Changes In Substrate Utilization Research Articles

929-P: A Study to Evaluate Clinical and Metabolic Profile of Type 2 Diabetes Patients Receiving SGLT2 Inhibitors

Aim: The aim of the study was to determine the efficacy of SGLT2i and its impact on metabolic profile of type 2 diabetes (T2DM) patients with reference to serum glucagon and blood ketones. Methodology: The study was conducted in T2DM patients with inadequate glycemic control on a background therapy of either metformin and sulphonylurea (Group A) or metformin and DPP4 inhibitor(Group B) Blood samples were taken for estimation of fasting plasma glucose (FPG), post prandial plasma glucose (PPPG), HbA1c, beta-hydroxybutyrate (β-HB) and glucagon levels. Empagliflozin 10mg, was added to the existing anti-diabetic medication. The metabolic parameters were reassessed after 12 weeks. Results: At the end of 12 weeks glucagon levels increased significantly (28.8 ± 28.74 at baseline vs 108 ± 74 pg/ml; p<0.001). A significant increase in β-HB levels was also observed (0.1 ± 0.07 mmol/L at baseline versus 0.12 ± 0.07 mmol/L (p=0.03). FPG, PPPG and HbA1c decreased significantly by 30.33mg%, 53.16mg% and 1.05% respectively(p<0.01) In group A, FPG and PPPG decreased by 34.43 mg/dl and 51.71mg/dl respectively (p<0.001) with a mean HbA1c reduction of 1.09% (p<0.001) Serum glucagon and β-HB levels increased significantly [82.63 pg/ml (p<0.001) and 0.04 mmol/L (p<0.01) respectively]. In group B, there was decrease in FPG (mean difference 23.6mg %; p=0.003) and PPPG (mean difference 55.5mg%; p<0.001) at 12 weeks. HbA1c reduction of 0.99% was observed. (p=0.003) There was a significant increase in glucagon levels (mean difference +73.52 pg/ml; p<0.001). Conclusion: Addition of Empagliflozin to T2DM patients with inadequate glycemic control on either metformin and sulphonylurea or metformin and DPP4 inhibitors significantly improved efficacy. Plasma glucagon and β-HB levels increased with chronic empagliflozin treatment suggesting a change in substrate utilization towards fat. Disclosure S. Kandula: None. M.A. Meshram: None. A.C. Sonwane: None.

Myocardial Metabolism in Heart Failure with Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is increasingly prevalent and now accounts for half of all heart failure cases. This rise is largely attributed to growing rates of obesity, hypertension, and diabetes. Despite its prevalence, the pathophysiological mechanisms of HFpEF are not fully understood. The heart, being the most energy-demanding organ, appears to have a compromised bioenergetic capacity in heart failure, affecting all phenotypes and aetiologies. While metabolic disturbances in heart failure with reduced ejection fraction (HFrEF) have been extensively studied, similar insights into HFpEF are limited. This review collates evidence from both animal and human studies, highlighting metabolic dysregulations associated with HFpEF and its risk factors, such as obesity, hypertension, and diabetes. We discuss how changes in substrate utilisation, oxidative phosphorylation, and energy transport contribute to HFpEF. By delving into these pathological shifts in myocardial energy production, we aim to reveal novel therapeutic opportunities. Potential strategies include modulating energy substrates, improving metabolic efficiency, and enhancing critical metabolic pathways. Understanding these aspects could be key to developing more effective treatments for HFpEF.

