Adipocyte hypertrophy associates with in vivo postprandial fatty acid metabolism and adipose single-cell transcriptional dynamics.

Adipocyte hypertrophy is associated with metabolic complications independent of obesity. We aimed to determine: 1) the association between adipocyte size and postprandial fatty acid metabolism; 2) the potential mechanisms driving the obesity-independent, hypertrophy-associated dysmetabolism in vivo and at a single-cell resolution. Tracers with positron emission tomography were used to measure fatty acid metabolism in 40 men and women with normal or impaired glucose tolerance (NCT02808182), and single nuclei RNA-sequencing (snRNA-seq) to determine transcriptional dynamics of subcutaneous adipose tissue (AT) between individuals with AT hypertrophy vs. hyperplasia matched for sex, ethnicity, glucose-tolerance status, BMI, total and percent body fat, and waist circumference. Adipocyte size was associated with high postprandial total cardiac fatty acid uptake and higher visceral AT dietary fatty acid uptake, but lower lean tissue dietary fatty acid uptake. We found major shifts in cell transcriptomal dynamics with AT hypertrophy that were consistent with in vivo metabolic changes.

Reduction in Insulin Uncovers a Novel Effect of VEGFB on Cardiac Substrate Utilization.

BACKGROUND: The heart relies heavily on external fatty acid (FA) for energy production. VEGFB (vascular endothelial growth factor B) has been shown to promote endothelial FA uptake by upregulating FA transporters. However, its impact on LPL (lipoprotein lipase)-mediated lipolysis of lipoproteins, a major source of FA for cardiac use, is unknown. METHODS: VEGFB transgenic (Tg) rats were generated by using the α-myosin heavy chain promoter to drive cardiomyocyte-specific overexpression. To measure coronary LPL activity, Langendorff hearts were perfused with heparin. In vivo positron emission tomography imaging with [18F]-triglyceride-fluoro-6-thia-heptadecanoic acid and [11C]-palmitate was used to determine cardiac FA uptake. Mitochondrial FA oxidation was evaluated by high-resolution respirometry. Streptozotocin was used to induce diabetes, and cardiac function was monitored using echocardiography. RESULTS: In Tg hearts, the vectorial transfer of LPL to the vascular lumen is obstructed, resulting in LPL buildup within cardiomyocytes, an effect likely due to coronary vascular development with its associated augmentation of insulin action. With insulin insufficiency following fasting, VEGFB acted unimpeded to facilitate LPL movement and increase its activity at the coronary lumen. In vivo PET imaging following fasting confirmed that VEGFB induced a greater FA uptake to the heart from circulating lipoproteins as compared with plasma-free FAs. As this was associated with augmented mitochondrial oxidation, lipid accumulation in the heart was prevented. We further examined whether this property of VEGFB on cardiac metabolism could be useful following diabetes and its associated cardiac dysfunction, with attendant loss of metabolic flexibility. In Tg hearts, diabetes inhibited myocyte VEGFB gene expression and protein secretion together with its downstream receptor signaling, effects that could explain its lack of cardioprotection. CONCLUSIONS: Our study highlights the novel role of VEGFB in LPL-derived FA supply and utilization. In diabetes, loss of VEGFB action may contribute toward metabolic inflexibility, lipotoxicity, and development of diabetic cardiomyopathy.

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).

Catechins as a Potential Dietary Supplementation in Prevention of Comorbidities Linked with Down Syndrome.

Plant-derived polyphenols flavonoids are increasingly being recognized for their medicinal potential. These bioactive compounds derived from plants are gaining more interest in ameliorating adverse health risks because of their low toxicity and few side effects. Among them, therapeutic approaches demonstrated the efficacy of catechins, a major group of flavonoids, in reverting several aspects of Down syndrome, the most common genomic disorder that causes intellectual disability. Down syndrome is characterized by increased incidence of developing Alzheimer's disease, obesity, and subsequent metabolic disorders. In this focused review, we examine the main effects of catechins on comorbidities linked with Down syndrome. We also provide evidence of catechin effects on DYRK1A, a dosage-sensitive gene encoding a protein kinase involved in brain defects and metabolic disease associated with Down syndrome.

