Substrate Partitioning Research Articles

Cytoplasmic and nuclear quality control and turnover of single-stranded RNA modulate post-transcriptional gene silencing in plants

Eukaryotic RNA quality control (RQC) uses both endonucleolytic and exonucleolytic degradation to eliminate dysfunctional RNAs. In addition, endogenous and exogenous RNAs are degraded through post-transcriptional gene silencing (PTGS), which is triggered by the production of double-stranded (ds)RNAs and proceeds through short-interfering (si)RNA-directed ARGONAUTE-mediated endonucleolytic cleavage. Compromising cytoplasmic or nuclear 5′–3′ exoribonuclease function enhances sense-transgene (S)-PTGS in Arabidopsis, suggesting that these pathways compete for similar RNA substrates. Here, we show that impairing nonsense-mediated decay, deadenylation or exosome activity enhanced S-PTGS, which requires host RNA-dependent RNA polymerase 6 (RDR6/SGS2/SDE1) and SUPPRESSOR OF GENE SILENCING 3 (SGS3) for the transformation of single-stranded RNA into dsRNA to trigger PTGS. However, these RQC mutations had no effect on inverted-repeat–PTGS, which directly produces hairpin dsRNA through transcription. Moreover, we show that these RQC factors are nuclear and cytoplasmic and are found in two RNA degradation foci in the cytoplasm: siRNA-bodies and processing-bodies. We propose a model of single-stranded RNA tug-of-war between RQC and S-PTGS that ensures the correct partitioning of RNA substrates among these RNA degradation pathways.

A Fully Integrated Continuous‐Flow System for Asymmetric Catalysis: Enantioselective Hydrogenation with Supported Ionic Liquid Phase Catalysts Using Supercritical CO2 as the Mobile Phase

A continuous-flow process based on a chiral transition-metal complex in a supported ionic liquid phase (SILP) with supercritical carbon dioxide (scCO(2)) as the mobile phase is presented for asymmetric catalytic transformations of low-volatility organic substrates at mild reaction temperatures. Enantioselectivity of >99% ee and quantitative conversion were achieved in the hydrogenation of dimethylitaconate for up to 30 h, reaching turnover numbers beyond 100000 for the chiral QUINAPHOS-rhodium complex. By using an automated high-pressure continuous-flow setup, the product was isolated in analytically pure form without the use of any organic co-solvent and with no detectable catalyst leaching. Phase-behaviour studies and high-pressure NMR spectroscopy assisted the localisation of optimum process parameters by quantification of substrate partitioning between the IL and scCO(2). Fundamental insight into the molecular interactions of the metal complex, ionic liquid and the surface of the support in working SILP catalyst materials was gained by means of systematic variations, spectroscopic studies and labelling experiments. In concert, the obtained results provided a rationale for avoiding progressive long-term deactivation. The optimised system reached stable selectivities and productivities that correspond to 0.7 kgL(-1)h(-1) space-time yield and at least 100 kg product per gram of rhodium, thus making such processes attractive for larger-scale application.

Regulation of Peripheral Metabolism by Substrate Partitioning in the Brain

All organisms must adapt to changing nutrient availability, with nutrient surplus promoting glucose metabolism and nutrient deficit promoting alternative fuels (in mammals, mainly free fatty acids). A major function of glucose-sensing neurons in the hypothalamus is to regulate blood glucose. When these neurons sense glucose levels are too low, they activate robust counterregulatory responses to enhance glucose production, primarily from liver, and reduce peripheral metabolism. Some hypothalamic neurons can metabolize free fatty acids via β-oxidation, and β-oxidation generally opposes effects of glucose on hypothalamic neurons. Thus hypothalamic β-oxidation promotes obese phenotypes, including enhanced hepatic glucose output.