Abstract 16786: Integrative Omics in Failing Myocardium Highlights Metabolic Substrate Utilization Defects in Human Heart Failure

Introduction: Changes in substrate utilization may be a biomarker of, or a contributor to, heart failure with reduced ejection fraction (HFrEF). Previous work has described circulating metabolites, proteins and transcripts that reflect myocardial bioenergetics, but direct assessment in relevant tissues is lacking. Here, we leverage integrative omics to identify tissue-level biomarkers and pathways of HFrEF that may play a role in pathogenesis. Methods: Myocardial tissue was obtained from 27 HFrEF donors and 21 non-failing hearts (noHF) from Duke University and the University of Colorado Medical Centers. Targeted (n=139 metabolites) and nontargeted (Metabolon, n=817) metabolic profiling was performed; in addition, 496 proteins were assayed (Olink) and ~31,000 transcripts were quantified via RNA sequencing. Individual metabolites were tested for association with HFrEF in models adjusted for age, sex and diabetes. Metabolomics, proteomics and RNA-seq data were integrated using block sparse partial least squares discriminant analysis (sPLS-DA) to identify correlated biomarkers that discriminate HFrEF from noHF hearts. Results: The targeted metabolomics platform primarily assayed metabolic fuel substrate pathways; 71 analytes (51%) were associated with HFrEF after controlling the false discovery rate (FDR) at 5%. Medium- and long-chain acylcarnitines (C10s-C18s) were significantly lower in tissue from failing hearts, while branched-chain amino acids (BCAA) and ketoacids were higher. In the nontargeted set, 293 metabolites (36%) differed between HFrEF and noHF. BCAA and acylcarnitine associations were recapitulated along with a decrease in malonylcarnitine. The sPLS-DA model selected 25 targeted and 50 nontargeted metabolites, 35 proteins and 35 transcripts, and successfully discriminated HFrEF from no HF (balanced error rate = 3.2%). 39/186 tested KEGG pathways were overrepresented in these analytes, including fatty acid metabolism (FDR q=0.002). Conclusions: Analysis of tissue-level metabolites suggests both decreased use of fatty acids as a fuel and disrupted enzymatic breakdown of BCAAs in the failing heart, while integrative omics pathway analysis also supports the association of disrupted fatty acid metabolism with HF.

Metabolomic Profiling in Patients with Different Hemodynamic Subtypes of Severe Aortic Valve Stenosis.

Severe aortic stenosis (AS) is a common pathological condition in an ageing population imposing significant morbidity and mortality. Based on distinct hemodynamic features, i.e., ejection fraction (EF), transvalvular gradient and stroke volume, four different AS subtypes can be distinguished: (i) normal EF and high gradient, (ii) reduced EF and high gradient, (iii) reduced EF and low gradient, and (iv) normal EF and low gradient. These subtypes differ with respect to pathophysiological mechanisms, cardiac remodeling, and prognosis. However, little is known about metabolic changes in these different hemodynamic conditions of AS. Thus, we carried out metabolomic analyses in serum samples of 40 AS patients (n = 10 per subtype) and 10 healthy blood donors (controls) using ultrahigh-performance liquid chromatography-tandem mass spectroscopy. A total of 1293 biochemicals could be identified. Principal component analysis revealed different metabolic profiles in all of the subgroups of AS (All-AS) vs. controls. Out of the determined biochemicals, 48% (n = 620) were altered in All-AS vs. controls (p < 0.05). In this regard, levels of various acylcarnitines (e.g., myristoylcarnitine, fold-change 1.85, p < 0.05), ketone bodies (e.g., 3-hydroxybutyrate, fold-change 11.14, p < 0.05) as well as sugar metabolites (e.g., glucose, fold-change 1.22, p < 0.05) were predominantly increased, whereas amino acids (e.g., leucine, fold-change 0.8, p < 0.05) were mainly reduced in All-AS. Interestingly, these changes appeared to be consistent amongst all AS subtypes. Distinct differences between AS subtypes were found for metabolites belonging to hemoglobin metabolism, diacylglycerols, and dihydrosphingomyelins. These findings indicate that relevant changes in substrate utilization appear to be consistent for different hemodynamic subtypes of AS and may therefore reflect common mechanisms during AS-induced heart failure. Additionally, distinct metabolites could be identified to significantly differ between certain AS subtypes. Future studies need to define their pathophysiological implications.

Four weeks of electrical stimulation improves glucose tolerance in a sedentary overweight or obese Hispanic population.

