Respiratory Quotient Research Articles

Altered function of arcuate leptin receptor expressing neuropeptide Y neurons depending on energy balance

ObjectiveOne of leptin's main targets in the hypothalamus are neuropeptide Y (NPY) neurons, with selective deletion of leptin receptors (Lepr) specifically in Npy neurons resulting in major alterations of energy partitioning between fat and bone mass. However, the specific action of these Npy+/Lepr+ neurons compared to Npy-negative Lepr (Npy−/Lepr+) neurons in regard to energy homeostasis regulation is unknown. MethodsSpecific AAV viral vectors were generated using DREADD and INTRSECT technology and used in male LeprCre/+ and LeprCre/+;NpyFlp/+ mice to assess the effect of activating either all Lepr neurons or specifically Npy+/Lepr+ or Npy−/Lepr+ neurons only on feeding, energy homeostasis control, and body composition. ResultsSelective stimulation of Npy+/Lepr+ neurons led to an immediate decrease in respiratory quotient followed by a delayed increase in food intake in standard chow fed, but interestingly not in high fat diet (HFD) fed mice. In addition, stimulation of Npy+/Lepr+ neurons led to a robust increase in brown adipose tissue thermogenesis and improved glucose tolerance. These effects were not observed in standard chow fed mice when Npy−/Lepr+ expressing neurons were specifically activated, suggesting the effects of leptin on these parameters are driven by NPY. However, under HFD condition when leptin levels are elevated, the stimulation of the Npy−/Lepr+ neurons increased food intake, physical activity and energy expenditure. Interestingly, chronic stimulation of Npy-positive Lepr neurons was able to increase bone mass independently of bodyweight, whilst chronic stimulation of the Npy−/Lepr+ neurons resulted in increased bodyweight and fat mass with proportionate increases in bone mass. ConclusionsTogether, these data indicate that leptin signalling through Npy-positive Lepr-expressing neurons controls energy partitioning via stimulation of thermogenesis, energy expenditure, and the use of fat as a fuel source. However, under prolonged HFD, leptin resistance may occur and actions of leptin signalling through Npy-negative Lepr hypothalamic neurons may exacerbate excess food intake.

NEFA Dynamics in Adults With Severe Obesity and Insulin Resistance: No Coupling to the rs9939609 FTO Risk Allele.

The FTO gene is highly expressed in adipose tissues; however, whether nonesterified fatty acids (NEFA) dynamics are impacted by FTO has not been rigorously tested for in a uniformly obese study population comprising both sexes. To test for associations of the rs9939609 FTO risk allele with NEFA suppression. We investigated 97 subjects with severe obesity but without diabetes, having genotype TT (n = 32), AT (n = 31), or AA (n = 34) in a cross-sectional observation study. NEFA suppression was assessed from a low-dose hyperinsulinemic euglycemic clamp with glucose-tracer as well as from the response to a standardized meal. Insulin sensitivity was assessed by hepatic and total insulin sensitivity measurements in the clamp and by the Matsuda index during the meal. Variables of possible importance for NEFA dynamics were primarily assessed by linear regression. No genotype associations with fasting or suppressed NEFA were found, whether in the clamp or meal situation (P > .7 for all comparisons). Independent of genotype, higher fasting concentrations of NEFA and larger NEFA suppression were found in female compared with male subjects. Fasting NEFA or degree of suppression were not associated with total fat mass or body mass index. The respiratory quotient was negatively associated with NEFA suppression. In a gender-mixed adult population of obese individuals, an FTO obesity-risk allele did not affect fasting NEFA nor suppression thereof. These negative results on NEFA dynamics appear strengthened by the documentation of gender influence and associations with parameters reflective of insulin resistance.

Short-duration cold exposure decreases fasting-induced glucose intolerance but has no effect on resting energy expenditure

The aim of the present study was to investigate whether brief cold exposure can reverse fasting-induced glucose intolerance and insulin resistance, and improve resting energy expenditure (REE). Twelve young non-obese women were randomly assigned to undergo the following conditions: 2 days of fasting with two 10-min whole-body cold-water immersions on separate days (FAST-COLD), 2 days of fasting without cold-water immersions (FAST), 2 days of usual diet with two 10-min whole-body cold-water immersions on separate days (COLD), or 2 days of usual diet without cold-water immersions (CON) in a randomised crossover fashion. Changes in REE and substrate utilisation, and glucose tolerance and insulin sensitivity from the oral glucose tolerance test were examined. The results showed that FAST-COLD and FAST trials increased (P < 0.05) REE and decreased (P < 0.05) respiratory quotient, but these variables did not differ significantly between the FAST-COLD and FAST trials. The glucose and insulin area under the curves (AUCs) were higher (P < 0.05) in the FAST-COLD and FAST trials than in the CON and COLD trials, and these AUCs were lower (P < 0.05) in the FAST-COLD than in the FAST trial. Matsuda index was lower in the FAST trial than in the CON trial (P < 0.05), and tended to be greater after the FAST-COLD trial than after the FAST trial (P = 0.060). In conclusion, cold exposure had no effect on REE but decreased fasting-induced glucose intolerance which was accompanied by a maintained insulin sensitivity.