Molecular Insight into Affinities of Drugs and Their Metabolites to Lipid Bilayers

The penetration properties of drug-like molecules on human cell membranes are crucial for understanding the metabolism of xenobiotics and overall drug distribution in the human body. Here, we analyze partitioning of substrates of cytochrome P450s (caffeine, chlorzoxazone, coumarin, ibuprofen, and debrisoquine) and their metabolites (paraxanthine, 6-hydroxychlorzoxazone, 7-hydroxycoumarin, 3-hydroxyibuprofen, and 4-hydroxydebrisoquine) on two model membranes: dioleoylphosphatidylcholine (DOPC) and palmitoyloleoylphophatidylglycerol (POPG). We calculated the free energy profiles of these molecules and the distribution coefficients on the model membranes. The drugs were usually located deeper in the membrane than the corresponding metabolites and also had a higher affinity to the membranes. Moreover, the behavior of the molecules on the membranes differed, as they seemed to have a higher affinity to the DOPC membrane than to POPG, implying they have different modes of action in human (mostly PC) and bacterial (mostly PG) cells. As the xenobiotics need to pass through lipid membranes on their way through the body and the effect of some drugs might depend on their accumulation on membranes, we believe that detailed information of penetration phenomenon is important for understanding the overall metabolism of xenobiotics.

Lipid Bilayer Properties Control Membrane Partitioning, Binding, and Transport of P-Glycoprotein Substrates

The ABC protein P-glycoprotein (Pgp or ABCB1) is a multidrug efflux pump capable of transporting many structurally diverse substrates from within the lipid bilayer. Previous studies have demonstrated the importance of the membrane in modulating Pgp function, but few have quantified these effects. We employed purified Pgp reconstituted into phospholipid bilayers with defined gel to liquid-crystalline melting transitions to investigate the effect of membrane environment on the transporter and three of its substrates. Equilibrium dialysis measurements indicated that Hoechst 33342, LDS-751, and MK-571 partitioned much more readily into liquid-crystalline phase bilayers than into gel phase bilayers. However, drug binding affinities revealed that Pgp bound the three substrates more tightly when the lipid bilayer was in the gel phase. The binding affinity of the transporter for substrates within the bilayer was low, in the millimolar range, suggesting that it interacts with them weakly. Thermodynamic analysis revealed that both drug-Pgp and drug-lipid interactions contribute to binding affinity. The kinetics of LDS-751 and Hoechst 33342 transport by reconstituted Pgp was monitored using a real-time fluorescence-based assay to obtain apparent turnover frequencies. Transport rates were found to be sensitive to both drug structure and lipid environment. Arrhenius and transition state analysis of transport rates suggested that the rate of drug transport depends on both the affinity of Pgp for substrate and protein conformational changes. Transport rates did not appear to be limited exclusively by the rate of ATP hydrolysis and may be partially controlled by the rate of drug dissociation.

In situ substrate preferences of abundant bacterioplankton populations in a prealpine freshwater lake

The substrate partitioning of sympatric populations of freshwater bacterioplankton was studied via microautoradiography and fluorescence in situ hybridization. Fourteen radiolabeled tracers were used to assess microbial acquisition spectra of low-molecular-weight (LMW) organic compounds. The most abundant group, ac1 Actinobacteria, were highly active in leucine, thymidine and glucose assimilation, whereas Alphaproteobacteria from the LD12 lineage (the freshwater sister clade of SAR11) only weakly incorporated these tracers, but exhibited a distinct preference for glutamine and glutamate. Different Bacteroidetes showed contrasting uptake patterns: Flavobacteriales did not incorporate significant amounts of any LMW compound, and Cyclobacteriaceae were clearly specialized on leucine, glucose and arginine. Betaproteobacteria represented the most active and versatile bacterioplankton fraction and >90% of them could be assigned to eight species- to genus-like populations with contrasting substrate specialization. Limnohabitans sp. were the most abundant and active Betaproteobacteria, incorporating almost all tracers. While three closely related betaproteobacterial populations substantially differed in their uptake spectra, two more distantly related lineages had very similar preferences, and one population did not incorporate any tracer. The dominant phototrophic microorganism, the filamentous cyanobacterium Planktothrix rubescens, assimilated several substrates, whereas other (pico)cyanobacteria had no heterotrophic activity. The variable extent of specialization by the studied bacterial taxa on subsets of LMW compounds contrasts theoretical considerations about non-selective microbial substrate assimilation at oligotrophic conditions. This physiological niche separation might be one explanation for the coexistence of freshwater bacterioplankton species in a seemingly uniform environment.