Introduction/purposeMost US adults (54%) do not meet the minimum exercise recommendations by the American College of Sports Medicine. Neuromuscular electrical stimulation (NMES) is a novel alternate strategy to induce muscle contraction. However, the effectiveness of NMES to improve insulin sensitivity and energy expenditure is unclear. The purpose of this study was to investigate the effects of 4 weeks of NMES on glucose tolerance in a sedentary overweight or obese population.MethodsParticipants (n = 10; age: 36.8 ± 3.8 years; BMI = 32 ± 1.3 kg/m2) were randomized into either control or NMES group. All participants received bilateral quadriceps stimulation (12 sessions; 30 min/session; three times/week at 50 Hz and 300 µs pulse width) altering pulse amplitude to either provide low-intensity sensory level (control; tingling sensation) or at high-intensity neuromuscular level (NMES; maximum tolerable levels with visible muscle contraction). Glucose tolerance was assessed by a 3-h oral glucose tolerance test (OGTT), and substrate utilization was measured by indirect calorimetry and body composition via dual X-ray absorptiometry at baseline and after 4 weeks of NMES intervention.ResultsControl and NMES groups had comparable fasting blood glucose, glucose tolerance, substrate utilization, and muscle mass at baseline. Four weeks of NMES resulted in a significant improvement in glucose tolerance measured by OGTT, whereas no change was observed in the control group. There was no change in substrate utilization and muscle mass in both control and NMES groups.ConclusionNMES is a novel and effective strategy to improve glucose tolerance in an at-risk overweight or obese sedentary population.

Molecular Mechanisms of Obesity-Linked Cardiac Dysfunction: An Up-Date on Current Knowledge.

Obesity is defined as excessive body fat accumulation, and worldwide obesity has nearly tripled since 1975. Excess of free fatty acids (FFAs) and triglycerides in obese individuals promote ectopic lipid accumulation in the liver, skeletal muscle tissue, and heart, among others, inducing insulin resistance, hypertension, metabolic syndrome, type 2 diabetes (T2D), atherosclerosis, and cardiovascular disease (CVD). These diseases are promoted by visceral white adipocyte tissue (WAT) dysfunction through an increase in pro-inflammatory adipokines, oxidative stress, activation of the renin-angiotensin-aldosterone system (RAAS), and adverse changes in the gut microbiome. In the heart, obesity and T2D induce changes in substrate utilization, tissue metabolism, oxidative stress, and inflammation, leading to myocardial fibrosis and ultimately cardiac dysfunction. Peroxisome proliferator-activated receptors (PPARs) are involved in the regulation of carbohydrate and lipid metabolism, also improve insulin sensitivity, triglyceride levels, inflammation, and oxidative stress. The purpose of this review is to provide an update on the molecular mechanisms involved in obesity-linked CVD pathophysiology, considering pro-inflammatory cytokines, adipokines, and hormones, as well as the role of oxidative stress, inflammation, and PPARs. In addition, cell lines and animal models, biomarkers, gut microbiota dysbiosis, epigenetic modifications, and current therapeutic treatments in CVD associated with obesity are outlined in this paper.

846-P: Improvement in Glucose Metabolism with Four Weeks of Neuromuscular Electrical Stimulation in Sedentary Adults

