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Papers by Éric Turcotte

The FASEB Journal, Mar 31, 2016

American Journal of Physiology-endocrinology and Metabolism, Jun 1, 2021

The mechanism of increased postprandial nonesterified fatty acid (NEFA) appearance in the circula... more The mechanism of increased postprandial nonesterified fatty acid (NEFA) appearance in the circulation in impaired glucose tolerance (IGT) is due to increased adipose tissue lipolysis but could also be contributed to by reduced adipose tissue (AT) dietary fatty acid (DFA) trapping and increased "spillover" into the circulation. Thirty-one subjects with IGT (14 women, 17 men) and 29 with normal glucose tolerance (NGT, 15 women, 14 men) underwent a meal test with oral and intravenous palmitate tracers and the oral [ 18 F]-fluoro-thia-heptadecanoic acid positron emission tomography method. Postprandial palmitate appearance (Ra palmitate) was higher in IGT versus NGT (P < 0.001), driven exclusively by Ra palmitate from obesity-associated increase in intracellular lipolysis (P = 0.01), as Ra palmitate from DFA spillover was not different between the groups (P = 0.19) and visceral AT DFA trapping was even higher in IGT versus NGT (P = 0.02). Plasma glycerol appearance was lower in IGT (P = 0.01), driven down by insulin resistance and increased insulin secretion. Thus, we found higher AT DFA trapping, limiting spillover to lean organs and in part offsetting the increase in Ra palmitate from intracellular lipolysis. Whether similar findings occur in frank diabetes, a condition also characterized by insulin resistance but relative insulin deficiency, requires further investigation (Clinicaltrials.gov: NCT04088344, NCT02808182). NEW & NOTEWORTHY We found higher adipose tissue dietary fatty acid trapping, limiting spillover to lean organs, that in part offsets the increase in appearance rate of palmitate from intracellular lipolysis in prediabetes. These results point to the adaptive nature of adipose tissue trapping and dietary fatty acid spillover as a protective mechanism against excess obesity-related palmitate appearance rate from intracellular adipose tissue lipolysis.

Ye et al, "Total postprandial hepatic non-esterified and dietary fatty acid uptake is increased a... more Ye et al, "Total postprandial hepatic non-esterified and dietary fatty acid uptake is increased and insufficiently curbed by adipose tissue fatty acid trapping in prediabetes with overweight" Supplementary methods PET CT analyses Correction for circulating metabolites was performed during the [ 11 C]-palmitate acquisition as described in [24]; however, this did not impact the kinetic model (see Supplemental Figure 4). Baseline PET acquisition was performed prior to [ 11 C]-palmitate acquisition to subtract any Supplemental Material: Ye et al, "Total postprandial hepatic non-esterified and dietary fatty acid uptake is increased and insufficiently curbed by adipose tissue fatty acid trapping in prediabetes with overweight"

The FASEB Journal, Apr 1, 2013

Recent studies examining brown adipose tissue (BAT) metabolism in adult humans have provided conv... more Recent studies examining brown adipose tissue (BAT) metabolism in adult humans have provided convincing evidence that it can significantly contribute to cold‐induced thermogenesis under acute mild‐cold exposure. Although, many mammalian models have demonstrated the adaptability of this tissue through chronic cold exposure, little is known about its plasticity in humans. Using electromyography combined with positron emission tomography with 11C‐acetate and 18F‐fluorodeoxyglucose, shivering intensity and BAT oxidative metabolism and glucose uptake prior to and following four weeks of cold acclimation were examined. Non‐acclimated men were exposed to 10°C, two hours daily for four weeks (5 days/week), using a liquid‐conditioned suit (LCS). Preliminary data suggests a 5‐fold increase in BAT oxidative metabolism (from 0.005±0.004to 0.025±0.007 sec−1, n=3) resulting in a ~40% decrease in shivering intensity (from 3.2±1.4 to 2.0±1.3 %MVC, n=3), through four weeks of cold‐acclimation, despite similar 1.8‐fold increases in cold‐induced energy expenditure (10.6±1.4 and 10.3±1.3 kJ·min−1, pre‐and postacclimation, respectively, n=3). Fractional and net glucose uptake in BAT increased 2.2‐fold (from 0.017±0.007 to 0.037±0.015 min−1 and from 81±35 to 183±82 nmol·g−1·min−1) following cold‐acclimation. Our preliminary results demonstrate an increased capacity of BAT‐derived thermogenesis during acute cold exposure after a 4‐week cold acclimation period in healthy men. This research was supported by the Natural Sciences and Engineering Research Council of Canada and the Canadian Diabetes Association (grant OG 3–10‐2970‐AC).

Journal of Nuclear Medicine

Cyclotron production of gallium-68 (68 Ga) is a promising approach to supply 68 Ga radiopharmaceu... more Cyclotron production of gallium-68 (68 Ga) is a promising approach to supply 68 Ga radiopharmaceuticals. To validate this capability, an integrated solution for a robust synthesis of 68 Ga-DOTATATE prepared from cyclotron produced 68 Ga (further on referred to as cyclotron produced 68 Ga-DOTATATE) was achieved. A retrospective comparison analysis was performed in patients who underwent PET/CT imaging after injection of DOTATATE labeled with 68 Ga produced by cyclotron or eluted from a generator to demonstrate the clinical safety and diagnostic efficacy of the radiopharmaceutical for a routine standard-of-care diagnostic tool in clinic. Methods: An enriched zinc-68 pressed target was irradiated by cyclotron with a proton beam set at 12.7 MeV for 100 min. The fully automated process utilizes an in-vault dissolution system where a liquid distribution system transfers the dissolved target to a dedicated hotcell for the purification of 68 GaCl3 and radiolabeling of DOTATATE using a cassette-based automated module. Quality control tests were performed on the resulting tracer solution. The internal radiation dose for 68 Ga-DOTATATE was calculated based on extrapolation from rat biodistribution experiments. A retrospective comparison analysis was performed in patients who underwent PET/CT imaging after injection of DOTATATE labeled with 68 Ga produced by cyclotron or eluted from a generator. Results: The synthesis of 68 Ga-DOTATATE (20.7 ± 1.3 GBq) with high apparent molar activity (518 ± 32 GBq/µmole at end of synthesis (EOS)) was completed in 65 min and the radiopharmaceutical met the requirements specified in the European Pharmacopoeia monograph on Gallium (68 Ga) chloride (accelerator produced) solution for radiolabeling. 68 Ga-DOTATATE was stable for at least 5 h after formulation. The dosimetry calculated with OLINDA for 68 Ga-DOTATATE from cyclotron produced 68 Ga and generator eluted 68 Ga was roughly equivalent. The SUVmean or SUVmax of tumoral lesions with cyclotron produced 68 Ga-DOTATATE was equivalent to that with generator-eluted 68 Ga. Among physiological uptakes, a significant difference was found in kidneys, spleen and stomach wall, with lower values in cyclotron produced 68 Ga-DOTATATE in all cases. Conclusion: Integrated cyclotron production achieves reliable high yields of clinical-grade 68 Ga-DOTATATE. The clinical safety, and imaging efficacy of cyclotron produced 68 Ga-DOTATATE in humans provide supporting evidence for its use in routine clinical practice.

