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Aim: Pharmacological stimulation of human brown adipose tissue (BAT) has been hindered by ineffective activation or undesirable off‐target effects. Oral administration of the maximal allowable dose of mirabegron (200 mg), a β3‐adrenergic receptor (β3‐AR) agonist, has been effective in stimulating BAT thermogenesis and whole‐body energy expenditure. However, this has been accompanied by undesirable cardiovascular effects. Therefore, we hypothesized that combining mirabegron with a β1‐AR antagonist could suppress these unwanted effects and increase the stimulation of the β3‐AR and β2‐AR in BAT. Methods: We performed a randomized crossover trial (NCT04823442) in 8 lean men. Mirabegron (200 mg) was administered orally with or without the β1‐AR antagonist bisoprolol (10 mg). Dynamic [11C]‐acetate and 2‐deoxy‐2‐[18F]fluoro‐d‐glucose PET/CT scans were performed sequentially after oral administration of mirabegron ± bisoprolol. Results: Compared to room temperature, mirabegron alone increased BAT oxidative metabolism (0.84 ± 0.46 vs. 1.79 ± 0.91 min−1, p = 0.0433), but not when combined with bisoprolol. The metabolic rate of glucose in BAT, measured using [18F]FDG PET, was significantly higher with mirabegron than mirabegron with bisoprolol (24 ± 10 vs. 16 ± 8 nmol/g/min, p = 0.0284). Bisoprolol inhibited the mirabegron‐induced increase in systolic blood pressure and heart rate. Conclusion: The administration of bisoprolol decreases the adverse cardiovascular effects of mirabegron. However, the provided dose also blunted the mirabegron‐stimulated increase in BAT lipolysis, thermogenesis, and glucose uptake. The attenuation in BAT blood flow induced by the large dose of bisoprolol may have limited BAT thermogenesis. [ABSTRACT FROM AUTHOR]

In rodents, loss of estradiol (E2) reduces brown adipose tissue (BAT) metabolic activity. Whether E2 impacts BAT activity in women is not known. BAT oxidative metabolism was measured in premenopausal (n = 27; 35 ± 9 yr; body mass index = 26.0 ± 5.3 kg/m2) and postmenopausal (n = 25; 51 ± 8 yr; body mass index = 28.0 ± 5.0 kg/m2) women at room temperature and during acute cold exposure using [11C]acetate with positron emission tomography coupled with computed tomograph. BAT glucose uptake was also measured during acute cold exposure using 2-deoxy-2-[18F]fluoro- d -glucose. To isolate the effects of ovarian hormones from biological aging, measurements were repeated in a subset of premenopausal women (n = 8; 40 ± 4 yr; BMI = 28.0 ± 7.2 kg/m2) after 6 mo of gonadotropin-releasing hormone agonist therapy to suppress ovarian hormones. At room temperature, there was no difference in BAT oxidative metabolism between premenopausal (0.56 ± 0.31 min−1) and postmenopausal women (0.63 ± 0.28 min−1). During cold exposure, BAT oxidative metabolism (1.28 ± 0.85 vs. 0.91 ± 0.63 min−1, P = 0.03) and net BAT glucose uptake (84.4 ± 82.5 vs. 29.7 ± 31.4 nmol·g−1·min−1, P < 0.01) were higher in premenopausal than postmenopausal women. In premenopausal women who underwent gonadotropin-releasing hormone agonist, cold-stimulated BAT oxidative metabolism was reduced to a similar level (from 1.36 ± 0.66 min−1 to 0.91 ± 0.41 min−1) to that observed in postmenopausal women (0.91 ± 0.63 min−1). These results provide the first evidence in humans that reproductive hormones are associated with BAT oxidative metabolism and suggest that BAT may be a target to attenuate age-related reduction in energy expenditure and maintain metabolic health in postmenopausal women. NEW & NOTEWORTHY: In rodents, loss of estrogen reduces brown adipose tissue (BAT) activity. Whether this is true in humans is not known. We found that BAT oxidative metabolism and glucose uptake were lower in postmenopausal compared to premenopausal women. In premenopausal women who underwent ovarian suppression to reduce circulating estrogen, BAT oxidative metabolism was reduced to postmenopausal levels. Thus the loss of ovarian function in women leads to a reduction in BAT metabolic activity independent of age. [ABSTRACT FROM AUTHOR]