The transcription factor hepatocyte nuclear factor 4A acts in the intestine to promote white adipose tissue energy storage.

The transcription factor hepatocyte nuclear factor 4 A (HNF4A) controls the metabolic features of several endodermal epithelia. Both HNF4A and HNF4G are redundant in the intestine and it remains unclear whether HNF4A alone controls intestinal lipid metabolism. Here we show that intestinal HNF4A is not required for intestinal lipid metabolism per se, but unexpectedly influences whole-body energy expenditure in diet-induced obesity (DIO). Deletion of intestinal HNF4A caused mice to become DIO-resistant with a preference for fat as an energy substrate and energetic changes in association with white adipose tissue (WAT) beiging. Intestinal HNF4A is crucial for the fat-induced release of glucose-dependent insulinotropic polypeptide (GIP), while the reintroduction of a stabilized GIP analog rescues the DIO resistance phenotype of the mutant mice. Our study provides evidence that intestinal HNF4A plays a non-redundant role in whole-body lipid homeostasis and points to a non-cell-autonomous regulatory circuit for body-fat management.

DeepImageTranslator: A free, user-friendly graphical interface for image translation using deep-learning and its applications in 3D CT image analysis.

The advent of deep-learning has set new standards in an array of image translation applications. At present, the use of these methods often requires computer programming experience. Non-commercial programs with graphical interface usually do not allow users to fully customize their deep-learning pipeline. Therefore, our primary objective is to provide a simple graphical interface that allows researchers with no programming experience to easily create, train, and evaluate custom deep-learning models for image translation. We also aimed to test the applicability of our tool in CT image semantic segmentation and noise reduction. DeepImageTranslator was implemented using the Tkinter library, the standard Python interface to the Tk graphical user interface toolkit; backend computations were implemented using data augmentation packages such as Pillow, Numpy, OpenCV, Augmentor, Tensorflow, and Keras libraries. Convolutional neural networks (CNNs) were trained using DeepImageTranslator. The effects of data augmentation, deep-supervision, and sample size on model accuracy were also systematically assessed. The DeepImageTranslator a simple tool that allows users to customize all aspects of their deep-learning pipeline, including the CNN, training optimizer, loss function, and the types of training image augmentation scheme. We showed that DeepImageTranslator can be used to achieve state-of-the-art accuracy and generalizability in semantic segmentation and noise reduction. Highly accurate 3D segmentation models for body composition can be obtained using training sample sizes as small as 17 images. In conclusion, an open-source deep-learning tool for accurate image translation with a user-friendly graphical interface was presented and evaluated. This standalone software can be downloaded at: https://sourceforge.net/projects/deepimagetranslator/.

Elabela Protects Spontaneously Hypertensive Rats From Hypertension and Cardiorenal Dysfunctions Exacerbated by Dietary High-Salt Intake.

Objectives: Arterial hypertension, when exacerbated by excessive dietary salt intake, worsens the morbidity and mortality rates associated with cardiovascular and renal diseases. Stimulation of the apelinergic system appears to protect against several circulatory system diseases, but it remains unknown if such beneficial effects are conserved in severe hypertension. Therefore, we aimed at determining whether continuous infusion of apelinergic ligands (i.e., Apelin-13 and Elabela) exerted cardiorenal protective effects in spontaneously hypertensive (SHR) rats receiving high-salt diet. Methods: A combination of echocardiography, binding assay, histology, and biochemical approaches were used to investigate the cardiovascular and renal effects of Apelin-13 or Elabela infusion over 6 weeks in SHR fed with normal-salt or high-salt chow. Results: High-salt intake upregulated the cardiac and renal expression of APJ receptor in SHR. Importantly, Elabela was more effective than Apelin-13 in reducing high blood pressure, cardiovascular and renal dysfunctions, fibrosis and hypertrophy in high-salt fed SHR. Unlike Apelin-13, the beneficial effects of Elabela were associated with a counter-regulatory role of the ACE/ACE2/neprilysin axis of the renin-angiotensin-aldosterone system (RAAS) in heart and kidneys of salt-loaded SHR. Interestingly, Elabela also displayed higher affinity for APJ in the presence of high salt concentration and better resistance to RAAS enzymes known to cleave Apelin-13. Conclusion: These findings highlight the protective action of the apelinergic system against salt-induced severe hypertension and cardiorenal failure. As compared with Apelin-13, Elabela displays superior pharmacodynamic and pharmacokinetic properties that warrant further investigation of its therapeutic use in cardiovascular and kidney diseases.