Diabetes, 2018

Postprandial dietary fatty acid (FA) biodistribution is impaired in subjects with glucose intoler... more Postprandial dietary fatty acid (FA) biodistribution is impaired in subjects with glucose intolerance, with decreased FA storage in adipose tissues (AT) and increased FA uptake by the myocardium. These abnormalities are improved after 1 year of lifestyle-induced weight loss. Bariatric surgery leads to early metabolic improvements before weight loss, but the early effects on dietary FA metabolism and biodistribution have never been studied. 9 subjects with T2D underwent a 6-hour postprandial metabolic protocol before and 12 days after SG. A liquid meal containing [U-13C]-palmitate and [2H]-glucose was ingested at time 0, with an IV perfusion of [3H]-glucose and [7,7,8,8-2H]-palmitate, allowing quantification of glucose absorption, endogenous glucose production (EGP), lipolysis and dietary FA spillover. A capsule containing a positron-emitting long-chain FA analog (18FTHA) was taken with the meal for the quantification of organ-specific dietary FA uptake using PET/CT (n=6). Twelve day...

Clinical Lipidology, 2015

Abstract The presence of brown adipose tissue (BAT) in adult humans has been rediscovered through... more Abstract The presence of brown adipose tissue (BAT) in adult humans has been rediscovered through the clinical use of the radioactive glucose analog 18F-fluorodeoxyglucose with PET. This has led to numerous studies demonstrating cold exposure as the major physiological modulator of BAT activity. These reports also suggested that age, gender, BMI and the presence of diabetes are also important modulators of BAT volume and metabolic activity. Although 18F-fluorodeoxyglucose PET has provided important information on BAT glucose metabolism, other techniques are being developed and applied to assess other aspects of BAT metabolism. Here, we summarize the current understanding of the pathophysiological functions of BAT in humans and discuss some of the strengths and limitations of the current investigational techniques.

The Journal of Clinical Endocrinology & Metabolism, 2011

Context: In humans, the prevalence, mass, and glucose-uptake activity of 18F-fluorodeoxyglucose (... more Context: In humans, the prevalence, mass, and glucose-uptake activity of 18F-fluorodeoxyglucose (18F-FDG)-detected brown adipose tissue (BAT), which are expectedly enhanced by a cold stimulus, also appear modulated by other factors that still have to be disentangled. Objective: The objective of the study was to investigate the factors determining the prevalence, mass, and glucose-uptake activity of 18F-FDG-detected BAT in humans. Research Design and Methods: We retrospectively analyzed all 18F-FDG positron emission tomography/computed tomography examinations performed between January 2007 and December 2008 at our institution for 18F-FDG uptake within the cervical/supraclavicular, mediastinal, paravertebral, and perirenal fat areas. The influence of outdoor temperature, sex, age, body mass index (BMI), plasma glucose level, diabetes diagnosis, day length, and cancer status on the prevalence, mass, and glucose-uptake activity of 18F-FDG-detected BAT depots was investigated. Results: T...

Diabetes & Metabolism, 2013

Objectif : Les effets hypophagiques des antagonistes sélectifs du récepteur aux endocannabinoïdes... more Objectif : Les effets hypophagiques des antagonistes sélectifs du récepteur aux endocannabinoïdes CB1 (CB1R) sont attribués à des mécanismes centraux notamment hypothalamiques. On trouve aussi des CB1Rs sur les fibres nerveuses innervant le tractus gastro-intestinal. En induisant un signal glucose portal, la néoglucogenèse intestinale (NGI) induit la satiété et potentialise la suppression de la production hépatique de glucose par l'insuline. Nous avons émis l'hypothèse que les CB1Rs périphériques pourraient initier un circuit nerveux intestin-cerveau-foie par induction de la NGI. Matériels et méthodes : Des rats vigiles sont perfusés dans la veine porte pendant 8 h par un antagoniste des CB1Rs semblable au Rimonabant (AM251). Leur prise alimentaire est étudiée. Après euthanasie, leur néoglucogenèse intestinale et hépatique est quantifiée. Un marquage c-fos des noyaux hypothalamiques et des relais centraux des voies spinales et vagales a été également réalisé. Résultats : L'activité de la glucose-6 phosphatase (G6Pase) intestinale est augmentée par l'AM251 (44,3 ± 4,0 U/g de protéines vs 18,9 ± 4,3 U/g avec le véhicule ; p < 0,01; n = 6). La phosphoénolpyruvate carboxykinase est également augmentée. Au contraire, l'activité G6Pase hépatique est diminuée par l'AM251 (41,3 ± 3,2 U/g de protéines vs 70,3 ± 7,8 U/g avec le véhicule ; p < 0,05; n = 6). La perfusion de l'AM251 est associée à une diminution de la prise alimentaire (0,33 ± 0,33 g vs 4,6 ± 1,1 g avec le véhicule ; p < 0,01; n = 6). On constate une activation neuronale des centres de satiété ainsi que des relais centraux des voies spinale et vagale en réponse à l'inhibition des CB1Rs portaux. L'ensemble de ces effets est aboli par dénervation portale (capsaïcine). Discussion : Cette étude suggère que l'inhibition des CB1Rs portaux par un antagoniste sélectif induirait la NGI et produirait ainsi ses effets bénéfiques sur la prise alimentaire et l'homéostasie glucidique au niveau hépatique. Le système nerveux portal serait essentiel dans l'initiation de ce circuit nerveux intestin-cerveau-foie. O84 Glycogénose de type 1a et diabète : un mécanisme commun de dysfonctionnement rénal

