Elevated blood branched-chain amino acids (BCAA) are often associated with insulin resistance and type 2 diabetes, which might result from a reduced cellular utilization and/or incomplete BCAA oxidation. White adipose tissue (WAT) has become appreciated as a potential player in whole body BCAA metabolism. We tested if expression of the mitochondrial BCAA oxidation checkpoint, branched-chain ␣-ketoacid dehydrogenase (BCKD) complex, is reduced in obese WAT and regulated by metabolic signals. WAT BCKD protein (E1␣ subunit) was significantly reduced by 35-50% in various obesity models (fa/fa rats, db/db mice, diet-induced obese mice), and BCKD component transcripts significantly lower in subcutaneous (SC) adipocytes from obese vs. lean Pima Indians. Treatment of 3T3-L1 adipocytes or mice with peroxisome proliferatoractivated receptor-␥ agonists increased WAT BCAA catabolism enzyme mRNAs, whereas the nonmetabolizable glucose analog 2-deoxy-D-glucose had the opposite effect. The results support the hypothesis that suboptimal insulin action and/or perturbed metabolic signals in WAT, as would be seen with insulin resistance/type 2 diabetes, could impair WAT BCAA utilization. However, cross-tissue flux studies comparing lean vs. insulin-sensitive or insulin-resistant obese subjects revealed an unexpected negligible uptake of BCAA from human abdominal SC WAT. This suggests that SC WAT may not be an important contributor to blood BCAA phenotypes associated with insulin resistance in the overnight-fasted state. mRNA abundances for BCAA catabolic enzymes were markedly reduced in omental (but not SC) WAT of obese persons with metabolic syndrome compared with weight-matched healthy obese subjects, raising the possibility that visceral WAT contributes to the BCAA metabolic phenotype of metabolically compromised individuals. bariatric; diabetes; hyperinsulinemia; mammalian target of rapamycin; protein IN THE SEARCH FOR BIOMARKERS that associate with or predict type 2 diabetes mellitus (T2DM), it has become appreciated that circulating concentrations of the branched-chain amino acids (BCAA; valine, leucine, isoleucine) are often increased in obese, insulin-resistant states and in T2DM. Higher fasting plasma BCAA concentrations were initially reported in obese subjects by Adibi and by Felig et al. (2,12). Recent metabolomic studies found that plasma concentrations of BCAAs and large neutral amino acids are negatively correlated with insulin sensitivity in overweight and obese subjects (24), whereas the principal component that differentiated lean and obese individuals contained BCAA, methionine, phenylalanine, and tyrosine, with a linear relationship between plasma BCAA and homeostasis model assessment of insulin resistance (HOMA-IR) (36). Plasma concentrations of leucine and valine, as well as the leucine metabolite ␣-ketoisocaproate, were increased in obese female African-American T2DM subjects compared with age-and body mass index (BMI)-matched nondiabetic subjects, and plasma leucine significantly correlated with hemoglobin A ...

plays an important role in the maintenance of white adipose tissue (WAT) architecture and function, and proper ECM remodeling is critical to support WAT malleability to accomodate changes in energy storage needs. Obesity and adipocyte hypertrophy place a strain on the ECM remodeling machinery, which may promote disordered ECM and altered tissue integrity and could promote proinflammatory and cell stress signals. To explore these questions, new methods were developed to quantify omental and subcutaneous WAT tensile strength and WAT collagen content by three-dimensional confocal imaging, using collagen VI knockout mice as a methods validation tool. These methods, combined with comprehensive measurement of WAT ECM proteolytic enzymes, transcript, and blood analyte analyses, were used to identify unique pathophenotypes of metabolic syndrome and type 2 diabetes mellitus in obese women, using multivariate statistical modeling and univariate comparisons with weightmatched healthy obese individuals. In addition to the expected differences in inflammation and glycemic control, approximately 20 ECMrelated factors, including omental tensile strength, collagen, and enzyme transcripts, helped discriminate metabolically compromised obesity. This is consistent with the hypothesis that WAT ECM physiology is intimately linked to metabolic health in obese humans, and the studies provide new tools to explore this relationship. matrix metalloproteinase; bariatric surgery; adipose inflammation; type 2 diabetes mellitus; extracellular matrix WHITE ADIPOSE TISSUE (WAT) is the primary site of energy storage in humans and by its nature must be malleable to respond to changes in energy balance through expansion and contraction. Under healthy conditions, changes in WAT architecture and the extracellular matrix (ECM) are coordinated with alterations in adipocyte size to accommodate fat storage needs. In contrast, sustained excessive energy intake with concomitant development of hypertrophic adipocytes creates a strain on ECM adaptation with pathophysiological consequences such as inflammation and insulin resistance.Adipose transcript abundances of several ECM-related genes were increased in obese compared with nonobese human subjects, including cell adhesion molecules and ECM receptor interaction genes, whereas weight loss after gastric bypass surgery led to decreased expression of these genes (18). Collagen VI is enriched in adipose tissue, and visceral WAT mass is related to increased expression of collagen 6␣3 in humans and in genetically obese mice (21, 38). Some studies have indicated that, at least in severe obesity, WAT fibrosis is more prevalent compared with nonobese individuals and that fibrosis decreases with weight loss (13,14), and this is believed to play a role in obesity-associated inflammation. Genetically obese ob/ob mice deficient in collagen VI (and thus lower fibrosis) fed a high-fat diet have improved glucose tolerance, insulin signaling, and triglyceride disposal with greater adipocyte size along with reduced WAT inf...