IGFBP-2 partly mediates the early metabolic improvements caused by bariatric surgery.

Insulin-like growth factor-binding protein (IGFBP)-2 is a circulating biomarker of cardiometabolic health. Here, we report that circulating IGFBP-2 concentrations robustly increase after different bariatric procedures in humans, reaching higher levels after biliopancreatic diversion with duodenal switch (BPD-DS) than after Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG). This increase is closely associated with insulin sensitization. In mice and rats, BPD-DS and RYGB operations also increase circulating IGFBP-2 levels, which are not affected by SG or caloric restriction. In mice, Igfbp2 deficiency significantly impairs surgery-induced loss in adiposity and early improvement in insulin sensitivity but does not affect long-term enhancement in glucose homeostasis. This study demonstrates that the modulation of circulating IGFBP-2 may play a role in the early improvement of insulin sensitivity and loss of adiposity brought about by bariatric surgery.

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.

Contribution of perfusion to the 11 C-acetate signal in brown adipose tissue assessed by DCE-MRI and 68 Ga-DOTA PET in a rat model.

PURPOSE: Determine if dynamic contrast enhanced (DCE) -MRI and/or 68 gallium 1,4,7,10-tetraazacyclododecane N, N', N″, N‴-tretraacetic acid (68 Ga-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 11 C-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 68 Ga-DOTA PET following exposure to 10 °C for 48 h. 11 C-Acetate PET was also performed to assess oxidation. In group 2 (N = 4), only 68 Ga-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 11 C-acetate. Perfusion was quantified with a two-compartment pharmacokinetic model, while oxidation was assessed by a four-compartment model. RESULTS: DCE-MRI and 68 Ga-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 11 C-acetate signal increased in BAT at 10 °C. Without prior information about blood volume, the 11 C-acetate compartment model overestimated blood volume and underestimated oxidation in 10 °C BAT. CONCLUSION: Precise assessment of oxidation via 11 C-acetate PET requires prior information about blood volume which can be obtained by DCE-MRI or 68 Ga-DOTA PET. Since perfusion can change rapidly, simultaneous PET-MRI would be preferred.

Adipose ABHD6 regulates tolerance to cold and thermogenic programs.

Enhanced energy expenditure in brown (BAT) and white adipose tissues (WAT) can be therapeutic against metabolic diseases. We examined the thermogenic role of adipose α/ß-hydrolase domain 6 (ABHD6), which hydrolyzes monoacylglycerol (MAG), by employing adipose-specific ABHD6-KO mice. Control and KO mice showed similar phenotypes at room temperature and thermoneutral conditions. However, KO mice were resistant to hypothermia, which can be accounted for by the simultaneously increased lipolysis and lipogenesis of the thermogenic glycerolipid/free fatty acid (GL/FFA) cycle in visceral fat, despite unaltered uncoupling protein 1 expression. Upon cold stress, nuclear 2-MAG levels increased in visceral WAT of the KO mice. Evidence is provided that 2-MAG causes activation of PPARα in white adipocytes, leading to elevated expression and activity of GL/FFA cycle enzymes. In the ABHD6-ablated BAT, glucose and oxidative metabolism were elevated upon cold induction, without changes in GL/FFA cycle and lipid turnover. Moreover, response to in vivo ß3-adrenergic stimulation was comparable between KO and control mice. Our data reveal a MAG/PPARα/GL/FFA cycling metabolic signaling network in visceral adipose tissue, which contributes to cold tolerance, and that adipose ABHD6 is a negative modulator of adaptive thermogenesis.

14-3-3ζ mediates an alternative, non-thermogenic mechanism in male mice to reduce heat loss and improve cold tolerance.