The Journal of Nuclear Medicine, May 1, 2020

Molecular Imaging and Biology, Jul 22, 2020

Purpose: A retrospective analysis was performed of preclinical and clinical data acquired during ... more Purpose: A retrospective analysis was performed of preclinical and clinical data acquired during the evaluation of the estrogen receptor (ER) PET tracer 4-fluoro-11β-methoxy-16α-[ 18 F]fluoroestradiol (4FMFES) and its comparison with 16α-[ 18 F]-fluoroestradiol (FES) in mice, rats and humans with a focus on the brain uptake. Procedures: Breast cancer tumor-bearing female BALB/c mice from a previous study and female Sprague-Dawley rats (control and ovariectomized) were imaged by 4FMFES or FES-PET imaging. Immediately after, low-dose CT was performed in the same bed position. Semiquantitative analysis was conducted to extract %ID/g data. Small cohorts of mice and rats were imaged with 4FMFES in an ultra-high-resolution small animal PET scanner prototype (LabPET II). Rat brains were dissected and imaged separately with both PET and autoradiography. In parallel, 31 breast cancer patients were enrolled in a clinical phase II study to compare 4FMFES with FES for oncological assessment. Since the head was included in the field-of-view, brain uptake of discernable foci was measured and reported as SUV Max. Results: Regardless of the species studied, 4FMFES and FES uptake was relatively uniform in most regions of the brain, except for bilateral foci at the base of the skull, at the midsection of the brain. Anatomical localization of the PET signal using CT image fusion indicates that the signal origins from the pituitary in all studied species. 4FMFES yielded lower pituitary uptake than FES in patients, but an inverse trend was observed in rodents. 4FMFES pituitary contrast was higher than FES in all assessed groups. High-resolution small animal imaging of the brain of rats and mice revealed a supplemental signal anterior to the pituitary, which is likely to be the medial

medRxiv (Cold Spring Harbor Laboratory), Mar 28, 2023

doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by pee... more doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

Alzheimers & Dementia, Jul 1, 2014

Background:Beta-amyloid (A b) deposition occurs years before the onset of Alzheimer’s disease (AD... more Background:Beta-amyloid (A b) deposition occurs years before the onset of Alzheimer’s disease (AD) dementia, but its relation to grey matter (GM) changes and FDG-PET metabolism in the pre-dementia stages remains unclear. Here we examined the effect of abnormally high A b on the regional rates of GM and FDG-PET change separately, and assessed the joint spatial variations across both modalities over 3 years. Methods: Forty cognitively healthy (HC) and fifty-three mildly impaired (MCI) adults underwent annual MRI and FDG-PET imaging for three years within the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Based on CSF A b 1-42 and global brain amyloid-PET (Av-45 and PiB-PET), the HC and MCI subjects were dichotomized into groups with high (A b +) and low (A b -) amyloid burden, according to pre-established criteria. Voxel-wise rates of change in GM, FDG-PET and atrophy-corrected FDGPET were estimated for each subject. In voxel-wise analyses, the rates of change in each modality were compared between groups, controlling for age, gender, years of education and ApoE genotype. In joint independent component analysis (jICA) the patterns of covariance in the change across modalities were assessed. Results: HC A b + subjects showed faster rates of GM atrophy in the medial parietal lobe (MPL) and medial temporal lobe (MTL) when compared to HC A b -. No differences in the FDGPET rates of change were found. For MCIs, A b + subjects showed faster rates of GM atrophy than A b in the MTL, MPL, frontal and temporal lobes. Faster decline in FDG-PET metabolism was found throughout the forebrain, but not within the MTL. After correcting for atrophy, MCI A b + showed increasing FDG-PET metabolism within the MTL when compared to MCI A b (Figure). The jICA analysis assessing covarying changes between modalities showed higher rates of decline in both FDGPET and GM. However, after atrophy correction, decreasing GM volume was associated with increasing FDG-PET. Conclusions: At the pre-symptomatic stages of AD, A b-related changes in GM volume are apparent primarily within medial temporo-parietal regions. At the mild symptomatic stage, atrophy spreads to adjacent regions and is accompanied by FDG-PET decline in cortical areas. The A b -associated increase in FDG-PET after atrophy correction within the MTL suggests the existence of compensatory mechanisms in MCI. IC-P-115 BRAIN FUEL CONSUMPTION IN MILD ALZHEIMER’S DISEASE (AD): COMPARISON OF GLUCOSE AND KETONES USING PET IMAGING

The Journal of Nuclear Medicine, May 1, 2020

411 Objectives: Quantitative SPECT (QSPECT)/CT is increasingly used in 177Lu theranostics. Beside... more 411 Objectives: Quantitative SPECT (QSPECT)/CT is increasingly used in 177Lu theranostics. Beside dosimetry, QSPECT/CT enables real-time therapeutic response assessment that is potentially predictive of longer-term response, such as molecular imaging response assessed with 68Ga-PET/CT, for which we previously proposed the Theranostic Response Criteria In Solid Tumors (THERCIST) based on molecular tumor volume (MTV). Our aim was to assess if an early decrease in total lesion fraction (TLF: total lesion activity divided by body weight, expressed in percentage of injected activity) on QSPECT during peptide receptor radionuclide therapy (PRRT) predicted an objective response on post-treatment 68Ga-PET/CT. Methods: 32 consecutive patients with neuroendocrine tumor who underwent 68Ga-octreotate-PET/CTs within 4 months prior to and after a personalized, dosimetry-based 177Lu-octreotate PRRT induction course were included. A threshold of 25% of the SUVpeak was used for tumor segmentation. The 177Lu-QSPECT/CTs performed 3 days after the first and second 177Lu-octreotate administrations were compared. An early response was defined as a decrease in TLF of 30% or more. Pre- and post-PRRT 68Ga-PET/CTs were compared according to THERCIST: CMR (complete molecular response): disappearance of all lesions; PMR (partial molecular response): ≥50% decrease in tumor burden; SMD (stable molecular disease): <50% variation in tumor burden; PMD (progressive molecular disease): ≥50% increase in tumor burden. Late PET response was correlated to early QSPECT response, and the predictive performance of the latter was assessed. Results: 10 (31%) patients were identified as early responders and 22 (69%) as non-early responders based on QSPECT. The final PET molecular imaging outcome was PMR in 9 (28%) and non-PMR in 23 patients (72%; SMD in 21 and PMD in 2). The late PET response was significantly correlated with the early QSPECT response (Figure; r=0.56, P=0.0009). An early response on QSPECT predicted a PMR with a sensitivity, specificity, positive and negative predictive values and accuracy of 67%, 83%, 60%, 86% and 78%, respectively (P=0.0126). An early QSPECT response at cycle 2, i.e. only 2 mo. after PRRT initiation, conferred a likelihood ratio of 3.8 to obtain a PMR after the induction course completion. Of note, 19 (83%) of patients who failed to demonstrate an early decrease in TLF did not experience a PMR (17 SMD; 2 PMD). Conclusion: QSPECT response 2 mo. after PRRT initiation is an early predictor of objective response to PRRT. As such, early QSPECT response represents a novel imaging biomarker of radiosensitivity and tumor biology, which could be useful to prospectively tailor a precision PRRT regimen, e.g. treatment escalation to maximize debulking or de-escalation to avoid toxicity, in radiosensitive and radioresistant neuroendocrine tumors, respectively. Research Support: Scholarship from Fonds de recherche du Quebec - Sante to JMB.