Metabolic inflexibility of white and brown adipose tissues in abnormal fatty acid partitioning of type 2 diabetes.

Type 2 diabetes (T2D) is characterized by a general dysregulation of postprandial energy substrate partitioning. Although classically described in regard to glucose metabolism, it is now evident that metabolic inflexibility of plasma lipid fluxes is also present in T2D. The organ that is most importantly involved in the latter metabolic defect is the white adipose tissue (WAT). Both catecholamine-induced nonesterified fatty acid mobilization and insulin-stimulated storage of meal fatty acids are impaired in many WAT depots of insulin-resistant individuals. Novel molecular imaging techniques now demonstrate that these defects are linked to increased dietary fatty acid fluxes toward lean organs and myocardial dysfunction in humans. Recent findings also demonstrate functional abnormalities of brown adipose tissues in T2D, thus suggesting that a generalized adipose tissue dysregulation of energy storage and dissipation may be at play in the development of lean tissue energy overload and lipotoxicity.

Protein folding rates and thermodynamic stability are key determinants for interaction with the Hsp70 chaperone system

The Hsp70 family of molecular chaperones participates in vital cellular processes including the heat shock response and protein homeostasis. E. coli's Hsp70, known as DnaK, works in concert with the DnaJ and GrpE co-chaperones (K/J/E chaperone system), and mediates cotranslational and post-translational protein folding in the cytoplasm. While the role of the K/J/E chaperones is well understood in the presence of large substrates unable to fold independently, it is not known if and how K/J/E modulates the folding of smaller proteins able to fold even in the absence of chaperones. Here, we combine experiments and computation to evaluate the significance of kinetic partitioning as a model to describe the interplay between protein folding and binding to the K/J/E chaperone system. First, we target three nonobligatory substrates, that is, proteins that do not require chaperones to fold. The experimentally observed chaperone association of these client proteins during folding is entirely consistent with predictions from kinetic partitioning. Next, we develop and validate a computational model (CHAMP70) that assumes kinetic partitioning of substrates between folding and interaction with K/J/E. CHAMP70 quantitatively predicts the experimentally measured interaction of RNase H(D) as it refolds in the presence of various chaperones. CHAMP70 shows that substrates are posed to interact with K/J/E only if they are slow-folding proteins with a folding rate constant k(f) <50 s⁻¹, and/or thermodynamically unstable proteins with a folding free energy ΔG⁰ (UN) ≥-2 kcal mol⁻¹. Hence, the K/J/E system is tuned to use specific protein folding rates and thermodynamic stabilities as substrate selection criteria.

Mitochondrial ROS and muscle glucose uptake during exercise in transgenic mice

much research has examined the factors regulating skeletal muscle glucose uptake during exercise. Part of the impetus for this work has been to describe and understand the effects of regular physical activity (i.e., exercise training) on muscle glucose uptake and energy substrate partitioning,

Subjective Measures of Exercise Intensity to Gauge Substrate Partitioning in Persons With Paraplegia