The addition of electrocardiographically gated Tc-99m sestamibi SPECT images to the reading of stress and rest perfusion images alone resulted in shifting the final scan interpretations to a more normal designation in patients with a low pretest likelihood of coronary artery disease, and to more abnormal defects consistent with coronary artery disease in patients with known coronary artery disease. The number of "borderline normal" and "borderline abnormal" interpretations are significantly reduced when gated SPECT images are interpreted simultaneously with stress and rest perfusion images.

Serial myocardial imaging with technetium-99m methoxyisobutyl isonitrile (9'Tc-MIBI) has been proposed for evaluating myocardial salvage after reperfusion. To define 'mTc-MIBI uptake before and after reperfusion, 17 open-chest dogs underwent 3 hours of left anterior descending artery occlusion and 3 hours of reperfusion. 9'Tc-MIBI was injected during occlusion (group 1) or after 90 minutes of reperfusion (group 2). Myocardial 99'Tc-MIBI activity was correlated with microsphere flow during occlusion and reperfusion. Anatomic risk area and infarct area were defined by postmortem vital staining and correlated with the perfusion defects defined by analysis of 99mTc-MIBI macroautoradiographs and gamma camera images of myocardial slices. The left ventricle was divided into 96 segments for gamma well counting. Flow and '9"Tc-MIBI activity were normalized to nonischemic values. Myocardial segments were grouped, based on occlusion flow, into zones: severely ischemic (<30% nonischemic), moderately ischemic (>30%o, .60%o nonischemic), mildly ischemic (>60%o, <90%1 nonischemic), and nonischemic (>90%o, < 120% nonischemic). Among dogs injected with "'Tc-MIBI during coronary occlusion (group 1), myocardial 99'Tc-MIBI activity correlated linearly with occlusion flow for both endocardial (r=0.91) and transmural (r=0.91) segments. The risk area defined by '9mTc-MIBI autoradiography (group 1) correlated with the postmortem risk area (p=0.94) but was 29O smaller than the anatomic risk area (p=0.03), reflecting the contribution of collateral flow. Among dogs injected with "'Tc-MIBI after reperfusion (group 2), myocardial 99"Tc-MIBI did not correlate with reperfusion flow in either endocardial or transmural segments. Among group 2 dogs, myocardial 9'Tc-MIBI activity was significantly less than reperfusion flow at the time of injection in the severely ischemic (25 ±5% versus 74±24% nonischemic,p=0.002), moderately ischemic (54±12% versus 96+15% nonischemic, p=0.001), and mildly ischemic (84±6% versus 93±3% nonischemic, p=0.002) zones. The defect area defined by 'mTc-MIBI autoradiography (group 2) correlated very closely with the postmortem infarct area (p=0.98). Thus, the myocardial uptake of 99mTc-MIBI during coronary occlusion correlates with occlusion flow and reflects the "area at risk." When 99mTc-MIBI was given after 90 minutes of reperfusion following 3 hours of coronary occlusion, the myocardial activity was significantly reduced compared with reperfusion flow in both necrotic and perinecrotic regions, reflecting myocardial viability more than the degree of reperfusion. (Circulation 1990;82:1424-1437 T X ahe current management of myocardial infarcinfarction, the extent of myocardial necrosis is detertion focuses on the application of acute mined by the "area at risk," collateral flow, and the interventional reperfusion techniques to duration of coronary occlusion.2 A noninvasive imagreduce myocardial necrosis.1 During myocardial ing technique that could 1) assess the area at risk, 2)

Thus, with adenosine-induced hyperemic flow, both 201Tl and sestamibi significantly underestimated the magnitude of the flow disparity between stenotic and normal perfusion beds. The degree of underestimation was greater for sestamibi. The clinical implication of these experimental findings for vasodilator perfusion imaging remains to be determined, since factors such as greater redistribution and scatter with 201Tl could offset its advantages.