Lucie Bouffard

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 organ-specific 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.

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.

OBJECTIVE: Assess whether changes in permeability of the muscle regional microcirculation occur in the obese Zucker rat model. RESEARCH METHODS AND PROCEDURES: Capillary permeability to albumin was assessed in vivo in Zucker rats (n = 15) and lean controls (n = 15) by quantifying the extravasation of albumin-bound Evans Blue (EB) in different organs. Unanaesthetized animals were injected with EB 20 mg/kg in the caudal vein, and EB was extracted by formamide from selected organs collected after exsanguination. RESULTS: Relative to control animals, Zucker rats had higher body weight (Delta = +33%; p < 0.001), plasma triglycerides (Delta = +244%; p < 0.001), and insulin (Delta = +240%; p < 0.001) concentrations. Plasma glucose concentrations were not different between the two groups (p = not significant). Using the EB technique, we showed a 30% to 50% (p < 0.01) increase in the extravasation of EB in the obese rats, regardless of the skeletal muscle group studied. This increase in skeletal muscle vasopermeability was not paralleled by any increase in the expression of the muscle endothelium-nitric oxide (NO) system because the total NO synthase (NOS) activity in skeletal muscle of the obese Zucker rat was significantly lower (p < 0.001), as was the endothelial NOS immunoreactive mass (p < 0.001), compared with lean controls. DISCUSSION: In conclusion, there seems to be dissociation between capillary permeability and local regulation of microcirculation in skeletal muscles of the obese Zucker rat. It is suggested that the increase in skeletal muscle vasopermeability (extravasation of macromolecules) is a compensation for the loss of NO-dependent vasodilation and capillary recruitment noted in this model of obesity and insulin resistance.

Excessive lean tissue uptake of fatty acids (FAs) is important in the development of insulin resistance and may be caused by impaired dietary FA (DFA) storage and/or increased nonesterified FA (NEFA) flux from adipose tissue intracellular lipolysis. Cardiac and hepatic total postprandial FA uptake of NEFA+DFA has, however, never been reported in prediabetes with overweight. In this study, 20 individuals with impaired glucose tolerance (IGT) and 19 participants with normal glucose tolerance (NGT) and normal fasting glucose underwent postprandial studies with whole-body positron emission tomography/computed tomography (PET/CT) with oral [18F]fluoro-thia-heptadecanoic acid and dynamic PET/CT with intravenous [11C]palmitate. Hepatic (97 [range 36-215] mmol/6 h vs. 68 [23-132] mmol/6 h, P = 0.03) but not cardiac (11 [range 4-24] mmol/6 h vs. 8 [3-20] mmol/6 h, P = 0.09) uptake of most sources of postprandial FA (NEFA + DFA uptake) integrated over 6 h was higher in IGT versus NGT. DFA accounted for lower fractions of total cardiac (21% [5-47] vs. 25% [9-39], P = 0.08) and hepatic (19% [6-52] vs. 28% [14-50], P = 0.04) uptake in IGT versus NGT. Increased adipose tissue DFA trapping predicted lower hepatic DFA uptake and was associated with higher total cardiac FA uptake. Hence, enhanced adipose tissue DFA trapping in the face of increased postprandial NEFA flux is insufficient to fully curb increased postprandial lean organ FA uptake in prediabetes with overweight (ClinicalTrials.gov; NCT02808182).

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 (&amp;lt;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 &amp;lt; 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.