Ketones are alternative energy substrates for the heart and kidney but no studies have investigated their metabolism simultaneously in both organs in humans. The present double tracer positron emission tomography (PET) study evaluated the organ distribution and basal kinetic rates of the radiolabeled ketone, 11C-acetoacetate (11C-AcAc), in the heart and kidney compared to 11C-acetate (11C-Ac), which is a well-validated metabolic radiotracer. Both tracers were highly metabolized by the left ventricle and the renal cortex. In the heart, kinetic rates were similar for both tracers. But in the renal cortex, uptake of 11C-Ac was higher compared to 11C-AcAc, while the reverse was observed for the clearance. Interestingly, infusion of 11C-AcAc led to a significantly delayed release of radioactivity in the renal medulla and pelvis, a phenomenon not observed with 11C-Ac. This suggests an equilibrium of 11C-AcAc with the other ketone, 11C-D-beta-hydroxybutyrate, and a different clearance profile. Overall, this suggests that in the kidney, the absorption and metabolism of 11C-AcAc is different compared to 11C-Ac. This dual tracer PET protocol provides the opportunity to explore the relative importance of ketone metabolism in cardiac and renal diseases, and to improve our mechanistic understanding of new metabolic interventions targeting these two organs. [ABSTRACT FROM AUTHOR]

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 [18F]-fluoro-thia-heptadecanoic acid positron emission tomography method. Postprandial palmitate appearance (Rapalmitate) was higher in IGT versus NGT (P < 0.001), driven exclusively by Rapalmitate from obesity-associated increase in intracellular lipolysis (P = 0.01), as Rapalmitate 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 Rapalmitate 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). [ABSTRACT FROM AUTHOR]

Purpose: Determine if dynamic contrast enhanced (DCE) ‐MRI and/or 68 gallium 1,4,7,10‐tetraazacyclododecane N, N′, N″, N‴‐tretraacetic acid (68Ga‐DOTA) positron emission tomography (PET) can assess perfusion in rat brown adipose tissue (BAT). Evaluate changes in perfusion between cold‐stimulated and heat‐inhibited BAT. Determine if the 11C‐acetate pharmacokinetic model can be constrained with perfusion information to improve assessment of BAT oxidative metabolism. Methods: Rats were split into three groups. In group 1 (N = 6), DCE‐MRI with gadobutrol was compared directly to 68Ga‐DOTA PET following exposure to 10 °C for 48 h. 11C‐Acetate PET was also performed to assess oxidation. In group 2 (N = 4), only 68Ga‐DOTA PET was acquired following exposure to 10 °C for 48 h. Finally, in group 3 (N = 10), perfusion was assessed with DCE‐MRI in rats exposed to 10 °C or 30 °C for 48 h, and oxidation was measured with 11C‐acetate. Perfusion was quantified with a two‐compartment pharmacokinetic model, while oxidation was assessed by a four‐compartment model. Results: DCE‐MRI and 68Ga‐DOTA PET provided similar perfusion measures, but a decrease in the perfusion signal was noted with longer imaging sessions. Exposure to 10 °C or 30 °C did not affect the perfusion measures, but the 11C‐acetate signal increased in BAT at 10 °C. Without prior information about blood volume, the 11C‐acetate compartment model overestimated blood volume and underestimated oxidation in 10 °C BAT. Conclusion: Precise assessment of oxidation via 11C‐acetate PET requires prior information about blood volume which can be obtained by DCE‐MRI or 68Ga‐DOTA PET. Since perfusion can change rapidly, simultaneous PET‐MRI would be preferred. [ABSTRACT FROM AUTHOR]