Most U.S. adults do not meet minimum exercise recommendations by ACSM. We and others have shown an increase in GLUT4 protein and glucose uptake with electrical stimulation induced muscle contraction using an in vitro cell culture model. However, effectiveness of neuromuscular electrical stimulation (NMES) in humans to improve insulin sensitivity is not clear. Purpose: To determine the effects of four weeks of NMES on insulin sensitivity, substrate utilization, and muscle mass in sedentary humans. Methods: Sedentary overweight/obese subjects (n=10; Age 36.8 ±3.8 yrs; BMI 32.0 ±1.3 kg/m2) were randomized into a control (Con) or NMES group. All participants received bilateral quadriceps stimulation (3x/wk; 30 min/ses) either at low intensity sensory level (Con) or high intensity neuromuscular level (NMES) for 4 weeks (50Hz). Insulin sensitivity was assessed by oral glucose tolerance test (OGTT), substrate utilization by indirect calorimetry, blood lactate by lactate analyzer, and body composition by DXA. Results: Con and NMES groups had comparable fasting blood glucose, glucose tolerance, substrate utilization, and muscle mass (all p&amp;gt;0.05) at baseline. Four weeks of NMES tended to improve glucose tolerance, measured by glucose area under the curve (AUC) (455.6 ±26.1 to 415.4 ±25.9 AU; p=0.07) whereas no change was observed in Con (430.7 ±20.2 to 494.7 ±77.2 AU; p=0.76). Glucose level after 2 hours of glucose consumption during OGTT was significantly lower after 4 weeks of NMES (150.9 ±7.6 to 138.2 ±7.6 mg/dL; p=0.03) whereas no change was observed in Con (151.8 ±6.1 to 173.2 ±34.2 mg/dL; p=0.33).Additionally, lactate AUC assessed during 30 min of NMES, was significantly greater compared to that of Con (p&amp;lt;0.02). There was no change in substrate utilization (p=0.85) or muscle mass (p=0.17) after NMES intervention. Conclusion: NMES is a novel and effective strategy to improve insulin sensitivity and glucose utilization in an at-risk overweight/obese sedentary population. Disclosure S. Bajpeyi: None. M. Galvan: None. M.J. Sanchez: None. J.B. Boyle: None. K. Min: None. F.J. Agullo: None. J.D. Covington: None. Funding University of Texas at El Paso

Role of YAP/TAZ in Energy Metabolism in the Heart.

The heart requires a high amount of energy, in the form of adenosine triphosphate, to maintain its viability and pump function. Anaerobic glycolysis and mitochondrial oxidative phosphorylation are the two main metabolic pathways by which adenosine triphosphate is generated, using fatty acids, glucose, lactate, and ketone bodies as primary substrates. Previous studies have demonstrated that, in response to stress, the heart undergoes alterations in metabolism, ranging from changes in substrate utilization to mitochondrial function, collectively called metabolic remodeling. However, the molecular mechanism mediating metabolic remodeling in the heart remains unclear. Yes-associated protein 1 (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), which are major downstream effectors of the Hippo signaling pathway, play an important role in the regulation of heart size and cellular homeostasis of cardiomyocytes through the regulation of various transcriptional factors under both physiological and pathophysiological conditions. Recent findings in various organs and cell types have revealed that YAP and TAZ play an important role in energy metabolism. Here, we summarize what is currently known about YAP/TAZ in the regulation of metabolism of various substrates and mitochondrial function in various organs and cell types and discuss the potential role of YAP/TAZ in mediating metabolic remodeling of the heart during stress and heart failure.

Changes in Energy Expenditure of Patients with Obesity Following Bariatric Surgery: a Systematic Review of Prospective Studies and Meta-analysis.

We herein summarize the available literature on the effects of bariatric surgery (BS) on energy expenditure in individuals with obesity. We conducted a systematic literature review, and 35 prospective studies met our inclusion criteria. The findings indicate that BS contributes to increased diet-induced thermogenesis (DIT) and decreased total energy expenditure (TEE) and resting energy expenditure (REE) in patients with obesity. The meta-analysis demonstrated a significant decrease in TEE and REE within 6months following BS. With the sustained decrease in REE, there was no further decrease in TEE between the 6- and 12-month follow-up. Increased DIT might explain the variance between the patterns of REE and TEE change. The postoperative decrease in REE/FFM and increase in REE/BW were observed. The changes in substrate utilization might be consistent with the change in the respiration quotient postoperatively.