Physiology

Background: We previously revealed that oral administration of the β3-adrenergic receptor (AR) ag... more Background: We previously revealed that oral administration of the β3-adrenergic receptor (AR) agonist mirabegron only elicited small increases in brown adipose tissue (BAT) thermogenesis when ingested at the maximal allowable dose (200 mg). This led to off-target binding of the β1- and β2-AR, thereby increasing cardiovascular responses and white adipose tissue lipolysis, respectively. We hypothesize that a balanced activation between β1- and β3-AR is key to stimulating metabolic benefits without cardiovascular side effects. Method: We performed a randomized crossover trial in 8 lean men over two study days. The intervention consisted of oral administration of mirabegron (200 mg) with or without the cardio selective β1-AR antagonist bisoprolol (10 mg). Dynamic [11C]-acetate and 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) PET/CT scans were performed sequentially starting at 210 min after oral administration of mirabegron ± bisoprolol. Results: Compared to baselines measures, mirabegro...

Journal of Nuclear Medicine, 2021

In this study, the preliminary results of a phase II clinical trial investigating the use of the ... more In this study, the preliminary results of a phase II clinical trial investigating the use of the Estrogen Receptor (ER) targeting PET tracer 4-fluoro-11β-methoxy-16α-[ 18 F]fluoroestradiol (18F-4FMFES) and [ 18 F]-fluorodeoxyglucose (18F-FDG)-PET in endometrial cancers will be accounted. In parallel, non-invasive interventions will be attempted to slow down progression of 18F-4FMFES metabolites in the intestines to reduce abdominal background. Methods: In an ongoing study, 25 patients that received prior pathological confirmation of an ER+ endometrial cancer or endometrial intraepithelial neoplasia agreed to participate to the ongoing clinical trial. Patients were scheduled for 18F-FDG and 18F-4FMFES PET/CT imaging in random order and within 2 weeks. Patients were administered either 4 mg loperamide per os before 18F-4FMFES tracer injection or repeated intravenous injection of 20 mg hyoscine Nbutylbromide during 18F-4FMFES-PET/CT. Regions-of-interest (ROIs) covering the whole abdomen and excluding the liver, bladder and uterus were drawn for the 18F-4FMFES-PET images, and a threshold of SUV > 4 was applied. The volume of the resulting region was compared between the different interventions to estimate the extent of the intestinal background. Results: Repeated injection of hyoscine N-butylbromide substantially reduced the intestinal background volume, whereas loperamide had a significant but moderate effect. 18F-4FMFES tumor uptake ranged between SUV Max 3.0 and 14.4 (9.4 ± 3.2), whereas 18F-FDG uptake spreaded between SUV Max 0 and 22.0 (7.5 ± 5.1). Tumor-to-background ratio were significantly higher for 18F-4FMFES (16.4 ± 5.4) than for 18F-FDG (7.4 ± 4.6). Significant differences were observed between grade 1 and higher-grade tumors concerning 18F-4FMFES uptake and contrast. 18F-FDG uptake, and the 18F-FDG/18F-4FMFES uptake ratio. Conclusions: It is possible to improve 18F-4FMFES abdominal background using hyoscine Nbutylbromide. Both 18F-FDG and 18F-4FMFES-PET are suitable for detection of ER+ endometrial cancers, although 18F-4FMFES yielded a better tumor contrast than 18F-FDG.

The Journal of Nuclear Medicine, 2015

Cell Metabolism, 2020

Highlights d A therapeutic dose (50 mg) of mirabegron does not stimulate human BAT thermogenesis ... more Highlights d A therapeutic dose (50 mg) of mirabegron does not stimulate human BAT thermogenesis d Human brown adipocytes lack b 3-AR and do not respond to mirabegron in vitro d Norepinephrine-induced respiration is driven by b 2-AR, which co-localizes with UCP1 d b 2-AR is the main target for pharmacological activation of human brown adipocytes

Diabetes, 2020

Excessive exposure of lean tissues to fatty acids leads to insulin resistance. Proper dietary fat... more Excessive exposure of lean tissues to fatty acids leads to insulin resistance. Proper dietary fatty acids (DFA) storage in white adipose tissue (WAT) is thought to prevent lean tissue lipotoxicity. We showed that WAT storage of DFA was impaired in IGT (impaired glucose tolerance) and was associated with greater cardiac DFA uptake and subclinical left-ventricular dysfunction. Whether WAT DFA storage directly impacts cardiac DFA uptake in IGT subjects is not known. We aimed at investigating how inhibition of intracellular lipolysis affected WAT DFA storage, spillover, and cardiac DFA uptake. We recruited 23 participants: 12 IGT, 5 women/7 men, aged (mean ± sem) 64±2.5, BMI= 34.9±3.1 kg/m2 and 11 NGT, 7 women/4 men, aged 62±2, BMI= 30.4±1.6 kg/m2. Cardiac DFA uptake and whole-body organ-specific DFA partitioning were assessed using PET/CT method with oral administration of 18FTHA. NEFA appearance and WAT DFA spillover were measured using stable isotope tracer methods. Nicotinic acid (NA) was used to inhibit WAT DFA spillover. In both groups, NA decreased AUC DFA spillover rate (-31%±19, p=0.014) and AUC NEFA appearance rate (-28%±10, p=0.0002). In NGT group, NA decreased muscle and liver DFA distribution by 30%±8 (p=0.007) and 25%±8 (p=0.024), respectively, and increased WAT DFA distribution by 48%±8 (p=0.001). The same trend was observed in IGT group, but with blunted differences in WAT DFA storage vs. NGT (p=0.73). NA-induced increase in visceral WAT DFA distribution was correlated negatively with change in AUC. Nonesterified fatty acids (NEFA) appearance rate (ρ=-0.58, p=0.004). In both groups, NA did not significantly affect cardiac DFA distribution. In both groups, we estimated that DFA spillover may account for 31%±23 of DFA reaching lean organs over a 6-hour period after meals. Inhibition of WAT DFA spillover enhances DFA WAT storage and reduces liver and skeletal muscle, but not cardiac DFA partitioning. Disclosure E. Montastier: None. C. Noll: None. R. Ye: None. M. Amrani: None. F. Frisch: None. M. Fortin: None. L. Bouffard: None. O. Sarrhini: None. S. Phoenix: None. B. Guerin: None. E.E. Turcotte: None. A.C. Carpentier: Advisory Panel; Self; HLS Therapeutics, Inc.