Increased myocardial partitioning of dietary fatty acids (DFA) and decreased left ventricular (LV) function is associated with insulin resistance in prediabetes. We hypothesized that enhanced myocardial DFA partitioning and reduced LV function might be induced concomitantly with reduced insulin sensitivity upon a 7-day hypercaloric (+50% in caloric intake), high-saturated fat (~11%energy), and simple carbohydrates (~54%energy) diet (HIGHCAL) versus an isocaloric diet (ISOCAL) with a moderate amount of saturated fat (~8%energy) and carbohydrates (~50%energy). Thirteen healthy subjects (7 men/6 women) underwent HIGHCAL versus ISOCAL in a randomized crossover design, with organ-specific DFA partitioning and LV function measured using the oral 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid and [11C]acetate positron emission tomography methods at the end of both interventions. HIGHCAL induced a decrease in insulin sensitivity indexes with no significant change in body composition. HIGHCAL led to increased subcutaneous abdominal (+4.2 ± 1.6%, P < 0.04) and thigh (+2.4 ± 1.2%, P < 0.08) adipose tissue storage and reduced cardiac (−0.31 ± 0.11 mean standard uptake value [(SUV), P < 0.03] and skeletal muscle (−0.17 ± 0.08 SUV, P < 0.05) DFA partitioning without change in LV function. We conclude that early increase in adipose tissue DFA storage protects the heart and skeletal muscles from potential deleterious effects of DFA. [ABSTRACT FROM AUTHOR]

The demonstration of metabolically active brown adipose tissue (BAT) in humans primarily using positron emission tomography coupled to computed tomography (PET/CT) with the glucose tracer 18-fluorodeoxyglucose (18FDG) has renewed the interest of the scientific and medical community in the possible role of BAT as a target for the prevention and treatment of obesity and type 2 diabetes (T2D). Here, we offer a comprehensive review of BAT energy metabolism in humans. Considerable advances in methods to measure BAT energy metabolism, including nonesterified fatty acids (NEFA), chylomicron-triglycerides (TG), oxygen, Krebs cycle rate, and intracellular TG have led to very good quantification of energy substrate metabolism per volume of active BAT in vivo. These studies have also shown that intracellular TG are likely the primary energy source of BAT upon activation by cold. Current estimates of BAT's contribution to energy expenditure range at the lower end of what would be potentially clinically relevant if chronically sustained. Yet, 18FDG PET/CT remains the gold-standard defining method to quantify total BAT volume of activity, used to calculate BAT's total energy expenditure. Unfortunately, BAT glucose metabolism better reflects BAT's insulin sensitivity and blood flow. It is now clear that most glucose taken up by BAT does not fuel mitochondrial oxidative metabolism and that BAT glucose uptake can therefore be disconnected from thermogenesis. Furthermore, BAT thermogenesis is efficiently recruited upon repeated cold exposure, doubling to tripling its total oxidative capacity, with reciprocal reduction of muscle thermogenesis. Recent data suggest that total BAT volume may be much larger than the typically observed 50–150 ml with 18FDG PET/CT. Therefore, the current estimates of total BAT thermogenesis, largely relying on total BAT volume using 18FDG PET/CT, may underestimate the true contribution of BAT to total energy expenditure. Quantification of the contribution of BAT to energy expenditure begs for the development of more integrated whole body in vivo methods. [ABSTRACT FROM AUTHOR]

Disordered postprandial metabolism of energy substrates is one of the main defining features of prediabetes and contributes to the development of several chronic diseases associated with obesity, such as type 2 diabetes and cardiovascular diseases. Postprandial energy metabolism has been studied using classical isotopic tracer approaches that are limited by poor access to splanchnic metabolism and highly dynamic and complex exchanges of energy substrates involving multiple organs and systems. Advances in noninvasive molecular imaging modalities, such as PET and MRI/magnetic resonance spectroscopy (MRS), have recently allowed important advances in our understanding of postprandial energy metabolism in humans. The present review describes some of these recent advances, with particular focus on glucose and fatty acid metabolism in the postprandial state, and discusses current gaps in knowledge and new perspectives of application of PET and MRI/MRS for the investigation and treatment of human metabolic diseases. [ABSTRACT FROM AUTHOR]