The Borg Rating of Perceived Exertion (RPE) Scale and talk test (TT) are commonly recommended for persons to gauge exercise intensity. It is not known whether they are suitable to estimate substrate partitioning between carbohydrate and fat in persons with SCI. Investigate substrate partitioning/utilization patterns associated with RPE and TT. Twelve participants with chronic paraplegia underwent 2 arm crank exercise tests on nonconsecutive days within 2 weeks. Test 1 was a graded exercise test (GXT) to volitional exhaustion. Test 2 was a 15-minute self-selected steady state (SS) voluntary arm exercise bout simulating a brief, yet typical exercise session. For the GXT, very light intensity exercise (RPE < 9) and TT stage before last positive were associated with highest contribution of fat oxidation (~35%-50%) to total energy expenditure (TEE). Fat oxidation was low at all stages, with the highest rate (0.13 ± 0.07 g/min) occurring at stage 1 (10 W). Corresponding average RPE was 7 ± 2 and the TT was positive for all participants at this stage. For the SS, fuel partitioning throughout exercise was dominated by carbohydrate oxidation (1.47 ± 0.08 g/min), accounting for almost all (~94%) of TEE with only a minute contribution from fat oxidation (0.02 ± 0.004 g/min). A positive TT was associated with an average contribution of fat oxidation of ~10%. RPE but not the TT appears suitable to predict exercise intensities associated with the highest levels of fat oxidation. However, such intensities are below authoritative intensity thresholds for cardiorespiratory fitness promotion, and therefore the applicability of such a prediction for exercise prescriptions is likely limited to individuals with low exercise tolerance.

Increased serum concentrations of persistent organic pollutants among prediabetic individuals: potential role of altered substrate oxidation patterns.

There is a need for a better understanding of the potential role of persistent organic pollutants (POPs) in the pathogenesis of type 2 diabetes. Our objective was to determine the association of serum concentrations of POPs with early signs of type 2 diabetes in regard to glucose and lipid metabolism. In this cross-sectional study, we used recent studies of 148 Danish middle-aged normoglycemic, prediabetic, and diabetic individuals examined by the euglycemic-hyperinsulinemic clamp technique with indirect calorimetry; 66 of these individuals also had an i.v. glucose tolerance test. Concentrations of POPs were analyzed in banked serum from the participants. Associations with basal and insulin-stimulated glucose and lipid metabolism were assessed after adjustment for age, sex, and body fat percentage. Individuals with prediabetes and diabetes had higher serum concentrations of several POPs compared with normoglycemic individuals. In the nondiabetic population, higher POPs levels were associated with elevated fasting plasma glucose concentrations as well as reduced glucose oxidation, elevated lipid oxidation, and elevated serum concentrations of free fatty acids (P < 0.05). We found no associations of POPs with first-phase insulin secretion, hepatic or peripheral insulin sensitivity, or nonoxidative glucose metabolism. Diabetic and prediabetic individuals have elevated serum concentrations of POPs. In nondiabetic individuals, POPs exposure is related to altered substrate oxidation patterns with lower glucose oxidation and higher lipid oxidation rates. These findings indicate that POPs may affect peripheral glucose metabolism by modifying pathways involved in substrate partitioning rather than decreasing insulin-dependent glucose uptake.

Effects of Meal Frequency on Metabolic Profiles and Substrate Partitioning in Lean Healthy Males

IntroductionThe daily number of meals has an effect on postprandial glucose and insulin responses, which may affect substrate partitioning and thus weight control. This study investigated the effects of meal frequency on 24 h profiles of metabolic markers and substrate partitioning.MethodsTwelve (BMI:21.6±0.6 kg/m2) healthy male subjects stayed after 3 days of food intake and physical activity standardization 2×36 hours in a respiration chamber to measure substrate partitioning. All subjects randomly received two isoenergetic diets with a Low meal Frequency (3×; LFr) or a High meal Frequency (14×; HFr) consisting of 15 En% protein, 30 En% fat, and 55 En% carbohydrates. Blood was sampled at fixed time points during the day to measure metabolic markers and satiety hormones.ResultsGlucose and insulin profiles showed greater fluctuations, but a lower AUC of glucose in the LFr diet compared with the HFr diet. No differences between the frequency diets were observed on fat and carbohydrate oxidation. Though, protein oxidation and RMR (in this case SMR + DIT) were significantly increased in the LFr diet compared with the HFr diet. The LFr diet increased satiety and reduced hunger ratings compared with the HFr diet during the day.ConclusionThe higher rise and subsequently fall of insulin in the LFr diet did not lead to a higher fat oxidation as hypothesized. The LFr diet decreased glucose levels throughout the day (AUC) indicating glycemic improvements. RMR and appetite control increased in the LFr diet, which can be relevant for body weight control on the long term.Trial RegistrationClinicalTrails.gov NCT01034293

