Movement of circulating fatty acids (FAs) to parenchymal cells requires their transfer across the endothelial cell (EC) barrier. The multiligand receptor cluster of differentiation 36 (CD36) facilitates tissue FA uptake and is expressed in ECs and parenchymal cells such as myocytes and adipocytes. Whether tissue uptake of FAs is dependent on EC or parenchymal cell CD36, or both, is unknown. Using a cell-specific deletion approach, we show that EC, but not parenchymal cell, CD36 deletion increased fasting plasma FAs and postprandial triglycerides. EC-Cd36–KO mice had reduced uptake of radiolabeled long-chain FAs into heart, skeletal muscle, and brown adipose tissue; these uptake studies were replicated using [¹¹C]palmitate PET scans. High-fat diet–fed EC-CD36–deficient mice had improved glucose tolerance and insulin sensitivity. Both EC and cardiomyocyte (CM) deletion of CD36 reduced heart lipid droplet accumulation after fasting, but CM deletion did not affect heart glucose or FA uptake. Expression in the heart of several genes modulating glucose metabolism and insulin action increased with EC-CD36 deletion but decreased with CM deletion. In conclusion, EC CD36 acts as a gatekeeper for parenchymal cell FA uptake, with important downstream effects on glucose utilization and insulin action.

4-[F-18]fluoro- N -{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}- N -(2-pyridinyl)benzamide, a selective serotonin 1A (5-HT _1A ) molecular imaging probe, was used in conjunction with positron emission tomography (PET) for quantification of 5-HT _1A receptor densities in the living brains of Alzheimer's disease patients (ADs) ( n = 8), subjects with mild cognitive impairment ( n = 6), and controls ( n = 5). ADs had receptor densities significantly decreased in both hippocampi (binding potential: controls 1.62 ± 0.07; ADs 1.18 ± 0.26) and also in raphe nuclei (controls 0.63 ± 0.09; ADs 0.37 ± 0.20). When volume losses are included, 5-HT _1A losses are even more severe (i.e., average mean decreases of 24% in mild cognitive impairment patients and 49% in ADs). A strong correlation of 5-HT _1A receptor decreases in hippocampus with worsening of clinical symptoms (Mini Mental State Exam scores) was also found. Moreover, these decreases in 5-HT _1A receptor measures correlate with decreased glucose utilization as measured with 2-deoxy-2-[F-18]fluoro- d -glucose PET in the brains of ADs (standardized uptake values; globally: controls 0.89 ± 0.04, ADs 0.72 ± 0.04; posterior cingulate gyrus: controls 1.05 ± 0.09, ADs 0.79 ± 0.11). They also inversely correlate with increased neuropathological loads measured with 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile PET in several neocortical regions in the same subjects. The in vivo observations were confirmed independently by in vitro digital autoradiography with 4-[F-18]fluoro- N -{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}- N -(2-pyridinyl)benzamide and 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}-ethylidene)malononitrile on brain tissue specimens from two ADs and three nondemented subjects.

In the diabetic heart, chronic activation of the PPARα pathway drives excessive fatty acid (FA) oxidation, lipid accumulation, reduced glucose utilization, and cardiomyopathy. The related nuclear receptor, PPARβ/δ, is also highly expressed in the heart, yet its function has not been fully delineated. To address its role in myocardial metabolism, we generated transgenic mice with cardiac-specific expression of PPARβ/δ, driven by the myosin heavy chain (MHC-PPARβ/δ mice). In striking contrast to MHC-PPARα mice, MHC-PPARβ/δ mice had increased myocardial glucose utilization, did not accumulate myocardial lipid, and had normal cardiac function. Consistent with these observed metabolic phenotypes, we found that expression of genes involved in cellular FA transport were activated by PPARα but not by PPARβ/δ. Conversely, cardiac glucose transport and glycolytic genes were activated in MHC-PPARβ/δ mice, but repressed in MHC-PPARα mice. In reporter assays, we showed that PPARβ/δ and PPARα exerted differential transcriptional control of the GLUT4 promoter, which may explain the observed isotype-specific effects on glucose uptake. Furthermore, myocardial injury due to ischemia/reperfusion injury was significantly reduced in the MHC-PPARβ/δ mice compared with control or MHC-PPARα mice, consistent with an increased capacity for myocardial glucose utilization. These results demonstrate that PPARα and PPARβ/δ drive distinct cardiac metabolic regulatory programs and identify PPARβ/δ as a potential target for metabolic modulation therapy aimed at cardiac dysfunction caused by diabetes and ischemia.

Radiomics analyses has been proposed to interrogate the biology of tumour as well as to predict/assess response to therapy in vivo. The objective of this work was to assess the sensitivity of radiomics features to noise, resolution, and tumour volume in the context of a co-clinical trial. Triple negative breast cancer (TNBC) patients were recruited into an ongoing co-clinical imaging trial. Sub-typed matched TNBC patient-derived tumour xenografts (PDX) were generated to investigate optimal co-clinical MR radiomic features. The MR imaging protocol included T1-weighed and T2-weighted imaging. To test the sensitivity of radiomics to resolution, PDX were imaged at three different resolutions. Multiple sets of images with varying signal-to-noise ratio (SNR) were generated, and an image independent patch-based method was implemented to measure the noise levels. Forty-eight radiomic features were extracted from manually segmented 2D and 3D segmented tumours and normal tissues of T1- and T2- weighted co-clinical MR images. Sixteen radiomics features were identified as volume dependent and corrected for volume-dependency following normalization. Features from grey-level run-length matrix (GLRLM), grey-level size zone matrix (GLSZM) were identified as most sensitive to noise. Radiomic features Kurtosis and Run-length variance (RLV) from GLSZM were most sensitive to changes in resolution in both T1w and T2w MRI. In general, 3D radiomic features were more robust compared to 2D (single slice) measures, although the former exhibited higher variability between subjects. Tumour volume, noise characteristics, and image resolution significantly impact radiomic analysis in co-clinical studies.

Non-invasive imaging of reactive oxygen species (ROS) in vivo was investigated using a dihydroethidium analog [ ¹⁸ F] 12 as a PET radiotracer. The data shown indicates that [ ¹⁸ F] 12 is a promising PET tracer for non-invasive imaging of ROS in vivo .