OBJECTIVE: Adaptive thermogenesis, which is partly mediated by sympathetic input on brown adipose tissue (BAT), is a mechanism of heat production that confers protection against prolonged cold exposure. Various endogenous stimuli, for example, norepinephrine and FGF-21, can also promote the conversion of inguinal white adipocytes to beige adipocytes, which may represent a secondary cell type that contributes to adaptive thermogenesis. We previously identified an essential role of the molecular scaffold 14-3-3ζ in adipogenesis, but one of the earliest, identified functions of 14-3-3ζ is its regulatory effects on the activity of tyrosine hydroxylase, the rate-limiting enzyme in the synthesis of norepinephrine. Herein, we examined whether 14-3-3ζ could influence adaptive thermogenesis via actions on BAT activation or the beiging of white adipocytes. METHODS: Transgenic mice over-expressing a TAP-tagged human 14-3-3ζ molecule or heterozygous mice without one allele of Ywhaz, the gene encoding 14-3-3ζ, were used to explore the contribution of 14-3-3ζ to acute (3 h) and prolonged (3 days) cold (4 °C) exposure. Metabolic caging experiments, PET-CT imaging, and laser Doppler imaging were used to determine the effect of 14-3-3ζ over-expression on thermogenic and vasoconstrictive mechanisms in response to cold. RESULTS: Transgenic over-expression of 14-3-3ζ (TAP) in male mice significantly improved tolerance to acute and prolonged cold. In response to cold, body temperatures in TAP mice did not decrease to the same extent when compared to wildtype (WT) mice, and this was associated with increased UCP1 expression in beige inguinal white tissue (iWAT) and BAT. Of note was the paradoxical finding that cold-induced changes in body temperatures of TAP mice were associated with significantly decreased energy expenditure. The marked improvements in tolerance to prolonged cold were not due to changes in sensitivity to ß-adrenergic stimulation or BAT or iWAT oxidative metabolism; instead, over-expression of 14-3-3ζ significantly decreased thermal conductance and heat loss in mice via increased peripheral vasoconstriction. CONCLUSIONS: Despite being associated with elevations in cold-induced UCP1 expression in brown or beige adipocytes, these findings suggest that 14-3-3ζ regulates an alternative, non-thermogenic mechanism via vasoconstriction to minimize heat loss during cold exposure.

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.

Bariatric Surgery Rapidly Decreases Cardiac Dietary Fatty Acid Partitioning and Hepatic Insulin Resistance Through Increased Intra-abdominal Adipose Tissue Storage and Reduced Spillover in Type 2 Diabetes.

Reduced storage of dietary fatty acids (DFAs) in abdominal adipose tissues with enhanced cardiac partitioning has been shown in subjects with type 2 diabetes (T2D) and prediabetes. We measured DFA metabolism and organ partitioning using positron emission tomography with oral and intravenous long-chain fatty acid and glucose tracers during a standard liquid meal in 12 obese subjects with T2D before and 8-12 days after bariatric surgery (sleeve gastrectomy or sleeve gastrectomy and biliopancreatic diversion with duodenal switch). Bariatric surgery reduced cardiac DFA uptake from a median (standard uptake value [SUV]) 1.75 (interquartile range 1.39-2.57) before to 1.09 (1.04-1.53) after surgery (P = 0.01) and systemic DFA spillover from 56.7 mmol before to 24.7 mmol over 6 h after meal intake after surgery (P = 0.01), with a significant increase in intra-abdominal adipose tissue DFA uptake from 0.15 (0.04-0.31] before to 0.49 (0.20-0.59) SUV after surgery (P = 0.008). Hepatic insulin resistance was significantly reduced in close association with increased DFA storage in intra-abdominal adipose tissues (r = -0.79, P = 0.05) and reduced DFA spillover (r = 0.76, P = 0.01). We conclude that bariatric surgery in subjects with T2D rapidly reduces cardiac DFA partitioning and hepatic insulin resistance at least in part through increased intra-abdominal DFA storage and reduced spillover.

Specific loss of adipocyte CD248 improves metabolic health via reduced white adipose tissue hypoxia, fibrosis and inflammation.