C5L2 receptor disruption enhances the development of diet-induced insulin resistance in mice

IntroductionAcylation stimulating protein (ASP) is a hormone secreted by the adipose tissue that has been shown to increase triglyceride storage and glucose transport in adipocytes. These effects are mediated by C5L2 receptor, which has also been associated with inflammatory effects. C5L2 deficient mice on a low-fat diet are hyperphagic yet lean due to increased energy expenditure. The present study assessed insulin sensitivity and metabolic and inflammatory changes in C5L2KO mice vs WT in diet-induced obesity. MethodsWe placed C5L2KO and WT mice on a diabetogenic diet for 12 weeks and examined in vivo and ex vivo metabolism. ResultsC5L2KO mice on a diabetogenic diet exhibit decreased insulin sensitivity. Whole body substrate partitioning is evidenced through increased glucose uptake by the liver and decreased uptake by adipose tissue and skeletal muscle. Lipid content of both liver and skeletal muscle was higher in C5L2KO mice vs WT. Furthermore, elevated levels of macrophage markers were found in adipose tissue, liver and skeletal muscle of C5L2KO mice vs WT. Several inflammatory cytokines such as IL-6, MIP-1α and KC were also elevated in plasma of C5L2KO mice vs WT. ConclusionsOverall, we demonstrated that C5L2KO mice fed a diabetogenic diet develop more severe insulin resistance than WT mice through altered substrate partitioning, ectopic fat deposition and a pro-inflammatory phenotype.

Partitioning of Substrate within Aqueous Micelle Systems by Using Dead-End and Cross Flow Membrane Filtrations

The partition coefficients of different solutes as Itaconic acid (IA), dimethyl itaconate (DMI), diethyl itaconate (DEI) and dibuthyl itaconate (DBI) between water and micelles of Triton X-100 are determined by the two methods of separation namely Cross Flow Filtration and Dead-End Filtration by using a membrane that rejects the micelles and lets passing the molecules of solute. Partition coefficient of the solute between the aqueous phase and micelle aggregate was determined by titration and HPLC methods. The results obtained are discussed in our researcher's group and compared to others made with theoretical data reported from simulation. The effect of the different concentrations of solutes and transmembrane pressures have been investigated using a commercial membrane Nadir C005 (MWCO = 5 kDa).

Structure and Dynamics of Mycobacterium tuberculosis Truncated Hemoglobin N: Insights from NMR Spectroscopy and Molecular Dynamics Simulations

The potent nitric oxide dioxygenase (NOD) activity (trHbN-Fe²⁺-O₂ + (•)NO → trHbN-Fe³⁺-OH₂ + NO₃⁻) of Mycobacterium tuberculosis truncated hemoglobin N (trHbN) protects aerobic respiration from inhibition by (•)NO. The high activity of trHbN has been attributed in part to the presence of numerous short-lived hydrophobic cavities that allow partition and diffusion of the gaseous substrates (•)NO and O₂ to the active site. We investigated the relation between these cavities and the dynamics of the protein using solution NMR spectroscopy and molecular dynamics (MD). Results from both approaches indicate that the protein is mainly rigid with very limited motions of the backbone N-H bond vectors on the picoseconds-nanoseconds time scale, indicating that substrate diffusion and partition within trHbN may be controlled by side-chains movements. Model-free analysis also revealed the presence of slow motions (microseconds-milliseconds), not observed in MD simulations, for many residues located in helices B and G including the distal heme pocket Tyr33(B10). All currently known crystal structures and molecular dynamics data of truncated hemoglobins with the so-called pre-A N-terminal extension suggest a stable α-helical conformation that extends in solution. Moreover, a recent study attributed a crucial role to the pre-A helix for NOD activity. However, solution NMR data clearly show that in near-physiological conditions these residues do not adopt an α-helical conformation and are significantly disordered and that the helical conformation seen in crystal structures is likely induced by crystal contacts. Although this lack of order for the pre-A does not disagree with an important functional role for these residues, our data show that one should not assume an helical conformation for these residues in any functional interpretation. Moreover, future molecular dynamics simulations should not use an initial α-helical conformation for these residues in order to avoid a bias based on an erroneous initial structure for the N-termini residues. This work constitutes the first study of a truncated hemoglobin dynamics performed by solution heteronuclear relaxation NMR spectroscopy.