Dietary choline, but not L-carnitine, increases circulating lipid and lipoprotein concentrations, without affecting body composition, energy expenditure or respiratory quotient in lean and obese male cats during weight maintenance.

Due to the involvement in one-carbon metabolism and lipid mobilization, choline and L-carnitine supplementation have been recommended to minimize hepatic lipid accumulation and support fat oxidation, respectively. This study investigated the lipotropic benefits of choline or L-carnitine supplementation in lean and obese cats maintaining body weight (BW). Lean [n = 9; body condition score (BCS): 4-5/9] and obese (n = 9; BCS: 8-9/9) adult male neutered colony cats were used in a replicated 3 x 3 complete Latin square design. Treatments included choline (378 mg/kg BW0.67), L-carnitine (200 mg/kg BW) and control (no supplement). Treatments were supplemented to the food for 6 weeks each, with a 2-week washout between treatments. Cats were fed once daily to maintenance energy requirements, and BW and BCS were assessed weekly. Fasted blood collection, indirect calorimetry, and dual-energy X-ray absorptiometry occurred at the end of each treatment period. Serum was analyzed for cholesterol (CHOL), high-density lipoprotein CHOL (HDL-C), triglycerides (TAG), non-esterified fatty acids (NEFA), glucose, creatinine (CREAT), urea, alkaline phosphatase (ALP) and alanine aminotransferase (ALT). Very low-density lipoprotein CHOL (VLDL) and low-density lipoprotein CHOL (LDL-C) were calculated. Data were analyzed using proc GLIMMIX, with group and period as random effects, and treatment, body condition, and their interaction as fixed effects, followed by a Tukey's post-hoc test when significance occurred. Cats supplemented choline had lower food intake (P = 0.025). Treatment did not change BW, BCS and body composition (P > 0.05). Obese cats had greater ALP, TAG, and VLDL, and lower HDL-C compared to lean cats (P < 0.05). Choline resulted in greater CHOL, HDL-C, LDL-C and ALT (P < 0.05). L-carnitine resulted in lower CREAT (P = 0.010). Following the post-hoc test, differences between treatment means were not present for ALP (P = 0.042). No differences were found for glucose, urea or NEFA (P > 0.05). Obese cats had a lower fed respiratory quotient (RQ), regardless of treatment (P = 0.045). Treatment did not affect fed or fasted RQ and energy expenditure (P > 0.05). Choline appeared to increase circulating lipid and lipoprotein concentrations regardless of body condition, likely through enhanced lipid mobilization and hepatic elimination. Neither dietary choline or L-carnitine altered body composition or energy metabolism in the lean or obese cats, as compared to control.

Training effects of set- and repetition-interval rest time on recumbent-boxing exercise: Could virtual reality improve further?

This study examined the influence of set-interval and repetition-interval rest time of virtual reality (VR) boxing game in supine-lying posture. Fifty healthy middle-aged adults were randomly assigned into VR and non-VR groups to perform six different exercise protocols with varying set-interval and repetition-interval rest times (S0R0, S0R1/3, S0R2/3, S40R0, S40R1/3, and S40R2/3). Analysis on the non-VR group showed significant differences between exercise protocols for average heart rate (p<0.001), maximum ventilation volume (p<0.001), respiratory quotient (p<0.001), oxygen pulse (p<0.001), and excess post-exercise oxygen consumption (EPOC) (p= 0.003). VR appeared to have no further improvement on physical training effects in middle-aged adults, while the participants reported negative experience that might be associated with the over-exertion. Future study might need to explore game design elements that can accommodate high-exertion exercises.

Hydrogen online monitoring based on thermal conductivity for anaerobic microorganisms.