Short‐term changes in left ventricular dyssynchrony may lead to congestive heart failure

Ventricular dyssynchrony is characterized by a difference in timing or lack of synchrony in ventricular contraction, leading to an inefficiency of pumping blood. Ventricular dyssynchrony (VD) consists of a disruption in the normal electrical conduction system, which leads to congestive heart failure (CHF). Long‐term effects of VD that lead to CHF is well studied but little is known about the short‐term effects associated with VD. Short‐term physiological changes due to VD are crucial because electrical and mechanical abnormalities or structural changes cause a decrease in overall cardiac functionresulting in long‐term effects that may lead to CHF. Such physiological abnormalities can range from metabolic alterations, metabolic remodeling such as changes in substrate utilization, mitochondrial dysfunction, ATP deficiency, impaired contractility, and the progression of cell regeneration and cell growth, etc. Thus, theobjective of this study is to investigate short‐term cellular effects associated of induced VD in vivo. Our hypothesis is that induced left ventricular dyssynchrony (via pacing) in a non‐CHF model may lead to short‐term changes such as alterations in cardiac metabolism and mitochondrial dysfunctionresulting in structural rearrangements. Frogs will undergo ventricular pacing to induce VD. Strain patterns associated with contraction and relaxation will be analyzed to verify dyssynchrony. Paced and non‐paced regions of the heart will be analyzed to determine if reactive oxygen species (ROS) generation and mitochondrial abnormalities lead to cellular changes that may induce apoptosis leading to structural rearrangement, known as ventricular remodeling.Support or Funding InformationSupported by Cal State LA Minority Opportunities in Research MBRS‐RISE Program fund through NIH NIGMS under Grant No. R25 GM61331.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Field-deployable measurements of free-living individuals to determine energy balance: fuel substrate usage through δ13C in breath CO2 and diet through hair δ13C and δ15N values

ABSTRACTCarbon isotopes of breath CO2 vary depending on diet and fuel substrate used. This study examined if exercise-induced δ13C-CO2 changes in substrate utilization were distinguishable from baseline δ13C-CO2 variations in a population with uncontrolled diet, and compared hair isotope values and food logs to develop an isotope model of diet. Study participants included nine women with diverse Body Mass Index (BMI), age, ancestry, exercise history, and diet. Breath samples were collected prior to and up to 12 h after a 5- or 10 K walk/run. Indirect calorimetry was measured with a smartphone-enabled mobile colorimetric device, and a field-deployable isotope analyzer measured breath δ13C-CO2 values. Diet was assessed by food logs and δ13C, δ15N of hair samples. Post-exercise δ13C-CO2 values increased by 0.54 ± 1.09‰ (1 sd, n = 9), implying enhanced carbohydrate burning, while early morning δ13C-CO2 values were lower than daily averages (p = 0.0043), indicating lipid burning during overnight fasting. Although diurnal δ13C-CO2 variation (1.90 ± 0.77‰) and participant baseline range (3.06‰) exceeded exercise-induced variation, temporal patterns distinguished exercise from dietary isotope effects. Hair δ13C and δ15N values were consistent with a new dietary isotope model. Notwithstanding the small number of participants, this study introduces a novel combination of techniques to directly monitor energy balance in free-living individuals.

Caffeine Supplementation: Ergogenic in Both High and Low Caffeine Responders.

Purpose: Inconsistent results among studies examining the effects of caffeine on exercise performance are potentially due to interindividual variability in biological responses to caffeine ingestion. The aims, therefore, of the present study were to identify high and low caffeine responders and compare the influence of caffeine on exercise performance and biological responses between groups during a simulated soccer-game protocol on treadmill. Methods: Well-trained soccer players were distinguished as high (n = 11) and low (n = 9) caffeine responders based on resting blood pressure, plasma glycerol, nonesterified fatty acid, and epinephrine responses to caffeine. Participants underwent 2 simulated soccer-game protocols on a treadmill after caffeine (6mg·kg-1) or placebo ingestion. Exercise performance and several biological responses were evaluated. Results: Exercise performance did not differ between the high and low responders to caffeine (P > .05). However, time to fatigue (high, caffeine: 797 [201]s vs placebo: 487 [258]s; low, caffeine: 625 [357]s vs placebo 447 [198]s) and countermovement jump (high, caffeine: 42.1 [5.5]cm vs placebo: 40.5 [5.7]cm; low, caffeine: 41.0 [3.8]cm vs placebo: 38.8 [4.6]cm) improved with caffeine relative to placebo (P < .001). Rating of perceived exertion was lower (P < .001) in high (13.4 [2.3]) than in low responders (14.3 [2.4]) with caffeine ingestion. Conclusions: Caffeine improved aerobic endurance and neuromuscular performance in well-trained soccer players regardless of their responsiveness to caffeine at rest. Since no changes in substrate utilization were found with caffeine supplementation, performance improvements could be attributed to positive effects on the central nervous system and/or neuromuscular function, although the precise mechanism remains unclear.

