacologic approaches to study brown adipocyte activation in vivo with a potential of being translational to humans are desired. The aim of this study was to examine pre- and postsynaptic targeting of adrenergic system for enhancing brown adipose tissue (BAT) metabolism quantifiable by [18F]fluoro-2-deoxyglucose ([18F]FDG) positron emission tomography (PET)/ computed tomography (CT) in mice. Methods A β3-adrenoreceptor selective agonist (CL 316243), an adenylyl cyclase enzyme activator (forskolin) and a potent blocker of presynaptic norepinephrine transporter (atomoxetine) were injected through the tail vein of Swiss Webster mice 30 minutes before intravenous (iv) administration of [18F]FDG. The mice were placed on the PET/CT bed for 30 min PET acquisition followed by 10 min CT acquisition for attenuation correction and anatomical delineation of PET images. Results Activated interscapular (IBAT), cervical, periaortic and intercostal BAT were observed in 3-dimentional analysis of [18F]FDG PET images. CL 316243 increased the total [18F]FDG standard uptake value (SUV) of IBAT 5-fold greater compared to that in placebo-treated mice. It also increased the [18F]FDG SUV of white adipose tissue (2.4-fold), and muscle (2.7-fold), as compared to the control. There was no significant difference in heart, brain, spleen and liver uptakes between groups. Forskolin increased [18F]FDG SUV of IBAT 1.9-fold greater than that in placebo-treated mice. It also increased the [18F]FDG SUV of white adipose tissue (2.2-fold) and heart (5.4-fold) compared to control. There was no significant difference in muscle, brain, spleen, and liver uptakes between groups. Atomoxetine increased [18F]FDG SUV of IBAT 1.7-fold greater than that in placebo-treated mice. There were no significant differences in all other organs compared to placebo-treated mice except liver (1.6 fold increase). A positive correlation between SUV levels of IBAT and CT hounsfiled unit (HU) (R2=0.55, p<0.001) and between CT HU levels of IBAT and liver (R2=0.69, p<0.006) was observed. Conclusions The three pharmacologic approaches reported here enhanced BAT metabolism by targeting different sites in adrenergic system as measured by [18F]FDG PET/CT.

18F-FDG PET/CT Monitoring of β3 Agonist–Stimulated Brown Adipocyte Recruitment in White Adipose Tissue

“…Mirbolooki et al reported that WAT of rats shows an increase in 18 F-FDG uptake by a single dose of CL316,243 (15). In addition, Quarta et al treated mice with CL316,243 for 4 wk and observed an increase in inguinal WAT 18 F-FDG uptake along with elevations of UCP1 protein and peroxisome proliferator-activated receptor-g coactivator 1 mRNA expression (16).…”

“…However, such studies to date have been limited mostly to acute BAT activation. Although b3AR stimulation has recently been shown to increase 18 F-FDG uptake in WAT of rodents (15,16), whether the level of 18 F-FDG uptake has sufficient accuracy to faithfully represent the magnitude of WAT browning has not been properly investigated. If 18 F-FDG can be shown to be a reliable biomarker, PET/CT imaging may help foster the in vivo translation of recent molecular discoveries related to WAT browning and may provide insight on how obesity can be treated by modifying WAT metabolism.…”

Synthesis and in Silico Evaluation of Novel Compounds for PET-Based Investigations of the Norepinephrine Transporter

“…Since NE is a fundamental neurochemical messenger, its accurate regulation is of major importance. Thus, the NET, responsible for NE equilibrium in the synaptic cleft, is representing the reuptake site and considered to be involved in a variety of neurological/psychiatric disorders [1,2], but also plays a pivotal role in cardiovascular [1][2][3] and metabolic diseases [3][4][5]. Reduced NET levels go along with neurological disorders like major depression [6,7], Parkinson's disease (PD), Alzheimer's disease (AD) [8][9][10][11][12][13][14][15][16][17][18], and cardiovascular diseases such as hypertension, cardiomyopathy, and heart failure [5,13].…”

“…Furthermore, a dysfunction of the NE system was reported in Attention Deficit Hyperactivity Disorder (ADHD) [9,17,19], suicide [1,12,20], substance abuse (cocaine dependence) [16], and schizophrenia [10]. A more recent discovery is the involvement of the NET in diseases like diabetes and obesity, due to its presence in brown adipose tissue (BAT) and the proposed activation thereof via NE [4,5,21].…”

Synthesis, Characterization, Biodistribution and Scintigraphic Evaluation of Technetium-99m (99mTc) Labeled Pazufloxacin (PZN): A Novel Infection Radiotracer

“…Nevertheless, these investigative modalities depend only on morphological alterations and consequently most anomalies can only be detect at complex stages of ailment and diagnosis of in time infections and its discrimination from inflammation or other involvements can be tricky [5].…”