H2 -producing microorganisms are a promising source of sustainable biohydrogen. However, most H2 -producing microorganisms are anaerobes, which are difficult to cultivate and characterize. While several methods for measuring H2 exist, common H2 sensors often require oxygen, making them unsuitable for anaerobic processes. Other sensors can often not be operated at high gas humidity. Thus, we applied thermal conductivity(TC) sensors and developed a parallelized, online H2 monitoring for time-efficient characterization of H2 production by anaerobes. Since TC sensors are nonspecific for H2 , the cross-sensitivity of the sensors was evaluated regarding temperature, gas humidity, and CO2 concentrations. The systems' measurement range was validated with two anaerobes: a high H2 -producer (Clostridium pasteurianum) and a low H2 -producer (Phocaeicola vulgatus). Online monitoring of H2 production in shake flask cultivations was demonstrated, and H2 transfer rates were derived. Combined with online CO2 and pressure measurements, molar gas balances of the cultivations were closed, and an anaerobic respiration quotient was calculated. Thus, insight into the effect of medium components and inhibitory cultivation conditions on H2 production with the model anaerobes was gained. The presented online H2 monitoring method can accelerate the characterization of anaerobes for biohydrogen production and reveal metabolic changes without expensive equipment and offline analysis.

Severe COVID-19 associated hyperglycemia is caused by beta cell dysfunction: a prospective cohort study

BackgroundCOVID-19, an infectious disease caused by SARS-CoV-2, was shown to be associated with an increased risk of new-onset diabetes. Mechanisms contributing to the development of hyperglycemia are still unclear. We aimed to study whether hyperglycemia is related to insulin resistance and/or beta cell dysfunction.Materials and methodsSurvivors of severe COVID-19 but without a known history of diabetes were examined at baseline (T0) and after 3 (T3) and 6 (T6) months: corticosteroids use, indirect calorimetry, and OGTT. Insulin response and sensitivity (IS) were expressed as insulinogenic (IGI), disposition (DI), and Matsuda insulin sensitivity index (ISI). Resting energy expenditure (REE) and respiratory quotient (RQ) was calculated from the gas exchange and nitrogen losses.Results26 patients (out of 37) with complete outcome data were included in the analysis (age ~59.0 years; BMI ~ 30.4, 35% women). Patients were hypermetabolic at T0 (30.3 ± 4.0 kcal/kg lean mass/day, ~120% predicted) but REE declined over 6 months (ΔT6-T0 mean dif. T6-T0 (95% CI): −5.4 (−6.8, −4.1) kcal/kg FFM/day, p < 0.0001). 17 patients at T0 and 13 patients at T6 had hyperglycemia. None of the patients had positive islet autoantibodies. Insulin sensitivity in T0 was similarly low in hyperglycemic (H) and normoglycemic patients (N) (T0 ISIH = 3.12 ± 1.23, ISIN = 3.47 ± 1.78, p = 0.44), whereas insulin response was lower in the H group (DIH = 3.05 ± 1.79 vs DIN = 8.40 ± 5.42, p = 0.003). Over 6 months ISI (ΔT6-T0 mean dif. T6-T0 for ISI (95% CI): 1.84 (0.45, 3.24), p = 0.01)) increased in the H group only.ConclusionsPatients with severe COVID-19 had increased REE and insulin resistance during the acute phase due to the infection and corticosteroid use, but these effects do not persist during the follow-up period. Only patients with insufficient insulin response developed hyperglycemia, indicating that beta cell dysfunction, rather than insulin resistance, was responsible for its occurrence.

Venous Minus Arterial Carbon Dioxide Gradients in the Monitoring of Tissue Perfusion and Oxygenation: A Narrative Review.

According to Fick's principle, the total uptake of (or release of) a substance by tissues is the product of blood flow and the difference between the arterial and the venous concentration of the substance. Therefore, the mixed or central venous minus arterial CO2 content difference depends on cardiac output (CO). Assuming a linear relationship between CO2 content and partial pressure, central or mixed venous minus arterial PCO2 differences (Pcv-aCO2 and Pmv-aCO2) are directly related to CO. Nevertheless, this relationship is affected by alterations in the CO2Hb dissociation curve induced by metabolic acidosis, hemodilution, the Haldane effect, and changes in CO2 production (VCO2). In addition, Pcv-aCO2 and Pmv-aCO2 are not interchangeable. Despite these confounders, CO is a main determinant of Pcv-aCO2. Since in a study performed in septic shock patients, Pmv-aCO2 was correlated with changes in sublingual microcirculation but not with those in CO, it has been proposed as a monitor for microcirculation. The respiratory quotient (RQ)-RQ = VCO2/O2 consumption-sharply increases in anaerobic situations induced by exercise or critical reductions in O2 transport. This results from anaerobic VCO2 secondary to bicarbonate buffering of anaerobically generated protons. The measurement of RQ requires expired gas analysis by a metabolic cart, which is not usually available. Thus, some studies have suggested that the ratio of Pcv-aCO2 to arterial minus central venous O2 content (Pcv-aCO2/Ca-cvO2) might be a surrogate for RQ and tissue oxygenation. In this review, we analyze the physiologic determinants of Pcv-aCO2 and Pcv-aCO2/Ca-cvO2 and their potential usefulness and limitations for the monitoring of critically ill patients. We discuss compelling evidence showing that they are misleading surrogates for tissue perfusion and oxygenation, mainly because they are systemic variables that fail to track regional changes. In addition, they are strongly dependent on changes in the CO2Hb dissociation curve, regardless of changes in systemic and microvascular perfusion and oxygenation.