The role of exercise-induced myokines in regulating metabolism.

Exercise has beneficial effects in ameliorating metabolic disorders, and a combined therapeutic regimen of regular exercise and pharmaceutical treatment is often recommended. Exercise biology is complex and it involves various metabolic and molecular changes that translate into changes in substrate utilization, enzyme activation, and alternatively, improvement in exercise performance. Besides the effect of exercise on muscle metabolism, it has recently been discovered that contracting muscle can induce secretion of molecules called myokines. In the past few decades, a number of myokines have been discovered, such as interleukin-6, irisin, myostatin, interleukin-15, brain-derived neurotrophic factor, β-aminoisobutyric acid, meteorin-like, leukemia inhibitory factor, and secreted protein acidic and rich in cysteine, through secretome analysis. The existence of myokines has enhanced our understanding of how muscles communicate with other organs such as adipose tissue, liver, bone, and brain to exert beneficial effects of exercise at the whole body level. In this review, we focus on the role of these myokines in regulating local muscle metabolism as well as systemic metabolism in an autocrine/paracrine/endocrine fashion. The therapeutic potential of myokines and the natural or synthetic compounds known to date that regulate myokines are also discussed.

Sorafenib and FH535 in combination act synergistically on hepatocellular carcinoma by targeting cell bioenergetics and mitochondrial function

Treatment of advanced hepatocellular carcinoma (HCC) remains a challenge due to the high tumor heterogeneity. In the present study, we aim to evaluate the impact of the β-catenin inhibitor, FH535, alone or in combination with the Ras/Raf/MAPK inhibitor Sorafenib, on the bioenergetics profiles of the HCC cell lines Huh7 and PLC/PRF/5. Single low-dose treatments with FH535 or Sorafenib promoted different effects on mitochondrial respiration and glycolysis in a cell type specific manner. However, the combination of these drugs significantly reduced both mitochondrial respiration and glycolytic rates regardless of the HCC cells. The significant changes in mitochondrial respiration observed in cells treated with the Sorafenib-FH535 combination may correspond to differential targeting of ETC complexes and changes in substrate utilization mediated by each drug. Moreover, the bioenergetics changes and the loss of mitochondrial membrane potential that were evidenced by treatment of HCC cells with the combination of FH535 and Sorafenib, preceded the induction of cell apoptosis. Overall, our results demonstrated that Sorafenib-FH535 drug combination induce the disruption of the bioenergetics of HCC by the simultaneous targeting of mitochondrial respiration and glycolytic flux that leads the synergistic effect on inhibition of cell proliferation. These findings support the therapeutic potential of combinatory FH535-Sorafenib treatment of the HCC heterogeneity by the simultaneous targeting of different molecular pathways.

Measuring changes in substrate utilization in the myocardium in response to fasting using hyperpolarized [1-(13)C]butyrate and [1-(13)C]pyruvate.