Diversity and substrate partitioning of Discomycetes in a cloud forest in Venezuela

Diversity and substrate partitioning of Discomycetes in a cloud forest in Venezuela

The influence of distributional kinetics into a peripheral compartment on the pharmacokinetics of substrate partitioning between blood and brain tissue

Development of CNS-targeted agents often focuses on identifying compounds with "good" CNS exposure (brain-to-blood partitioning >1). Some compounds undergoing enterohepatic recycling (ER) evidence a partition coefficient, K (p,brain) (expressed as C (brain) /C (plasma)), that exceeds and then decreases to (i.e., overshoots) a plateau (distribution equilibrium) value, rather than increasing monotonically to this value. This study tested the hypothesis that overshoot in K (p,brain) is due to substrate residence in a peripheral compartment. Simulations were based on a 3-compartment model with distributional clearances between central and brain (CL (br)) and central and peripheral (CL (d)) compartments and irreversible clearance from the central compartment (CL). Parameters were varied to investigate the relationship between overshoot and peripheral compartment volume (V (p)), and how this relationship was modulated by other model parameters. Overshoot magnitude and duration were characterized as peak C (brain)/C (plasma) relative to the plateau value (%OS) and time to reach plateau (TRP). Except for systems with high CL (d), increasing V (p) increased TRP and %OS. Increasing brain (V (br)) or central (V (c)) distribution volumes eliminated V (p)-related OS. Parallel increases in all clearances shortened TRP, but did not alter %OS. Increasing either CL or CL (d) individually increased %OS related to V (p), while increasing CL (br) decreased %OS. Under realistic peripheral distribution scenarios, C (brain)/C (plasma) may overshoot substantially K (p,brain) at distribution equilibrium. This observation suggests potential for erroneous assessment of brain disposition, particularly for compounds which exhibit a large apparent V (p), and emphasizes the need for complete understanding of distributional kinetics when evaluating brain uptake.

Prevention of Overweight/Obesity as a Strategy to Optimize Cardiovascular Health

The prevalence of obesity in the United States and the world has risen to epidemic/pandemic proportions. This increase has occurred despite efforts by healthcare providers and consumers alike to improve the health-related behaviors of the population and a tremendous push from the scientific community to better understand the pathophysiology of obesity. This epidemic is all the more concerning given the clear association between excess adiposity and adverse health consequences such as cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM). These risks associated with overweight/obesity are primarily related to the deposition of excess adiposity or body fatness. Weight loss, specifically loss of body fat, is associated with benefits in all of the obesity-related comorbidities, but, unfortunately, most weight loss interventions are associated with weight regain and are therefore not successful in the long term. It is for these reasons that efforts to prevent weight gain and overweight/obesity are necessary. This is especially important when one considers younger individuals, who have even more to lose as a consequence of a longer duration of excess adiposity. After a brief review of the epidemiology of obesity, this statement will make the case for the importance of weight gain prevention. This argument will first include a review of the complications of overweight and obesity in both adults and children, including the future CVD risks of obesity in early life. Energy balance dysregulation and adaptations to the weight-reduced state, favoring weight regain, will then be reviewed as further argument for the need for obesity prevention. This will be followed by a discussion on the goals and strategies for accomplishing the difficult task of the prevention of weight gain and obesity. ### Classification of Overweight and Obesity The body mass index (BMI) is the most widely used and accepted method for the assessment and classification of excess adiposity or body fatness. Overweight …