The FASEB Journal, Mar 31, 2016

American Journal of Physiology-endocrinology and Metabolism, Jun 1, 2021

The mechanism of increased postprandial nonesterified fatty acid (NEFA) appearance in the circula... more The mechanism of increased postprandial nonesterified fatty acid (NEFA) appearance in the circulation in impaired glucose tolerance (IGT) is due to increased adipose tissue lipolysis but could also be contributed to by reduced adipose tissue (AT) dietary fatty acid (DFA) trapping and increased "spillover" into the circulation. Thirty-one subjects with IGT (14 women, 17 men) and 29 with normal glucose tolerance (NGT, 15 women, 14 men) underwent a meal test with oral and intravenous palmitate tracers and the oral [ 18 F]-fluoro-thia-heptadecanoic acid positron emission tomography method. Postprandial palmitate appearance (Ra palmitate) was higher in IGT versus NGT (P < 0.001), driven exclusively by Ra palmitate from obesity-associated increase in intracellular lipolysis (P = 0.01), as Ra palmitate from DFA spillover was not different between the groups (P = 0.19) and visceral AT DFA trapping was even higher in IGT versus NGT (P = 0.02). Plasma glycerol appearance was lower in IGT (P = 0.01), driven down by insulin resistance and increased insulin secretion. Thus, we found higher AT DFA trapping, limiting spillover to lean organs and in part offsetting the increase in Ra palmitate from intracellular lipolysis. Whether similar findings occur in frank diabetes, a condition also characterized by insulin resistance but relative insulin deficiency, requires further investigation (Clinicaltrials.gov: NCT04088344, NCT02808182). NEW & NOTEWORTHY We found higher adipose tissue dietary fatty acid trapping, limiting spillover to lean organs, that in part offsets the increase in appearance rate of palmitate from intracellular lipolysis in prediabetes. These results point to the adaptive nature of adipose tissue trapping and dietary fatty acid spillover as a protective mechanism against excess obesity-related palmitate appearance rate from intracellular adipose tissue lipolysis.

Ye et al, "Total postprandial hepatic non-esterified and dietary fatty acid uptake is increased a... more Ye et al, "Total postprandial hepatic non-esterified and dietary fatty acid uptake is increased and insufficiently curbed by adipose tissue fatty acid trapping in prediabetes with overweight" Supplementary methods PET CT analyses Correction for circulating metabolites was performed during the [ 11 C]-palmitate acquisition as described in [24]; however, this did not impact the kinetic model (see Supplemental Figure 4). Baseline PET acquisition was performed prior to [ 11 C]-palmitate acquisition to subtract any Supplemental Material: Ye et al, "Total postprandial hepatic non-esterified and dietary fatty acid uptake is increased and insufficiently curbed by adipose tissue fatty acid trapping in prediabetes with overweight"

The FASEB Journal, Apr 1, 2013

Recent studies examining brown adipose tissue (BAT) metabolism in adult humans have provided conv... more Recent studies examining brown adipose tissue (BAT) metabolism in adult humans have provided convincing evidence that it can significantly contribute to cold‐induced thermogenesis under acute mild‐cold exposure. Although, many mammalian models have demonstrated the adaptability of this tissue through chronic cold exposure, little is known about its plasticity in humans. Using electromyography combined with positron emission tomography with 11C‐acetate and 18F‐fluorodeoxyglucose, shivering intensity and BAT oxidative metabolism and glucose uptake prior to and following four weeks of cold acclimation were examined. Non‐acclimated men were exposed to 10°C, two hours daily for four weeks (5 days/week), using a liquid‐conditioned suit (LCS). Preliminary data suggests a 5‐fold increase in BAT oxidative metabolism (from 0.005±0.004to 0.025±0.007 sec−1, n=3) resulting in a ~40% decrease in shivering intensity (from 3.2±1.4 to 2.0±1.3 %MVC, n=3), through four weeks of cold‐acclimation, despite similar 1.8‐fold increases in cold‐induced energy expenditure (10.6±1.4 and 10.3±1.3 kJ·min−1, pre‐and postacclimation, respectively, n=3). Fractional and net glucose uptake in BAT increased 2.2‐fold (from 0.017±0.007 to 0.037±0.015 min−1 and from 81±35 to 183±82 nmol·g−1·min−1) following cold‐acclimation. Our preliminary results demonstrate an increased capacity of BAT‐derived thermogenesis during acute cold exposure after a 4‐week cold acclimation period in healthy men. This research was supported by the Natural Sciences and Engineering Research Council of Canada and the Canadian Diabetes Association (grant OG 3–10‐2970‐AC).

Journal of Nuclear Medicine

Cyclotron production of gallium-68 (68 Ga) is a promising approach to supply 68 Ga radiopharmaceu... more Cyclotron production of gallium-68 (68 Ga) is a promising approach to supply 68 Ga radiopharmaceuticals. To validate this capability, an integrated solution for a robust synthesis of 68 Ga-DOTATATE prepared from cyclotron produced 68 Ga (further on referred to as cyclotron produced 68 Ga-DOTATATE) was achieved. A retrospective comparison analysis was performed in patients who underwent PET/CT imaging after injection of DOTATATE labeled with 68 Ga produced by cyclotron or eluted from a generator to demonstrate the clinical safety and diagnostic efficacy of the radiopharmaceutical for a routine standard-of-care diagnostic tool in clinic. Methods: An enriched zinc-68 pressed target was irradiated by cyclotron with a proton beam set at 12.7 MeV for 100 min. The fully automated process utilizes an in-vault dissolution system where a liquid distribution system transfers the dissolved target to a dedicated hotcell for the purification of 68 GaCl3 and radiolabeling of DOTATATE using a cassette-based automated module. Quality control tests were performed on the resulting tracer solution. The internal radiation dose for 68 Ga-DOTATATE was calculated based on extrapolation from rat biodistribution experiments. A retrospective comparison analysis was performed in patients who underwent PET/CT imaging after injection of DOTATATE labeled with 68 Ga produced by cyclotron or eluted from a generator. Results: The synthesis of 68 Ga-DOTATATE (20.7 ± 1.3 GBq) with high apparent molar activity (518 ± 32 GBq/µmole at end of synthesis (EOS)) was completed in 65 min and the radiopharmaceutical met the requirements specified in the European Pharmacopoeia monograph on Gallium (68 Ga) chloride (accelerator produced) solution for radiolabeling. 68 Ga-DOTATATE was stable for at least 5 h after formulation. The dosimetry calculated with OLINDA for 68 Ga-DOTATATE from cyclotron produced 68 Ga and generator eluted 68 Ga was roughly equivalent. The SUVmean or SUVmax of tumoral lesions with cyclotron produced 68 Ga-DOTATATE was equivalent to that with generator-eluted 68 Ga. Among physiological uptakes, a significant difference was found in kidneys, spleen and stomach wall, with lower values in cyclotron produced 68 Ga-DOTATATE in all cases. Conclusion: Integrated cyclotron production achieves reliable high yields of clinical-grade 68 Ga-DOTATATE. The clinical safety, and imaging efficacy of cyclotron produced 68 Ga-DOTATATE in humans provide supporting evidence for its use in routine clinical practice.