Summary Indirect evidence from human studies suggests that brown adipose tissue (BAT) thermogenesis is fueled predominantly by fatty acids hydrolyzed from intracellular triglycerides (TGs). However, no direct experimental evidence to support this assumption currently exists in humans. The aim of this study was to determine the role of intracellular TG in BAT thermogenesis, in cold-exposed men. Using positron emission tomography with 11 C-acetate and 18 F-fluorodeoxyglucose, we showed that oral nicotinic acid (NiAc) administration, an inhibitor of intracellular TG lipolysis, suppressed the cold-induced increase in BAT oxidative metabolism and glucose uptake, despite no difference in BAT blood flow. There was a commensurate increase in shivering intensity and shift toward a greater reliance on glycolytic muscle fibers without modifying total heat production. Together, these findings show that intracellular TG lipolysis is critical for BAT thermogenesis and provides experimental evidence for a reciprocal role of BAT thermogenesis and shivering in cold-induced thermogenesis in humans. [ABSTRACT FROM AUTHOR]

Subjects with impaired glucose tolerance (IGT) have increased myocardial partitioning of dietary fatty acids (DFAs) with left ventricular dysfunction, both of which are improved by modest weight loss over 1 year induced by lifestyle changes. Here, we determined the effects of a 7-day hypocaloric diet (-500 kcal/day) low in saturated fat (<7% of energy) (LOWCAL study) versus isocaloric with the usual amount saturated fat (∼10% of energy) diet (ISOCAL) on DFA metabolism in subjects with IGT. Organ-specific DFA partitioning and cardiac and hepatic DFA fractional uptake rates were measured in 15 IGT subjects (7 males/8 females) using the oral 14(R,S)-[18F]-fluoro-6-thia-heptadecanoic acid positron emission tomography method after 7 days of an ISOCAL diet versus a LOWCAL diet using a randomized crossover design. The LOWCAL diet led to reductions in weight and postprandial insulin area under the curve. Myocardial DFA partitioning over 6 h was increased after the LOWCAL diet (2.3 ± 0.1 vs. 1.9 ± 0.2 mean standard uptake value, P < 0.04). However, the early (90-120 min) myocardial DFA fractional uptake was unchanged after the LOWCAL diet (0.055 ± 0.025 vs. 0.046 ± 0.009 min(-1), P = 0.7). Liver DFA partitioning was unchanged, but liver fractional uptake of DFA tended to be increased. Very short-term caloric and saturated fat dietary restrictions do not lead to the same changes in organ-specific DFA metabolism as those associated with weight loss in subjects with IGT. [ABSTRACT FROM AUTHOR]

The present study was designed to investigate the effects of cold on brown adipose tissue (BAT) energy substrate utilization in vivo using the positron emission tomography tracers [18F]fluorodeoxyglucose (glucose uptake), 14(R,S)-[18F]fluoro-6-thiaheptadecanoic acid [nonesterified fatty acid (NEFA) uptake], and [11C]acetate (oxidative activity). The measurements were performed in rats adapted to 27°C, which were acutely subjected to cold (10°C) for 2 and 6 hours, and in rats chronically adapted to 10°C for 21 days, which were returned to 27°C for 2 and 6 hours. Cold exposure (acutely and chronically) led to increases in BAT oxidative activity, which was accompanied by concomitant increases in glucose and NEFA uptake. The increases were particularly high in cold-adapted rats and largely readily reduced by the return to a warm environment. The cold-induced increase in oxidative activity was meaningfully blunted by nicotinic acid, a lipolysis inhibitor, which emphasizes in vivo the key role of intracellular lipid in BAT thermogenesis. The changes in BAT oxidative activity and glucose and NEFA uptakes were paralleled by inductions of genes involved in not only oxidative metabolism but also in energy substrate replenishment (triglyceride and glycogen synthesis). The capacity of BAT for energy substrate replenishment is remarkable. [ABSTRACT FROM AUTHOR]