1612-P: Energetic Contributions of GLP1 and GCGR Activity in GLP1/GIP/GCGR Triagonism

Glucagon has been implicated as a key diabetogenic factor. However, agonists that couple the lipolytic and thermogenic properties of Glucagon Receptor (GCGR) activity with the antidiabetic actions of incretins (GLP1, GIP), lack hyperglycemic side effects associated with GCGR activity. GCGR agonism stimulates energy expenditure (EE) that contributes to weight loss. Interestingly, we also identified that the anti-obesity effects of GCGR agonism persisted for 50d after treatment cessation. Thus, we hypothesized that GCGR activity paired with incretin action (GGG) will result in increased EE during treatment and prolonged weight loss after cessation. Diet-induced obese mice were treated for 14d with vehicle, GGG, or single receptor agonism via IUB288 (GCGR), Semagutide (Sema;GLP1R), or GIP-FA 085 (GIPR). Indirect calorimetry was conducted for d 2-4 of treatment and d 16-18 after cessation. Congruent with our prior studies, IUB288 increased EE compared to vehicle controls. Conversely, Sema-treated mice displayed decreased EE (d 2 and 3) while EE following GIP treatment was similar to vehicle controls. Intriguingly, GGG reduced EE on d 2, had similar EE to vehicle controls on d 3, with a trend towards increased EE on d 4, suggesting GGG treatment stimulates characteristics of both GLP1 and GCGR activity. Nutrient utilization, measured via Respiratory Quotient (RQ), was reduced during the light period with IUB288 treatment. GIP, Sema, and GGG reduced RQ, regardless of time of day. Interestingly, GGG regulation of RQ appeared most like Sema. After treatment cessation, Sema mice gained significantly more weight than IUB288 or GGG mice, despite similar food intake during rebound. Surprisingly, EE was not elevated in mice that formerly received IUB288 or GGG, suggesting another mechanism may be driving this effect. RQ was similar in all groups, except IUB288 mice, which exhibited increased RQ across the day. These data suggest that GGG exhibits effects of both GLP1R and GCGR agonism with respect to EE and RQ. Disclosure S.Nason: None. J.Antipenko: None. K.M.Habegger: Consultant; Glyscend Inc., Research Support; Eli Lilly and Company, Novo Nordisk, Glyscend Inc., Stock/Shareholder; Glyscend Inc. Funding Eli Lilly and Company

127-OR: The Effect of Tirzepatide during Weight Loss on Metabolic Adaption, Fat Oxidation, and Food Intake in People with Obesity

We hypothesized that tirzepatide (TZP) causes body weight loss by reducing food intake and, according to pre-clinical studies, decreasing metabolic adaptation during weight loss. In a randomized blinded clinical trial in people with obesity (PWO) undergoing caloric restriction, we investigated the effect of TZP vs Placebo (PBO) on energy metabolism after targeting a 10% (±2%) weight loss. In this 18wk phase 1 study, 55 PWO, were randomized (1:1) to TZP 15 mg or PBO (mean baseline body weight 102.5 vs 103.1 kg, respectively). The primary objective was to investigate the change from baseline in sleeping metabolic rate (SMR) measured by whole-room indirect calorimetry. Secondary measures were changes in 24-hr sedentary energy expenditure, 24-hr respiratory quotient (RQ), sleeping RQ, substrate utilization, body composition (BC) and food intake. TZP caused greater weight loss than PBO (-16.7 kg vs -8.3 kg; p&amp;lt;0.001). The decreases in SMR and 24-hr energy expenditure were not different between groups after adjusting for changes in body weight and BC. However, TZP significantly reduced 24-hr RQ and sleeping RQ compared to PBO; thus, significantly increasing fat oxidation while decreasing carbohydrate and protein oxidation rates. TZP also significantly reduced food intake. Overall, TZP did not affect metabolic adaptation but significantly increased fat oxidation. Disclosure E.Ravussin: Advisory Panel; Novartis, Research Support; Eli Lilly and Company, Novartis AG. A.Haupt: Employee; Lilly, Stock/Shareholder; Lilly. G.Sanchez-delgado: Research Support; Eli Lilly and Company, Novo Nordisk, Abbott, Maastricht instruments, Vyaire Medical, ParvoMedics, Cosmed, Speaker's Bureau; Eli Lilly and Company. C.K.Martin: Board Member; EHE Health, Wondr Health, Other Relationship; ABGIL, Research Support; Pack Health, Evidation Health, Lilly, WW International, Inc. H.Nishiyama: None. J.Li: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. S.Urva: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. E.J.Pratt: Employee; Eli Lilly and Company. T.Coskun: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. Z.Milicevic: Employee; Eli Lilly and Company. Funding Eli Lilly and Company