Diabetes, 2018

Postprandial dietary fatty acid (FA) biodistribution is impaired in subjects with glucose intoler... more Postprandial dietary fatty acid (FA) biodistribution is impaired in subjects with glucose intolerance, with decreased FA storage in adipose tissues (AT) and increased FA uptake by the myocardium. These abnormalities are improved after 1 year of lifestyle-induced weight loss. Bariatric surgery leads to early metabolic improvements before weight loss, but the early effects on dietary FA metabolism and biodistribution have never been studied. 9 subjects with T2D underwent a 6-hour postprandial metabolic protocol before and 12 days after SG. A liquid meal containing [U-13C]-palmitate and [2H]-glucose was ingested at time 0, with an IV perfusion of [3H]-glucose and [7,7,8,8-2H]-palmitate, allowing quantification of glucose absorption, endogenous glucose production (EGP), lipolysis and dietary FA spillover. A capsule containing a positron-emitting long-chain FA analog (18FTHA) was taken with the meal for the quantification of organ-specific dietary FA uptake using PET/CT (n=6). Twelve day...

Clinical Lipidology, 2015

Abstract The presence of brown adipose tissue (BAT) in adult humans has been rediscovered through... more Abstract The presence of brown adipose tissue (BAT) in adult humans has been rediscovered through the clinical use of the radioactive glucose analog 18F-fluorodeoxyglucose with PET. This has led to numerous studies demonstrating cold exposure as the major physiological modulator of BAT activity. These reports also suggested that age, gender, BMI and the presence of diabetes are also important modulators of BAT volume and metabolic activity. Although 18F-fluorodeoxyglucose PET has provided important information on BAT glucose metabolism, other techniques are being developed and applied to assess other aspects of BAT metabolism. Here, we summarize the current understanding of the pathophysiological functions of BAT in humans and discuss some of the strengths and limitations of the current investigational techniques.

The Journal of Clinical Endocrinology & Metabolism, 2011

Context: In humans, the prevalence, mass, and glucose-uptake activity of 18F-fluorodeoxyglucose (... more Context: In humans, the prevalence, mass, and glucose-uptake activity of 18F-fluorodeoxyglucose (18F-FDG)-detected brown adipose tissue (BAT), which are expectedly enhanced by a cold stimulus, also appear modulated by other factors that still have to be disentangled. Objective: The objective of the study was to investigate the factors determining the prevalence, mass, and glucose-uptake activity of 18F-FDG-detected BAT in humans. Research Design and Methods: We retrospectively analyzed all 18F-FDG positron emission tomography/computed tomography examinations performed between January 2007 and December 2008 at our institution for 18F-FDG uptake within the cervical/supraclavicular, mediastinal, paravertebral, and perirenal fat areas. The influence of outdoor temperature, sex, age, body mass index (BMI), plasma glucose level, diabetes diagnosis, day length, and cancer status on the prevalence, mass, and glucose-uptake activity of 18F-FDG-detected BAT depots was investigated. Results: T...

Diabetes & Metabolism, 2013

Objectif : Les effets hypophagiques des antagonistes sélectifs du récepteur aux endocannabinoïdes... more Objectif : Les effets hypophagiques des antagonistes sélectifs du récepteur aux endocannabinoïdes CB1 (CB1R) sont attribués à des mécanismes centraux notamment hypothalamiques. On trouve aussi des CB1Rs sur les fibres nerveuses innervant le tractus gastro-intestinal. En induisant un signal glucose portal, la néoglucogenèse intestinale (NGI) induit la satiété et potentialise la suppression de la production hépatique de glucose par l'insuline. Nous avons émis l'hypothèse que les CB1Rs périphériques pourraient initier un circuit nerveux intestin-cerveau-foie par induction de la NGI. Matériels et méthodes : Des rats vigiles sont perfusés dans la veine porte pendant 8 h par un antagoniste des CB1Rs semblable au Rimonabant (AM251). Leur prise alimentaire est étudiée. Après euthanasie, leur néoglucogenèse intestinale et hépatique est quantifiée. Un marquage c-fos des noyaux hypothalamiques et des relais centraux des voies spinales et vagales a été également réalisé. Résultats : L'activité de la glucose-6 phosphatase (G6Pase) intestinale est augmentée par l'AM251 (44,3 ± 4,0 U/g de protéines vs 18,9 ± 4,3 U/g avec le véhicule ; p < 0,01; n = 6). La phosphoénolpyruvate carboxykinase est également augmentée. Au contraire, l'activité G6Pase hépatique est diminuée par l'AM251 (41,3 ± 3,2 U/g de protéines vs 70,3 ± 7,8 U/g avec le véhicule ; p < 0,05; n = 6). La perfusion de l'AM251 est associée à une diminution de la prise alimentaire (0,33 ± 0,33 g vs 4,6 ± 1,1 g avec le véhicule ; p < 0,01; n = 6). On constate une activation neuronale des centres de satiété ainsi que des relais centraux des voies spinale et vagale en réponse à l'inhibition des CB1Rs portaux. L'ensemble de ces effets est aboli par dénervation portale (capsaïcine). Discussion : Cette étude suggère que l'inhibition des CB1Rs portaux par un antagoniste sélectif induirait la NGI et produirait ainsi ses effets bénéfiques sur la prise alimentaire et l'homéostasie glucidique au niveau hépatique. Le système nerveux portal serait essentiel dans l'initiation de ce circuit nerveux intestin-cerveau-foie. O84 Glycogénose de type 1a et diabète : un mécanisme commun de dysfonctionnement rénal