Using a novel positron emission tomography (PET) method with oral administration of 14(R,S)-[18F]-fluoro-6-thia-heptadecanoic acid (18FTHA), we recently demonstrated that subjects with impaired glucose tolerance (IGT) display an impairment in cardiac function associated with increased myocardial uptake of dietary fatty acids. Here, we determined whether modest weight loss induced by lifestyle changes might improve these cardiac metabolic and functional abnormalities. Nine participants with IGT, enrolled in a one-year lifestyle intervention trial, were invited to undergo determination of organspecific postprandial dietary fatty acids partition using the oral 18FTHA method, and cardiac function and oxidative metabolic index using PET [11C]acetate kinetics with ECG-gated PET ventriculography before and after the intervention. The intervention resulted in significant weight loss and reduction of waist circumference, with reduced postprandial plasma glucose, insulin, and triglycerides excursion. We observed a significant increase in stroke volume, cardiac output, and left ventricular ejection fraction associated with reduced myocardial oxidative metabolic index and fractional dietary fatty acid uptake. Modest weight loss corrects the exaggerated myocardial channeling of dietary fatty acids and improves myocardial energy substrate metabolism and function in IGT subjects. [ABSTRACT FROM AUTHOR]

A noninvasive method to determine postprandial fatty acid tissue partition may elucidate the link between excess dietary fat and type 2 diabetes. We hypothesized that the positron-emitting fatty acid analog 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid (18FTHA) administered orally during a meal would be incorporated into chylomicron triglycerides, allowing determination of interorgan dietary fatty acid uptake. We administered 18FTHA orally at the beginning of a standard liquid meal ingested in nine healthy men. There was no significant 18FTHA uptake in the portal vein and the liver during the 1st hour. Whole body PET/CT acquisition revealed early appearance of 18FTHA in the distal thoracic duct, reaching a peak at time 240 min. 18FTHA mean standard uptake value increased progressively in the liver, heart, quadriceps, and subcutaneous and visceral adipose tissues between time 60 and 240 min. Most circulating 18F activity between time 0 and 360 min was recovered into chylomicron triglycerides. Using Triton WR-1339 treatment in rats that received 18FTHA by gavage, we confirmed that >90% of this tracer reached the circulation as triglycerides. This novel noninvasive method to determine tissue dietary fatty acid distribution in humans should prove useful in the study of the mechanisms leading to lipotoxicity. [ABSTRACT FROM AUTHOR]

OBJECTIVE--Postprandial plasma nonesterified fatty acid (NEFA) appearance is increased in type 2 diabetes. Our objective was to determine whether skeletal muscle uptake of plasma NEFA is abnormal during the postprandial state in type 2 diabetes. RESEARCH DESIGN AND METHODS--Thigh muscle blood flow and oxidative metabolism indexes and NEFA uptake were determined using positron emission tomography coupled with computed tomography (PET/CT) with [11C]acetate and 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid (18FTHA) in seven healthy control subjects (CON) and seven subjects with type 2 diabetes during continuous oral intake of a liquid meal to achieve steady postprandial NEFA levels with insulin infusion to maintain similar plasma glucose levels in both groups. RESULTS--In the postprandial state, plasma NEFA level was higher in type 2 diabetic subjects versus CON (P < 0.01), whereas plasma glucose was at the same level in both groups. Muscle NEFA fractional extraction and blood flow index levels were 56% (P < 0.05) and 24% (P = 0.27) lower in type 2 diabetes, respectively. However, muscle NEFA uptake was similar to that of CON (quadriceps femoris [QF] 1.47 ± 0.23 vs. 1.37 ± 0.24 nmol ⋅ g-1 ⋅ min-1, P = 0.77; biceps femoris [BF] 1.54 ± 0.26 vs. 1.46 ± 0.28 nmol ⋅ g-1 ⋅ min-1, P = 0.85). Muscle oxidative metabolism was similar in both groups. Muscle NEFA fractional extraction and blood flow index were strongly and positively correlated (r = 0.79, P < 0.005). CONCLUSIONS--Postprandial muscle NEFA uptake is normal despite elevated systemic NEFA levels and acute normalization of plasma glucose in type 2 diabetes. Lower postprandial muscle blood flow with resulting reduction in muscle NEFA fractional extraction may explain this phenomenon. [ABSTRACT FROM AUTHOR]