Cardiac dysfunction is often associated with a shift in substrate preference for ATP production. Hyperpolarized (HP) 13C magnetic resonance spectroscopy (MRS) has the unique ability to detect real-time metabolic changes in vivo due to its high sensitivity and specificity. Here a protocol using HP [1-13C]pyruvate and [1-13C]butyrate is used to measure carbohydrate versus fatty acid metabolism in vivo. Metabolic changes in fed and fasted Sprague Dawley rats (n = 36) were studied at 9.4 T after tail vein injections. Pyruvate and butyrate competed for acetyl-CoA production, as evidenced by significant changes in [13C]bicarbonate (−48%), [1-13C]acetylcarnitine (+113%), and [5-13C]glutamate (−63%), following fasting. Butyrate uptake was unaffected by fasting, as indicated by [1-13C]butyrylcarnitine. Mitochondrial pseudoketogenesis facilitated the labeling of the ketone bodies [1-13C]acetoacetate and [1-13C]β-hydroxybutyryate, without evidence of true ketogenesis. HP [1-13C]acetoacetate was increased in fasting (250%) but decreased during pyruvate co-injection (−82%). Combining HP 13C technology and co-administration of separate imaging agents enables noninvasive and simultaneous monitoring of both fatty acid and carbohydrate oxidation. This protocol illustrates a novel method for assessing metabolic flux through different enzymatic pathways simultaneously and enables mechanistic studies of the changing myocardial energetics often associated with disease.

Triheptanoin Alleviates Ventricular Hypertrophy and Improves Myocardial Glucose Oxidation in Rats With Pressure Overload

ObjectiveCardiac hypertrophy is characterized by changes in substrate utilization and activity of the Krebs cycle. We assessed the effects of triheptanoin, an odd-chain fat that might support the Krebs cycle, on cardiac metabolism and function in a model of cardiac hypertrophy. Methods and ResultsRats were subjected to aortic banding (AoB) to induce pressure overload (PO). Starting at 1 week after AoB, rats were blindly fed a control diet or a special diet containing triheptanoin at 7% (T7 group) or 30% (T30 group) of total energy value. Six weeks after AoB, echocardiography revealed attenuated hypertrophy and improved diastolic function of the left ventricle. Isolated working heart perfusion showed similar cardiac power, fatty acid oxidation, substrate preference, and insulin response among groups. However, cardiac glucose oxidation (GO) was increased in the T30 group compared with the T7 and control groups. Blood levels of the odd-chain ketone body beta-hydroxypentanoate confirmed adequate bioavailability of triheptanoin. Importantly, they were directly proportional to cardiac GO. ConclusionsTreatment with triheptanoin-enriched diet reduces ventricular hypertrophy and improves diastolic function in rats with PO, which is associated with enhanced cardiac GO. The results suggest targeting supplementation of the Krebs cycle to approach ventricular and metabolic remodeling in cardiac hypertrophy.

Effect of a 1-week, eucaloric, moderately high-fat diet on peripheral insulin sensitivity in healthy premenopausal women

ObjectivesTo determine whether a weight-maintaining, moderate (50%) high-fat diet is deleterious to insulin sensitivity in healthy premenopausal women.Design/setting/participants23 African-American and non-Hispanic white, healthy, overweight, and obese premenopausal women recruited in...

Early Changes in Soil Metabolic Diversity and Bacterial Community Structure in Sugarcane under Two Harvest Management Systems

Preharvest burning is widely used in Brazil for sugarcane cropping. However, due to environmental restrictions, harvest without burning is becoming the predominant option. Consequently, changes in the microbial community are expected from crop residue accumulation on the soil surface, as well as alterations in soil metabolic diversity as of the first harvest. Because biological properties respond quickly and can be used to monitor environmental changes, we evaluated soil metabolic diversity and bacterial community structure after the first harvest under sugarcane management without burning compared to management with preharvest burning. Soil samples were collected under three sugarcane varieties (SP813250, SP801842 and RB72454) and two harvest management systems (without and with preharvest burning). Microbial biomass C (MBC), carbon (C) substrate utilization profiles, bacterial community structure (based on profiles of 16S rRNA gene amplicons), and soil chemical properties were determined. MBC was not different among the treatments. C-substrate utilization and metabolic diversity were lower in soil without burning, except for the evenness index of C-substrate utilization. Soil samples under the variety SP801842 showed the greatest changes in substrate utilization and metabolic diversity, but showed no differences in bacterial community structure, regardless of the harvest management system. In conclusion, combined analysis of soil chemical and microbiological data can detect early changes in microbial metabolic capacity and diversity, with lower values in management without burning. However, after the first harvest, there were no changes in the soil bacterial community structure detected by PCR-DGGE under the sugarcane variety SP801842. Therefore, the metabolic profile is a more sensitive indicator of early changes in the soil microbial community caused by the harvest management system.