The Journal of Nuclear Medicine, May 1, 2020

Molecular Imaging and Biology, Jul 22, 2020

Purpose: A retrospective analysis was performed of preclinical and clinical data acquired during ... more Purpose: A retrospective analysis was performed of preclinical and clinical data acquired during the evaluation of the estrogen receptor (ER) PET tracer 4-fluoro-11β-methoxy-16α-[ 18 F]fluoroestradiol (4FMFES) and its comparison with 16α-[ 18 F]-fluoroestradiol (FES) in mice, rats and humans with a focus on the brain uptake. Procedures: Breast cancer tumor-bearing female BALB/c mice from a previous study and female Sprague-Dawley rats (control and ovariectomized) were imaged by 4FMFES or FES-PET imaging. Immediately after, low-dose CT was performed in the same bed position. Semiquantitative analysis was conducted to extract %ID/g data. Small cohorts of mice and rats were imaged with 4FMFES in an ultra-high-resolution small animal PET scanner prototype (LabPET II). Rat brains were dissected and imaged separately with both PET and autoradiography. In parallel, 31 breast cancer patients were enrolled in a clinical phase II study to compare 4FMFES with FES for oncological assessment. Since the head was included in the field-of-view, brain uptake of discernable foci was measured and reported as SUV Max. Results: Regardless of the species studied, 4FMFES and FES uptake was relatively uniform in most regions of the brain, except for bilateral foci at the base of the skull, at the midsection of the brain. Anatomical localization of the PET signal using CT image fusion indicates that the signal origins from the pituitary in all studied species. 4FMFES yielded lower pituitary uptake than FES in patients, but an inverse trend was observed in rodents. 4FMFES pituitary contrast was higher than FES in all assessed groups. High-resolution small animal imaging of the brain of rats and mice revealed a supplemental signal anterior to the pituitary, which is likely to be the medial

medRxiv (Cold Spring Harbor Laboratory), Mar 28, 2023

doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by pee... more doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

Alzheimers & Dementia, Jul 1, 2014

Background:Beta-amyloid (A b) deposition occurs years before the onset of Alzheimer’s disease (AD... more Background:Beta-amyloid (A b) deposition occurs years before the onset of Alzheimer’s disease (AD) dementia, but its relation to grey matter (GM) changes and FDG-PET metabolism in the pre-dementia stages remains unclear. Here we examined the effect of abnormally high A b on the regional rates of GM and FDG-PET change separately, and assessed the joint spatial variations across both modalities over 3 years. Methods: Forty cognitively healthy (HC) and fifty-three mildly impaired (MCI) adults underwent annual MRI and FDG-PET imaging for three years within the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Based on CSF A b 1-42 and global brain amyloid-PET (Av-45 and PiB-PET), the HC and MCI subjects were dichotomized into groups with high (A b +) and low (A b -) amyloid burden, according to pre-established criteria. Voxel-wise rates of change in GM, FDG-PET and atrophy-corrected FDGPET were estimated for each subject. In voxel-wise analyses, the rates of change in each modality were compared between groups, controlling for age, gender, years of education and ApoE genotype. In joint independent component analysis (jICA) the patterns of covariance in the change across modalities were assessed. Results: HC A b + subjects showed faster rates of GM atrophy in the medial parietal lobe (MPL) and medial temporal lobe (MTL) when compared to HC A b -. No differences in the FDGPET rates of change were found. For MCIs, A b + subjects showed faster rates of GM atrophy than A b in the MTL, MPL, frontal and temporal lobes. Faster decline in FDG-PET metabolism was found throughout the forebrain, but not within the MTL. After correcting for atrophy, MCI A b + showed increasing FDG-PET metabolism within the MTL when compared to MCI A b (Figure). The jICA analysis assessing covarying changes between modalities showed higher rates of decline in both FDGPET and GM. However, after atrophy correction, decreasing GM volume was associated with increasing FDG-PET. Conclusions: At the pre-symptomatic stages of AD, A b-related changes in GM volume are apparent primarily within medial temporo-parietal regions. At the mild symptomatic stage, atrophy spreads to adjacent regions and is accompanied by FDG-PET decline in cortical areas. The A b -associated increase in FDG-PET after atrophy correction within the MTL suggests the existence of compensatory mechanisms in MCI. IC-P-115 BRAIN FUEL CONSUMPTION IN MILD ALZHEIMER’S DISEASE (AD): COMPARISON OF GLUCOSE AND KETONES USING PET IMAGING

The Journal of Nuclear Medicine, May 1, 2020

411 Objectives: Quantitative SPECT (QSPECT)/CT is increasingly used in 177Lu theranostics. Beside... more 411 Objectives: Quantitative SPECT (QSPECT)/CT is increasingly used in 177Lu theranostics. Beside dosimetry, QSPECT/CT enables real-time therapeutic response assessment that is potentially predictive of longer-term response, such as molecular imaging response assessed with 68Ga-PET/CT, for which we previously proposed the Theranostic Response Criteria In Solid Tumors (THERCIST) based on molecular tumor volume (MTV). Our aim was to assess if an early decrease in total lesion fraction (TLF: total lesion activity divided by body weight, expressed in percentage of injected activity) on QSPECT during peptide receptor radionuclide therapy (PRRT) predicted an objective response on post-treatment 68Ga-PET/CT. Methods: 32 consecutive patients with neuroendocrine tumor who underwent 68Ga-octreotate-PET/CTs within 4 months prior to and after a personalized, dosimetry-based 177Lu-octreotate PRRT induction course were included. A threshold of 25% of the SUVpeak was used for tumor segmentation. The 177Lu-QSPECT/CTs performed 3 days after the first and second 177Lu-octreotate administrations were compared. An early response was defined as a decrease in TLF of 30% or more. Pre- and post-PRRT 68Ga-PET/CTs were compared according to THERCIST: CMR (complete molecular response): disappearance of all lesions; PMR (partial molecular response): ≥50% decrease in tumor burden; SMD (stable molecular disease): <50% variation in tumor burden; PMD (progressive molecular disease): ≥50% increase in tumor burden. Late PET response was correlated to early QSPECT response, and the predictive performance of the latter was assessed. Results: 10 (31%) patients were identified as early responders and 22 (69%) as non-early responders based on QSPECT. The final PET molecular imaging outcome was PMR in 9 (28%) and non-PMR in 23 patients (72%; SMD in 21 and PMD in 2). The late PET response was significantly correlated with the early QSPECT response (Figure; r=0.56, P=0.0009). An early response on QSPECT predicted a PMR with a sensitivity, specificity, positive and negative predictive values and accuracy of 67%, 83%, 60%, 86% and 78%, respectively (P=0.0126). An early QSPECT response at cycle 2, i.e. only 2 mo. after PRRT initiation, conferred a likelihood ratio of 3.8 to obtain a PMR after the induction course completion. Of note, 19 (83%) of patients who failed to demonstrate an early decrease in TLF did not experience a PMR (17 SMD; 2 PMD). Conclusion: QSPECT response 2 mo. after PRRT initiation is an early predictor of objective response to PRRT. As such, early QSPECT response represents a novel imaging biomarker of radiosensitivity and tumor biology, which could be useful to prospectively tailor a precision PRRT regimen, e.g. treatment escalation to maximize debulking or de-escalation to avoid toxicity, in radiosensitive and radioresistant neuroendocrine tumors, respectively. Research Support: Scholarship from Fonds de recherche du Quebec - Sante to JMB.