Despite current advances in PET/CT systems, blood sampling still remains the standard method to obtain the radiotracer input function for tracer kinetic modelling. The purpose of this study was to validate the use of image-derived input functions (IDIF) of the carotid and femoral arteries to measure the arterial input function (AIF) in PET imaging. The data were obtained from two different research studies, one using 18F-FDG for brain imaging and the other using 11C-acetate and 18F-fluoro-6-thioheptadecanoic acid (18F-FTHA) in femoral muscles. The method was validated with two phantom systems. First, a static phantom consisting of syringes of different diameters containing radioactivity was used to determine the recovery coefficient (RC) and spill-in factors. Second, a dynamic phantom built to model bolus injection and clearance of tracers was used to establish the correlation between blood sampling, AIF and IDIF. The RC was then applied to the femoral artery data from PET imaging studies with 11C-acetate and 18F-FTHA and to carotid artery data from brain imaging with 18F-FDG. These IDIF data were then compared to actual AIFs from patients. With 11C-acetate, the perfusion index in the femoral muscle was 0.34±0.18 min−1 when estimated from the actual time–activity blood curve, 0.29±0.15 min−1 when estimated from the corrected IDIF, and 0.66±0.41 min−1 when the IDIF data were not corrected for RC. A one-way repeated measures (ANOVA) and Tukey’s test showed a statistically significant difference for the IDIF not corrected for RC ( p<0.0001). With 18F-FTHA there was a strong correlation between Patlak slopes, the plasma to tissue transfer rate calculated using the true plasma radioactivity content and the corrected IDIF for the femoral muscles (vastus lateralis r=0.86, p=0.027; biceps femoris r=0.90, p=0.017). On the other hand, there was no correlation between the values derived using the AIF and those derived using the uncorrected IDIF. Finally, in the brain imaging study with 18F-FDG, the cerebral metabolic rate of glucose (CMRglc) measured using the uncorrected IDIF was consistently overestimated. The CMRglc obtained using blood sampling was 13.1±3.9 mg/100 g per minute and 14.0±5.7 mg/100 g per minute using the corrected IDIF ( r 2=0.90). Correctly obtained, carotid and femoral artery IDIFs can be used as a substitute for AIFs to perform tracer kinetic modelling in skeletal femoral muscles and brain analyses. [ABSTRACT FROM AUTHOR]

The purpose of this study was to determine in vivo myocardial energy metabolism and function in a nutritional model of type 2 diabetes. Wistar rats rendered insulin-resistant and mildly hyperglycemic, hyperinsuline- mic, and hypertriglyceridemic with a high-fructose/high-fat diet over a 6-wk period with injection of a small dose of streptozotocin (HFI-IFS) and control rats were studied using micro-PET (μPET) without or with a euglycemic hyperinsulinemic clamp. During glucose clamp, myocardial metabolic rate of glucose measured with [18F]fluorodeoxyglucose ([18F]FDG) was reduced by ∼81% (P < 0.05), whereas myocardial plasma nonesterifled fatty acid (NEFA) uptake as determined by [18F]fluorothia-6-heptadecanoic acid ([18F]FTHA) was not significantly changed in HFHFS vs. control rats. Myocardial oxidative metabolism as assessed by [11C]acetate and myocardial perfusion index as assessed by [13N]ammonia were similar in both groups, whereas left ventricular ejection fraction as assessed by μPET was reduced by 26% in HFHFS rats (P < 0.05). Without glucose clamp, NEFA uptake was ∼40% lower in HFHFS rats (P < 0.05). However, myocardial uptake of [18F]FTHA administered by gastric gavage was significantly higher in HFHFS rats (P < 0.05). These abnormalities were associated with reduced GIut4 mRNA expression and increased Cd36 mRNA expression and mitochondrial carnitine palmitoyltransferase I activity (P < 0.05). HFHFS rats display type 2 diabetes complicated by left ventricular contractile dysfunction with profound reduction in myocardial glucose utilization, activation of fatty acid metabolic pathways, and preserved myocardial oxidative metabolism, suggesting reduced myocardial metabolic efficiency. In this model, increased myocardial fatty acid exposure likely occurs from circulating triglyceride, but not from circulating plasma NEFA. [ABSTRACT FROM AUTHOR]