BACKGROUND: A positive energy balance promotes white adipose tissue (WAT) expansion which is characterized by activation of a repertoire of events including hypoxia, inflammation and extracellular matrix remodelling. The transmembrane glycoprotein CD248 has been implicated in all these processes in different malignant and inflammatory diseases but its potential impact in WAT and metabolic disease has not been explored. METHODS: The role of CD248 in adipocyte function and glucose metabolism was evaluated by omics analyses in human WAT, gene knockdowns in human in vitro differentiated adipocytes and by adipocyte-specific and inducible Cd248 gene knockout studies in mice. FINDINGS: CD248 is upregulated in white but not brown adipose tissue of obese and insulin-resistant individuals. Gene ontology analyses showed that CD248 expression associated positively with pro-inflammatory/pro-fibrotic pathways. By combining data from several human cohorts with gene knockdown experiments in human adipocytes, our results indicate that CD248 acts as a microenvironmental sensor which mediates part of the adipose tissue response to hypoxia and is specifically perturbed in white adipocytes in the obese state. Adipocyte-specific and inducible Cd248 knockouts in mice, both before and after diet-induced obesity and insulin resistance/glucose intolerance, resulted in increased microvascular density as well as attenuated hypoxia, inflammation and fibrosis without affecting fat cell volume. This was accompanied by significant improvements in insulin sensitivity and glucose tolerance. INTERPRETATION: CD248 exerts detrimental effects on WAT phenotype and systemic glucose homeostasis which may be reversed by suppression of adipocyte CD248. Therefore, CD248 may constitute a target to treat obesity-associated co-morbidities.

Determination of a pharmacokinetic model for [11C]-acetate in brown adipose tissue.

BACKGROUND: [11C]-acetate positron emission tomography is used to assess oxidative metabolism in various tissues including the heart, tumor, and brown adipose tissue. For brown adipose tissue, a monoexponential decay model is commonly employed. However, no systematic assessment of kinetic models has been performed to validate this model or others. The monoexponential decay model and various compartmental models were applied to data obtained before and during brown adipose tissue activation by cold exposure in healthy men. Quality of fit was assessed visually and by analysis of residuals, including the Akaike information criterion. Stability and accuracy of compartmental models were further assessed through simulations, along with sensitivity and identifiability of kinetic parameters. RESULTS: Differences were noted in the arterial input function between the warm and cold conditions. These differences are not taken into account by the monoexponential decay model. They are accounted for by compartmental models, but most models proved too complex to be stable. Two and three-tissue models with no more than four distinct kinetic parameters, including blood volume fraction, provided the best compromise between fit quality and stability/accuracy. CONCLUSION: For healthy men, a three-tissue model with four kinetic parameters, similar to a heart [11C]-palmitate model seems the most appropriate based on model stability and its ability to describe the main [11C]-acetate pathways in BAT cells. Further studies are required to validate this model in women and people with metabolic disorders.

Combination of high-fat/high-fructose diet and low-dose streptozotocin to model long-term type-2 diabetes complications.

The epidemic of type 2 diabetes mellitus (T2DM) is fueled by added fructose consumption. Here, we thus combined high-fat/high-fructose diet, with multiple low-dose injections of streptozotocin (HF/HF/Stz) to emulate the long-term complications of T2DM. HF/HF/Stz rats, monitored over 56 weeks, exhibited metabolic dysfunctions associated with the different stages of the T2DM disease progression in humans: an early prediabetic phase characterized by an hyperinsulinemic period with modest dysglycemia, followed by a late stage of T2DM with frank hyperglycemia, normalization of insulinemia, marked dyslipidemia, hepatic fibrosis and pancreatic ß-cell failure. Histopathological analyses combined to [18F]-FDG PET imaging further demonstrated the presence of several end-organ long-term complications, including reduction in myocardial glucose utilization, renal dysfunction as well as microvascular neuropathy and retinopathy. We also provide for the first time a comprehensive µ-PET whole brain imaging of the changes in glucose metabolic activity within discrete cerebral regions in HF/HF/Stz diabetic rats. Altogether, we developed and characterized a unique non-genetic preclinical model of T2DM adapted to the current diet and lifestyle that recapitulates the major metabolic features of the disease progression, from insulin resistance to pancreatic ß-cell dysfunction, and closely mimicking the target-organ damage occurring in type 2 diabetic patients at advanced stages.

Plasma Palmitoyl-Carnitine (AC16:0) Is a Marker of Increased Postprandial Nonesterified Incomplete Fatty Acid Oxidation Rate in Adults With Type 2 Diabetes.