Differential effects of buffer pH on Ca(2+)-induced ROS emission with inhibited mitochondrial complexes I and III.

Excessive mitochondrial reactive oxygen species (ROS) emission is a critical component in the etiology of ischemic injury. Complex I and complex III of the electron transport chain are considered the primary sources of ROS emission during cardiac ischemia and reperfusion (IR) injury. Several factors modulate ischemic ROS emission, such as an increase in extra-matrix Ca2+, a decrease in extra-matrix pH, and a change in substrate utilization. Here we examined the combined effects of these factors on ROS emission from respiratory complexes I and III under conditions of simulated IR injury. Guinea pig heart mitochondria were suspended in experimental buffer at a given pH and incubated with or without CaCl2. Mitochondria were then treated with either pyruvate, a complex I substrate, followed by rotenone, a complex I inhibitor, or succinate, a complex II substrate, followed by antimycin A, a complex III inhibitor. H2O2 release rate and matrix volume were compared with and without adding CaCl2 and at pH 7.15, 6.9, or 6.5 with pyruvate + rotenone or succinate + antimycin A to simulate conditions that may occur during in vivo cardiac IR injury. We found a large increase in H2O2 release with high [CaCl2] and pyruvate + rotenone at pH 6.9, but not at pHs 7.15 or 6.5. Large increases in H2O2 release rate also occurred at each pH with high [CaCl2] and succinate + antimycin A, with the highest levels observed at pH 7.15. The increases in H2O2 release were associated with significant mitochondrial swelling, and both H2O2 release and swelling were abolished by cyclosporine A, a desensitizer of the mitochondrial permeability transition pore (mPTP). These results indicate that ROS production by complex I and by complex III is differently affected by buffer pH and Ca2+ loading with mPTP opening. The study suggests that changes in the levels of cytosolic Ca2+ and pH during IR alter the relative amounts of ROS produced at mitochondrial respiratory complex I and complex III.

No evidence for a bioenergetic advantage from forced swimming in rainbow trout under a restrictive feeding regime

Sustained swimming at moderate speeds is considered beneficial in terms of the productive performance of salmonids, but the causative mechanisms have yet to be unequivocally established. In the present study, the effects of moderate exercise on the bioenergetics of rainbow trout were assessed during a 15 week growth experiment, in which fish were reared at three different current speeds: 1 BL s−1, 0.5 BL s−1 and still water (≈ 0 BL s−1). Randomly selected groups of 100 fish were distributed among twelve 600 L tanks and maintained on a restricted diet regime. Specific growth rate (SGR) and feed conversion ratio (FCR) were calculated from weight and length measurements every 3 weeks. Routine metabolic rate (RMR) was measured every hour as rate of oxygen consumption in the tanks, and was positively correlated with swimming speed. Total ammonia nitrogen (TAN) excretion rates showed a tendency to decrease with increasing swimming speeds, yet neither they nor the resulting nitrogen quotients (NQ) indicated that swimming significantly reduced the fraction of dietary protein used to fuel metabolism. Energetic budgets revealed a positive correlation between energy expenditure and the current speed at which fish were reared, fish that were forced to swim and were fed restrictively consequentially had poorer growth and feed utilization. The results show that for rainbow trout, water current can negatively affect growth despite promoting minor positive changes in substrate utilization. We hypothesize that this may be the result of either a limited dietary energy supply from diet restriction being insufficient for both covering the extra costs of swimming and supporting enhanced growth.