The ketone body acetoacetate could be used as an alternate nutrient for the heart, and it also has the potential to improve cardiac function in an ischemic–reperfusion model or reduce the mitochondrial production of oxidative stress involved in cardiotoxicity. In this study, [ 11 C]-acetoacetate was investigated as an early marker of intracellular damage in heart failure. Methods A rat cardiotoxicity heart failure model was induced by doxorubicin, Dox(+). [ 14 C]-Acetoacetate, a non-positron (β −) emitting radiotracer, was used to characterize the arterial blood input function and myocardial mitochondrial uptake. Afterward, [ 11 C]-acetoacetate (β +) myocardial PET images were obtained for kinetic analysis and heart function assessment in control Dox(−) (n = 15) and treated Dox(+) (n = 6) rats. The uptake rate ( K 1 ) and myocardial clearance rate ( k 2 or k mono ) were extracted. Results [ 14 C]-Acetoacetate in the blood was increased in Dox(+), from 2 min post-injection until the last withdrawal point when the heart was harvested, as well as the uptake in the heart and myocardial mitochondria (unpaired t -test, p < 0.05). PET kinetic analysis of [ 11 C]-acetoacetate showed that rate constants K 1 , k 2 and k mono were decreased in Dox(+) ( p < 0.05) combined with a reduction of 24% of the left ventricular ejection fraction ( p < 0.001). Conclusion Radioactive acetoacetate ex vivo analysis [ 14 C], and in vivo kinetic [ 11 C] studies provided evidence that [ 11 C]-acetoacetate can assess heart failure Dox(+). Contrary to myocardial flow reserve (rest–stress protocol), [ 11 C]-acetoacetate can be used to assess reduced kinetic rate constants without requirement of hyperemic stress response. The proposed [ 11 C]-acetoacetate cardiac radiotracer in the investigation of heart disease is novel and paves the way to a potential role for [ 11 C]-acetoacetate in cardiac pathophysiology. [ABSTRACT FROM AUTHOR]

Brown adipose tissue (BAT) is vital for proper thermogenesis during cold exposure in rodents, but until recently its presence in adult humans and its contribution to human metabolism were thought to be minimal or insignificant. Recent studies using PET with 18F-fluorodeoxyglucose (18FDG) have shown the presence of BAT in adult humans. However, whether BAT contributes to cold-induced nonshivering thermogenesis in humans has not been proven. Using PET with 11C-acetate, 18FDG, and 18F-fluoro-thiaheptadecanoic acid (18FTHA), a fatty acid tracer, we have quantified BAT oxidative metabolism and glucose and nonesterified fatty acid (NEFA) turnover in 6 healthy men under controlled cold exposure conditions. All subjects displayed substantial NEFA and glucose uptake upon cold exposure. Furthermore, we demonstrated cold-induced activation of oxidative metabolism in BAT, but not in adjoining skeletal muscles and subcutaneous adipose tissue. This activation was associated with an increase in total energy expenditure. We found an inverse relationship between BAT activity and shivering. We also observed an increase in BAT radio density upon cold exposure, indicating reduced BAT triglyceride content. In sum, our study provides evidence that BAT acts as a nonshivering thermogenesis effector in humans. [ABSTRACT FROM AUTHOR]