Physiology

Background: We previously revealed that oral administration of the β3-adrenergic receptor (AR) ag... more Background: We previously revealed that oral administration of the β3-adrenergic receptor (AR) agonist mirabegron only elicited small increases in brown adipose tissue (BAT) thermogenesis when ingested at the maximal allowable dose (200 mg). This led to off-target binding of the β1- and β2-AR, thereby increasing cardiovascular responses and white adipose tissue lipolysis, respectively. We hypothesize that a balanced activation between β1- and β3-AR is key to stimulating metabolic benefits without cardiovascular side effects. Method: We performed a randomized crossover trial in 8 lean men over two study days. The intervention consisted of oral administration of mirabegron (200 mg) with or without the cardio selective β1-AR antagonist bisoprolol (10 mg). Dynamic [11C]-acetate and 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) PET/CT scans were performed sequentially starting at 210 min after oral administration of mirabegron ± bisoprolol. Results: Compared to baselines measures, mirabegro...

Journal of Nuclear Medicine, 2021

In this study, the preliminary results of a phase II clinical trial investigating the use of the ... more In this study, the preliminary results of a phase II clinical trial investigating the use of the Estrogen Receptor (ER) targeting PET tracer 4-fluoro-11β-methoxy-16α-[ 18 F]fluoroestradiol (18F-4FMFES) and [ 18 F]-fluorodeoxyglucose (18F-FDG)-PET in endometrial cancers will be accounted. In parallel, non-invasive interventions will be attempted to slow down progression of 18F-4FMFES metabolites in the intestines to reduce abdominal background. Methods: In an ongoing study, 25 patients that received prior pathological confirmation of an ER+ endometrial cancer or endometrial intraepithelial neoplasia agreed to participate to the ongoing clinical trial. Patients were scheduled for 18F-FDG and 18F-4FMFES PET/CT imaging in random order and within 2 weeks. Patients were administered either 4 mg loperamide per os before 18F-4FMFES tracer injection or repeated intravenous injection of 20 mg hyoscine Nbutylbromide during 18F-4FMFES-PET/CT. Regions-of-interest (ROIs) covering the whole abdomen and excluding the liver, bladder and uterus were drawn for the 18F-4FMFES-PET images, and a threshold of SUV > 4 was applied. The volume of the resulting region was compared between the different interventions to estimate the extent of the intestinal background. Results: Repeated injection of hyoscine N-butylbromide substantially reduced the intestinal background volume, whereas loperamide had a significant but moderate effect. 18F-4FMFES tumor uptake ranged between SUV Max 3.0 and 14.4 (9.4 ± 3.2), whereas 18F-FDG uptake spreaded between SUV Max 0 and 22.0 (7.5 ± 5.1). Tumor-to-background ratio were significantly higher for 18F-4FMFES (16.4 ± 5.4) than for 18F-FDG (7.4 ± 4.6). Significant differences were observed between grade 1 and higher-grade tumors concerning 18F-4FMFES uptake and contrast. 18F-FDG uptake, and the 18F-FDG/18F-4FMFES uptake ratio. Conclusions: It is possible to improve 18F-4FMFES abdominal background using hyoscine Nbutylbromide. Both 18F-FDG and 18F-4FMFES-PET are suitable for detection of ER+ endometrial cancers, although 18F-4FMFES yielded a better tumor contrast than 18F-FDG.

The Journal of Nuclear Medicine, 2015

Cell Metabolism, 2020

Highlights d A therapeutic dose (50 mg) of mirabegron does not stimulate human BAT thermogenesis ... more Highlights d A therapeutic dose (50 mg) of mirabegron does not stimulate human BAT thermogenesis d Human brown adipocytes lack b 3-AR and do not respond to mirabegron in vitro d Norepinephrine-induced respiration is driven by b 2-AR, which co-localizes with UCP1 d b 2-AR is the main target for pharmacological activation of human brown adipocytes

Diabetes, 2020

Excessive exposure of lean tissues to fatty acids leads to insulin resistance. Proper dietary fat... more Excessive exposure of lean tissues to fatty acids leads to insulin resistance. Proper dietary fatty acids (DFA) storage in white adipose tissue (WAT) is thought to prevent lean tissue lipotoxicity. We showed that WAT storage of DFA was impaired in IGT (impaired glucose tolerance) and was associated with greater cardiac DFA uptake and subclinical left-ventricular dysfunction. Whether WAT DFA storage directly impacts cardiac DFA uptake in IGT subjects is not known. We aimed at investigating how inhibition of intracellular lipolysis affected WAT DFA storage, spillover, and cardiac DFA uptake. We recruited 23 participants: 12 IGT, 5 women/7 men, aged (mean ± sem) 64±2.5, BMI= 34.9±3.1 kg/m2 and 11 NGT, 7 women/4 men, aged 62±2, BMI= 30.4±1.6 kg/m2. Cardiac DFA uptake and whole-body organ-specific DFA partitioning were assessed using PET/CT method with oral administration of 18FTHA. NEFA appearance and WAT DFA spillover were measured using stable isotope tracer methods. Nicotinic acid (NA) was used to inhibit WAT DFA spillover. In both groups, NA decreased AUC DFA spillover rate (-31%±19, p=0.014) and AUC NEFA appearance rate (-28%±10, p=0.0002). In NGT group, NA decreased muscle and liver DFA distribution by 30%±8 (p=0.007) and 25%±8 (p=0.024), respectively, and increased WAT DFA distribution by 48%±8 (p=0.001). The same trend was observed in IGT group, but with blunted differences in WAT DFA storage vs. NGT (p=0.73). NA-induced increase in visceral WAT DFA distribution was correlated negatively with change in AUC. Nonesterified fatty acids (NEFA) appearance rate (ρ=-0.58, p=0.004). In both groups, NA did not significantly affect cardiac DFA distribution. In both groups, we estimated that DFA spillover may account for 31%±23 of DFA reaching lean organs over a 6-hour period after meals. Inhibition of WAT DFA spillover enhances DFA WAT storage and reduces liver and skeletal muscle, but not cardiac DFA partitioning. Disclosure E. Montastier: None. C. Noll: None. R. Ye: None. M. Amrani: None. F. Frisch: None. M. Fortin: None. L. Bouffard: None. O. Sarrhini: None. S. Phoenix: None. B. Guerin: None. E.E. Turcotte: None. A.C. Carpentier: Advisory Panel; Self; HLS Therapeutics, Inc.