Total Postprandial Hepatic Nonesterified and Dietary Fatty Acid Uptake Is Increased and Insufficiently Curbed by Adipose Tissue Fatty Acid Trapping in Prediabetes With Overweight.

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).

Increased postprandial nonesterified fatty acid efflux from adipose tissue in prediabetes is offset by enhanced dietary fatty acid adipose trapping.

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).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.

Seven-day overfeeding enhances adipose tissue dietary fatty acid storage and decreases myocardial and skeletal muscle dietary fatty acid partitioning in healthy subjects.

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.

Seven-Day Caloric and Saturated Fat Restriction Increases Myocardial Dietary Fatty Acid Partitioning in Impaired Glucose-Tolerant Subjects.

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.

Improved cardiac function and dietary fatty acid metabolism after modest weight loss in subjects with impaired glucose tolerance.

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.

Enalapril increases the local extravasation of macromolecules and nitric oxide synthase in pancreas of the fructose-fed insulin-resistant rat model.

OBJECTIVES: Angiotensin-converting enzyme (ACE) inhibitors have been associated with an increased risk of acute pancreatitis. The pathogenesis of this condition remains unclear, but an activation of the kinin system and a resultant localized angioedema have been implicated in the initial step leading to acute pancreatic damage. The goal of the present study was to explore the impact of ACE inhibition on pancreatic microcirculation and capillary permeability in normal and insulin-resistant rats. METHODS: Chow- or fructose-fed Sprague-Dawley rats were treated with enalapril (dosage, 10 mg.kg.d) or vehicle for 4 weeks before measuring in vivo the extravasation of Evans blue (EB) dye in pancreas. Unanesthetized animals (n = 10-17 per group) were injected with EB 20 mg.kg in the caudal vein 10 minutes before killing, and EB dye was extracted from each pancreas by using formamide. RESULTS: Relative to controls, enalapril-treated animals showed a 5-fold increase in pancreatic extravasation of EB in the fructose-fed rat model (P < 0.001); smaller changes (2-fold) were observed in the chow-fed animals treated with enalapril (P < 0.001). The increase in pancreatic vasopermeability observed with enalapril in the fructose-fed animals was accompanied by a significant increase in total pancreatic nitric oxide synthase (NOS) activity compared to controls (Delta = +128%; P < 0.001). This increase in NOS activity seemed to be solely attributable to an upregulation of the endothelial NOS isoform because only the eNOS immunoreactive mass (as opposed to nNOS) seemed to be increased in the pancreas of these animals. Treatment with enalapril was not associated with any increase in serum amylase concentrations in either animal subgroup. CONCLUSIONS: Enalapril increases capillary permeability (extravasation of macromolecules) in the pancreas of the fructose-fed rat model. This suggests that ACE inhibition upregulates the eNOS isoform locally, increases vasopermeability of the pancreas, and can therefore result in local edema in the fructose-fed insulin-resistant rat model.

Increased extravasation of macromolecules in skeletal muscles of the Zucker rat model.

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.

Rosiglitazone increases extravasation of macromolecules and endothelial nitric oxide synthase in skeletal muscles of the fructose-fed rat model.

Reduced extravasation of macromolecules in skeletal muscle has recently been documented in the fructose-fed rat model, corroborating a hypothesis that a functional obliteration of muscle regional microcirculation might lead to hypertension and restrict access of nutrients and hormones to their target cells. The goal of this study was to assess the impact of a treatment with rosiglitazone on the reduced muscle vasopermeability observed previously in the fructose-fed rat model. Fructose-fed Sprague-Dawley rats were gavaged with rosiglitazone (10 micromol kg(-1) per day; n = 21) or the vehicle only (n = 19) for 3 consecutive weeks before assessing the extravasation of Evans Blue (EB) dye in vivo in distinct muscle groups. Relative to control group, rosiglitazone reduced mean arterial blood pressure (Delta = -16.7%, P < 0.001), plasma insulin (Delta= -39.1%, P < 0.05) and plasma triglyceride (Delta= -32.8 %, P < 0.01) concentrations in a significant manner. Plasma VEGF concentrations were significantly lower in the rosiglitazone-treated animals compared to the control animals (32.7 +/- 0.8 pg ml(-1) versus 46.1 +/- 1.2 pg ml(-1), P < 0.001). While no changes were observed in the lungs or the kidneys, fructose-fed rats treated with rosiglitazone had a 30-50% increase (P < 0.005) in the extravasation of EB regardless of the skeletal muscle group studied (rectus femoris, soleus, gastrocnemius lateralis, vastus lateralis and tibialis cranalis). In homogenates of skeletal muscles (vastus lateralis) of fructose-fed rats, rosiglitazone resulted in a significant increase in NO synthase (NOS) activity (Delta = +41.9 %, P < 0.003) as well as endothelial NOS immunoreactive mass (Delta = +37.8 %, P < 0.01) compared to the control animals. There was no change in the immunoreactive level of the nNOS isoform, the most abundant muscle isoform, or in the immunoreactive levels of VEGF. In conclusion, rosiglitazone appears to restore a vascular dysfunction previously documented in the skeletal muscle microcirculation, as evidenced by improved skeletal muscle vasopermeability and upregulation of the muscle endothelium-NO system in the fructose-fed rat model. These effects on muscle per se might also result in a partial improvement of the insulin resistance phenomenon by improving the distribution of nutrients and insulin to skeletal muscle. This effect appears to be independent of circulating levels of VEGF since changes in plasma concentrations of this permeability factor were lower in the rosiglitazone-treated group.