Nutrient Responsive Nesfatin-1 Regulates Energy Balance and Induces Glucose-Stimulated Insulin Secretion in Rats

Nesfatin-1 is a recently discovered anorexigen, and we first reported nesfatin-like immunoreactivity in the pancreatic β-cells. The aim of this study was to characterize the effects of nesfatin-1 on whole-body energy homeostasis, insulin secretion, and glycemia. The in vivo effects of continuous peripheral delivery of nesfatin-1 using osmotic minipumps on food intake and substrate partitioning were examined in ad libitum-fed male Fischer 344 rats. The effects of nesfatin-1 on glucose-stimulated insulin secretion (GSIS) were examined in isolated pancreatic islets. L6 skeletal muscle cells and isolated rat adipocytes were used to assess the effects of nesfatin-1 on basal and insulin-mediated glucose uptake as well as on major steps of insulin signaling in these cells. Nesfatin-1 reduced cumulative food intake and increased spontaneous physical activity, whole-body fat oxidation, and carnitine palmitoyltransferase I mRNA expression in brown adipose tissue but did not affect uncoupling protein 1 mRNA in the brown adipose tissue. Nesfatin-1 significantly enhanced GSIS in vivo during an oral glucose tolerance test and improved insulin sensitivity. Although insulin-stimulated glucose uptake in L6 muscle cells was inhibited by nesfatin-1 pretreatment, basal and insulin-induced glucose uptake in adipocytes from nesfatin-1-treated rats was significantly increased. In agreement with our in vivo results, nesfatin-1 enhanced GSIS from isolated pancreatic islets at both normal (5.6 mM) and high (16.7 mM), but not at low (2 mM), glucose concentrations. Furthermore, nesfatin-1/nucleobindin 2 release from rat pancreatic islets was stimulated by glucose. Collectively, our data indicate that glucose-responsive nesfatin-1 regulates insulin secretion, glucose homeostasis, and whole-body energy balance in rats.

Energy Substrate Partitioning and Efficiency in Individuals With Atherogenic Lipoprotein Phenotype

Individuals with an atherogenic lipoprotein phenotype (ALP) characterized by increased levels of small dense low-density lipoprotein (LDL) particles tend to have greater adiposity compared to unaffected subjects. We sought to determine whether this may be related to alterations in energy substrate partitioning or efficiency. These were assessed by indirect calorimetry in men with ALP (ALP(+), n = 7) and unaffected controls (ALP(-), n = 8) during rest (30 min) and exercise (10 min). Gross, net and delta efficiencies were calculated during graded leg-cycle ergometry at workloads of 10 and 50 W. Respiratory exchange ratios (RER) were significantly (P < 0.05) higher in ALP(+) vs. ALP(-) during rest (0.86 ± 0.01 vs. 0.83 ± 0.02) and exercise at 10 W (0.88 ± 0.02 vs. 0.84 ± 0.02) and 50 W (0.92 ± 0.01 vs. 0.87 ± 0.01, respectively) (P < 0.05). Lipid oxidation (kcal/min) was lower in ALP(+) vs. ALP(-) during rest (0.56 ± 0.02 vs. 0.71 ± 0.07) and exercise at 10 W (1.52 ± 0.25 vs. 2.00 ± 0.20) and 50 W (1.28 ± 0.10 vs. 2.32 ± 0.22, respectively) (P < 0.05). Gross and net efficiencies were significantly increased (P = 0.005) in ALP(+) vs. ALP(-) at 10 W. RER was correlated positively with plasma triglyceride during exercise and inversely with high-density lipoprotein (HDL) cholesterol and LDL peak particle diameter during rest and exercise (P < 0.05). These findings suggest that increased muscular efficiency at low exercise intensity and reduced lipid oxidation during rest and exercise may contribute to both dyslipidemia and increased adiposity in individuals with ALP.