1674-P: Increased Glucose Uptake in Brown Fat Promotes Energy Expenditure

Brown and beige fat dissipate energy as heat in response to β3-adrenergic receptor (β3AR) stimulation. Strategies to facilitate this response may be employed to promote weight loss and improve health in patients with metabolic disease. Previously, we discovered that GTPase RalA and its GAP complex RalGAP regulate exocytosis of glucose transporter GLUT4. We demonstrated in vivo, that adipose-tissue specific knockout of RalGAP subunit RalGAPB activates RalA and increases glucose uptake 7 times in brown fat (BAT), leading to improved glucose handling on high fat diet (HFD). Here we seek to test the effect of increased glucose uptake in BAT on energy expenditure (EE), using mice with BAT-specific knockout of RalGAPB (the KO mice). After 8 weeks on 45% HFD, the KO mice and control littermates (Ctr) were injected with β3AR agonist CL-316,243 (CL) or PBS for 8 days. Mice assigned to CL were placed in metabolic cages. Respiratory quotient was increased in the KO mice, indicating increased glucose oxidation (likely by BAT, due to increased glucose uptake). EE at room temperature was elevated in the KO mice. This was compensated by increased food uptake, explaining similar body weights between the KO and Ctr mice. CL injections, as expected, induced spikes in EE. Acute response to CL (arbitrarily defined as EE during 2 hours after CL injection) was consistent between daily CL injections in Ctr mice, and was increased twice in the KO mice compared to Ctr. In Ctr mice, 1st CL injection increased average day and night EE; this response gradually declined with consecutive CL injections. In the KO mice, 1st CL injection elicited similar to Ctr mice increase in average day and night EE; and the response to consecutive CL injections was preserved. As anticipated, CL reduced adiposity in Ctr mice, which was further augmented in the KO mice, consistent with finding on EE. We will further test the role of increased glucose uptake by BAT in EE of the KO mice, and will determine the mechanism of sustained CL responsiveness in the KO mice. Disclosure F.Rezayat: None. J.A.Resnick: None. I.M.Farah: None. Y.Skorobogatko: None. A.Saltiel: Board Member; Elgia Therapeutics. Funding National Institutes of Health (P30DK063491)