OBJECTIVES: Enhanced mitochondrial fatty acid utilization is known to increase radical oxidative stress and induce insulin resistance. An increased level of plasma acylcarnitine (AC) has been proposed to indicate mitochondrial energy substrate overload, a possible mechanism leading to insulin resistance. The aim of our study was to determine fasting and postprandial plasma acetyl-carnitine (AC2:0), palmitoyl-carnitine (AC16:0), oleoyl-carnitine (AC18:1) and linoleoyl-carnitine (AC18:2) levels and their relationships with plasma nonesterified fatty acid appearance and oxidation rates and insulin sensitivity in participants with type 2 diabetes and normoglycemic offspring of 2 parents with type 2 diabetes (FH+) compared to healthy participants without family histories of type 2 diabetes (FH-). METHODS: All participants underwent 3 metabolic protocols: 1) a euglycemic hyperinsulinemic clamp at fasting; 2) a 6-hour steady-state oral standard liquid meal and 3) an identical 6-hour steady-state meal intake study with a euglycemic hyperinsulinemic clamp. AC levels were measured by liquid chromatography with tandem mass spectrometry, and fatty acid oxidation (FAO) rates were measured by stable isotopic tracer techniques with indirect respiratory calorimetry. RESULTS: During the insulin clamp at fasting, AC16:0 was significantly higher in the group with type 2 diabetes vs. FH- (p<0.05). In the postprandial state, AC2:0, AC16:0 and AC18:1 decreased significantly, but this reduction was blunted in type 2 diabetes, even during normalization of postprandial glucose levels during the insulin clamp. Fasting AC16:0 correlated with FAO (ρ=+0.604; p=0.0002); triacylglycerol (ρ=+0.427; p<0.02) and waist circumference (ρ=+0.416; p=0.02). CONCLUSIONS: Spillover of AC occurs in type 2 diabetes but is not fully established in FH+. AC16:0 can be a useful biomarker of excessive FAO.

Dietary fatty acid metabolism of brown adipose tissue in cold-acclimated men.

In rodents, brown adipose tissue (BAT) plays an important role in producing heat to defend against the cold and can metabolize large amounts of dietary fatty acids (DFA). The role of BAT in DFA metabolism in humans is unknown. Here we show that mild cold stimulation (18 °C) results in a significantly greater fractional DFA extraction by BAT relative to skeletal muscle and white adipose tissue in non-cold-acclimated men given a standard liquid meal containing the long-chain fatty acid PET tracer, 14(R,S)-[18F]-fluoro-6-thia-heptadecanoic acid (18FTHA). However, the net contribution of BAT to systemic DFA clearance is comparatively small. Despite a 4-week cold acclimation increasing BAT oxidative metabolism 2.6-fold, BAT DFA uptake does not increase further. These findings show that cold-stimulated BAT can contribute to the clearance of DFA from circulation but its contribution is not as significant as the heart, liver, skeletal muscles or white adipose tissues.

Dietary fatty acid metabolism in prediabetes.

PURPOSE OF REVIEW: Experimental evidences are strong for a role of long-chain saturated fatty acids in the development of insulin resistance and type 2 diabetes. Ectopic accretion of triglycerides in lean organs is a characteristic of prediabetes and type 2 diabetes and has been linked to end-organ complications. The contribution of disordered dietary fatty acid (DFA) metabolism to lean organ overexposure and lipotoxicity is still unclear, however. DFA metabolism is very complex and very difficult to study in vivo in humans. RECENT FINDINGS: We have recently developed a novel imaging method using PET with oral administration of 14-R,S-F-fluoro-6-thia-heptadecanoic acid (FTHA) to quantify organ-specific DFA partitioning. Our studies thus far confirmed impaired storage of DFA per volume of fat mass in abdominal adipose tissues of individuals with prediabetes. They also highlighted the increased channeling of DFA toward the heart, associated with subclinical reduction in cardiac systolic and diastolic function in individuals with prediabetes. SUMMARY: In the present review, we summarize previous work on DFA metabolism in healthy and prediabetic states and discuss these in the light of our novel findings using PET imaging of DFA metabolism. We herein provide an integrated view of abnormal organ-specific DFA partitioning in prediabetes in humans.