1501-P: Deletion of miR-494 Induces Adipocyte Browning and Slows Aging in Mice

Adipocyte browning is a potent therapeutic strategy for obesity and metabolic disorders. We previously reported that miR-494 served as a negative regulator of mitochondrial biogenesis during browning in cultured adipocytes. However, the in vivo evidence has not been provided. In this study, we examined the role of miR-494 in adipocyte browning and aging using miR-494 knockout (KO) mice. KO mice were generated using CRISPR/Cas9 system. KO mice had equivalent energy expenditure, physical activity, food intake and body weight compared to wild-type (WT) mice; had lower resting respiratory quotient (0.95±0.006 vs 0.91±0.004), less visceral fat (16.3±1.08 vs 13.4±0.96 g/kg body weight) and 3.7-fold increased expression of Ucp1 in subcutaneous fat. In addition, KO mice showed cold tolerance during 3 hours exposure to 4ºC and increased oxygen consumption than WT mice after administration of a β3 agonist in thermoneutral condition, indicating an increase in non-shivering thermogenesis. In adipose tissues of KO mice, increased expression of Pgc-1α, a target gene of miR-494, and tendency to increase in mitochondrial DNA were observed. Primary adipocytes derived from KO mice showed enhanced mitochondrial respiration driven by fatty acids as determined by extracellular flux analysis. Finally, KO mice showed an extended median lifespan 29% relative to WT mice (from 113.7 to 146.7 weeks). Aged KO mice (≥ 2 years old) showed reduced age-related changes, such as hair graying and low physical activity. In conclusion, deletion of miR-494 demonstrated increased adipocyte browning and survival advantage in mice. Although there are numerous studies that focused on promoting adipocyte browning, its long-term effect has not been well evaluated. Thus, our data showing the association among miR-494, adipocyte browning and longevity provide a novel insight into adipocyte biology and aging study. The gene sequence of miR-494 and its binding site to Pgc-1α are conserved from mice to humans; it is expected to be applied to human research. Disclosure L.Sugawara: None. K.Morino: Research Support; AstraZeneca, Astellas Pharma Inc., Sanwa Kagaku Kenkyusho, Ono Pharmaceutical Co., Ltd. H.Iwasaki: None. S.Ida: None. T.Yanagimachi: None. M.Lemecha: None. H.Maegawa: None. Y.Fujita: Research Support; Terumo Corporation, Boehringer Ingelheim Japan, Inc., Japan Society for the Promotion of Science, Mitsubishi Tanabe Pharma Corporation, Sumitomo Dainippon Pharma Co., Ltd. S.Kume: Research Support; Boehringer Ingelheim International GmbH, Japan Society for the Promotion of Science. Funding Grants-in-Aid for Scientific Research (22K08650)

1557-P: Ctcfl Is a Fasting-Induced Epigenetic Regulator of Lipid Metabolism and Ketogenesis in the Liver

Engaging regulatory mechanisms mediating physiologic adaptations to fasting may be a potential tool for obesity and T2D. We previously demonstrated SGLT2i induce a fasting-like transcriptional program in liver, and identified Ctcfl (CCTC-binding factor (CTCF)-like) as a top-ranking transcript upregulated in SGLT2i-treated C57BL/6J mice (↑1.5-fold, p=0.01). Ctcfl was also upregulated 2.5-fold with fasting vs. fed littermates. We hypothesize Ctcfl mediates fasting-related transcriptional modulation via dynamic epigenetic regulation of chromatin accessibility. To identify drivers of Ctcfl expression, we studied AML12 hepatocytes, demonstrating key roles for AMPK activation and mTOR inhibition as upstream regulators. Moreover, in vivo inhibition of mTOR or insulin receptor increased hepatic Ctcfl expression (~2-fold), while insulin suppressed Ctcfl by ~50% within 3h. siRNA knockdown (KD) of Ctcfl indicates Ctcfl regulates transcriptional mediators of fasting (e.g. Hnf4, Srebf, Chrebp, Pgc1α), lipid/carbohydrate metabolism, and mitochondrial biogenesis. Single-cell RNAseq in Ctcfl-KD cells revealed distinct populations, enriched in mTOR, insulin signaling and Tfeb targets. Conversely, human CTCFL overexpression resulted in repression of regulators of lipid metabolism (Fas) and ketogenesis (Hmgcs2). In vivo liver-specific knockdown of Ctcfl, using N-acetyl galactosamine-conjugated siRNA, did not modulate body weight but increased circulating β-hydroxybutyrate and reduced respiratory quotient in the fasted state, suggesting shift to increased lipid utilization. Thus, we demonstrate Ctcfl is upregulated with fasting and fasting-like stimuli, including SGLT2i and AMPK activation, and repressed by refeeding, insulin signaling, and mTor pathways. Ctcfl can mediate a transcriptional program which may regulate lipid and ketone metabolism while acting as a “brake” to limit aberrant ketogenesis, potentially via alterations in chromatin accessibility. Disclosure V.Efthymiou: None. L.Poulos: None. L.Straub: None. V.Navarrete: None. B.Ozturk: None. S.Osataphan: None. J.I.Chimene-weiss: None. M.Patti: Consultant; MBX Biosciences, AstraZeneca, Hanmi Pharm. Co., Ltd., Other Relationship; Fractyl Health, Inc. Funding Swiss National Foundation; National Institutes of Health (R01DK106193)

Fully Integrated Wearable Device for Continuous Sweat Lactate Monitoring in Sports.

The chemical digitalization of sweat using wearable sensing interfaces is an attractive alternative to traditional blood-based protocols in sports. Although sweat lactate has been claimed to be a relevant biomarker in sports, an analytically validated wearable system to prove that has not yet been developed. We present a fully integrated sweat lactate sensing system applicable to in situ perspiration analysis. The device can be conveniently worn in the skin to monitor real-time sweat lactate during sports, such as cycling and kayaking. The novelty of the system is threefold: advanced microfluidics design for sweat collection and analysis, an analytically validated lactate biosensor based on a rational design of an outer diffusion-limiting membrane, and an integrated circuit for signal processing with a custom smartphone application. The sensor covering the range expected for lactate in sweat (1-20 mM), with appropriate sensitivity (-12.5 ± 0.53 nA mM-1), shows an acceptable response time (<90 s), and the influence of changes in pH, temperature, and flow rate are neglectable. Also, the sensor is analytically suitable with regard to reversibility, resilience, and reproducibility. The sensing device is validated through a relatively high number of on-body tests performed with elite athletes cycling and kayaking in controlled environments. Correlation outcomes between sweat lactate and other physiological indicators typically accessible in sports laboratories (blood lactate, perceived exhaustion, heart rate, blood glucose, respiratory quotient) are also presented and discussed in relation to the sport performance monitoring capability of continuous sweat lactate.

Role of inter-annual variability in the magnitude of river discharge on CO2 fluxes in the Godavari tidal river zone, India

Variations in the magnitude of river discharge may alter pH, pCO2 of surface water, and flux of CO2 to the atmosphere in the Tidal River Zone (TRZ). To test this hypothesis, a nearly decade-long time-series data of salinity, pH, and pCO2 data were collected and analyzed in the TRZ of Godavari River. The higher freshwater discharge occurred in the TRZ during the wet period (June to December) compared to the dry period (January to May). An increase in annual mean discharge was noticed between 2008 and 2019 due to surplus rainfall and the expansion of the hydropower plant. The surface water pH and pCO2 in the TRZ were controlled by the river discharge as evidenced by the linear positive and negative relationships with the rate of river discharge respectively. A strong relationship was observed between apparent oxygen utilization (AOU) and excess CO2 indicating a strong influence of heterotrophic activity on pCO2 levels in the TRZ. The respiration quotient (RQ) was above the aerobic respiration value of 1.35 indicating that terrestrial sources, such as sewage, and groundwater discharge, may have contributed to pH and pCO2 levels in the TRZ. The CO2 fluxes during the peak discharge period contribute to 48–88% of annual mean fluxes followed by moderate (12–52%) and dry periods (<4%). The annual mean CO2 emission amounted to 0.04 ± 0.05 TgC for the area of 36.9 × 106 m2 and increased at the rate of 0.005 TgC y−1 between 2008 and 2019 due to an increase in river discharge. The CO2 flux from the Godavari TRZ (0.04 TgC y−1) contributes to ∼0.2% of global tropical estuaries (18 TgC y−1). The CO2 flux contributed to ∼1.5% of the total carbon (both particulate and dissolved) exported from the Godavari TRZ to the Bay of Bengal and it is lower than the global mean contribution of 16%.

Coordinated transcriptional upregulation of oxidative metabolism proteins in long-lived endocrine mutant mice.

Caloric restriction (CR), which extends lifespan in rodents, leads to increased hepatic fatty acid β-oxidation and oxidative phosphorylation (OXPHOS), with parallel changes in proteins and their mRNAs. Genetic mutants that extend lifespan, including growth hormone receptor knockout (GHRKO) and Snell dwarf (SD) mice, have lower respiratory quotient, suggesting increased reliance on fatty acid oxidation, but the molecular mechanism(s) of this metabolic shift have not yet been worked out. Here we show that both GHRKO and SD mice have significantly higher mRNA and protein levels of enzymes involved in mitochondrial and peroxisomal fatty acid β-oxidation. In addition, multiple subunits of OXPHOS complexes I-IV are upregulated in GHRKO and SD livers, and Complex V subunit ATP5a is upregulated in liver of GHRKO mice. Expression of these genes is regulated by a group of nuclear receptors and transcription factors including peroxisome proliferator-activated receptors (PPARs) and estrogen-related receptors (ERRs). We found that levels of these nuclear receptors and their co-activator PGC-1α were unchanged or downregulated in liver of GHRKO and SD mice. In contrast, NCOR1, a co-repressor for the same receptors, was significantly downregulated in the two long-lived mouse models, suggesting a plausible mechanism for the changes in FAO and OXPHOS proteins. Hepatic levels of HDAC3, a co-factor for NCOR1 transcriptional repression, were also downregulated. The role of NCOR1 is well established in the contexts of cancer and metabolic disease, but may provide new mechanistic insights into metabolic control in long-lived mouse models.

Details of Respiratory Membrane, Diffusing Capacity, Respiratory Exchange Ratio as well as Respiratory Quotient

Details of Respiratory Membrane, Diffusing Capacity, Respiratory Exchange Ratio as well as Respiratory Quotient

Ketogenic diet acutely improves gas exchange and sleep apnoea in obesity hypoventilation syndrome: A non-randomized crossover study.

Obesity hypoventilation syndrome (OHS) causes hypercapnia which is often refractory to current therapies. We examine whether hypercapnia in OHS can be improved by a ketogenic dietary intervention. We conducted a single-arm crossover clinical trial to examine the impact of a ketogenic diet on CO2 levels in patients with OHS. Patients were instructed to adhere to 1 week of regular diet, 2 weeks of ketogenic diet, followed by 1 week of regular diet in an ambulatory setting. Adherence was assessed with capillary ketone levels and continuous glucose monitors. At weekly visits, we measured blood gases, calorimetry, body composition, metabolic profiles, and sleep studies. Outcomes were assessed with linear mixed models. A total of 20 subjects completed the study. Blood ketones increased from 0.14 ± 0.08 during regular diet to 1.99 ± 1.11 mmol/L (p < 0.001) after 2 weeks of ketogenic diet. Ketogenic diet decreased venous CO2 by 3.0 mm Hg (p = 0.008), bicarbonate by 1.8 mmol/L (p = 0.001), and weight by 3.4 kg (p < 0.001). Sleep apnoea severity and nocturnal oxygen levels significantly improved. Ketogenic diet lowered respiratory quotient, fat mass, body water, glucose, insulin, triglycerides, leptin, and insulin-like growth factor 1. Rebound hypercapnia was observed after resuming regular diet. CO2 lowering was dependent on baseline hypercapnia, and associated with circulating ketone levels and respiratory quotient. The ketogenic diet was well tolerated. This study demonstrates for the first time that a ketogenic diet may be useful for control of hypercapnia and sleep apnoea in patients with obesity hypoventilation syndrome.

Based on P (cv-a) CO2/C (a-cv) O2 and its changes are associated with an early reduction in multiple organ failure in patients with septic hyperlactocidemia

ABSTRACT The study aimed to investigate the relationship between the respiratory quotient (RQ), measured by the central venous-arterial carbon dioxide partial pressure difference/arterial-venous oxygenation difference ratio, and the early remission of multi-organ failure (MOF) in sepsis patients with hyperlactatemia. The study observed 49 septic patients with hyperlactatemia in the ICU, obtaining blood samples before and after resuscitation, and dividing the patients into two groups depending on whether the modified Sequential Organ Failure Assessment score improved after 24 hours of treatment. Results showed that lactate clearance was faster and the rate of change in RQ was higher in the improved group than in the unimproved group. Further analysis showed that an RQ ≤0.198 mmHg/mL/L or a change of ≥30.71% in RQ after 24 hours of resuscitation was associated with early improvement in MOF. In conclusion, changes in RQ were associated with early improvement in MOF in septic patients with hyperlactatemia, suggesting that RQ could be used as a potential marker for predicting early remission and guiding clinical interventions.

Prognostic significance of respiratory quotient in patients undergoing extracorporeal cardiopulmonary resuscitation in Korea.

Respiratory quotient (RQ) may be used as a tissue hypoxia marker in various clinical settings but its prognostic significance in patients undergoing extracorporeal cardiopulmonary resuscitation (ECPR) is not known. Medical records of adult patients admitted to the intensive care units after ECPR in whom RQ could be calculated from May 2004 to April 2020 were retrospectively reviewed. Patients were divided into good neurologic outcome and poor neurologic outcome groups. Prognostic significance of RQ was compared to other clinical characteristics and markers of tissue hypoxia. During the study period, 155 patients were eligible for analysis. Of them, 90 (58.1%) had a poor neurologic outcome. The group with poor neurologic outcome had a higher incidence of out-of-hospital cardiac arrest (25.6% vs. 9.2%, P=0.010) and longer cardiopulmonary resuscitation to pump-on time (33.0 vs. 25.2 minutes, P=0.001) than the group with good neurologic outcome. For tissue hypoxia markers, the group with poor neurologic outcome had higher RQ (2.2 vs. 1.7, P=0.021) and lactate levels (8.2 vs. 5.4 mmol/L, P=0.004) than the group with good neurologic outcome. On multivariable analysis, age, cardiopulmonary resuscitation to pump-on time, and lactate levels above 7.1 mmol/L were significant predictors for a poor neurologic outcome but not RQ. In patients who received ECPR, RQ was not independently associated with poor neurologic outcome.