Metabolic Rate Research Articles

Dietary sugar kelp consumption inhibits adipose tissue inflammation and fibrosis in male mouse model of diet-induced obesity

We previously demonstrated that consumption of U.S.-grown sugar kelp (Saccharina latissima) prohibits inflammation and fibrosis in the liver and white adipose tissue in male diet-induced obesity (DIO) mice. This study investigated whether sugar kelp can elicit similar benefits in female DIO mice. Male and female C57BL/6J mice were fed a low-fat (LF) control, a high-fat/high-sucrose/high-cholesterol (HF) control, or HF containing 6% sugar kelp (HF-Kelp) for 16 weeks. Body weight gain, serum triglyceride and total lipids, and glucose intolerance were decreased in male HF-Kelp compared with HF control. Furthermore, sugar kelp decreased gWAT weight with smaller adipocytes and total body fat in males. In gWAT, male HF-Kelp exhibited less inflammation and fibrosis than the HF control, confirmed by histological analysis. Moreover, HF-Kelp increased physical activity only in males. Gut microbiome analysis showed sugar kelp elevated observed species and altered beta diversity in both males and females, suggesting changes in the gut microbiome may contribute to the effects of sugar kelp on gWAT inflammation and fibrosis. Therefore, our results demonstrate that sugar kelp consumption prevents obesity-induced inflammation and fibrosis in WAT in male mice, which is attributed, at least in part, to modest increases in metabolic rates, energy expenditure, and physical activity, and also modulating the gut microbiota.

Ventilatory long-term facilitation following acute intermittent hypoxia in unanesthetized rats: influence of short hypoxic episodes and changes in metabolic rate

Plasticity is a hallmark feature of the neural system controlling breathing. Acute intermittent hypoxia (AIH) elicits plasticity in multiple respiratory motor pools ( e.g., phrenic, intercostal, XII, etc.) and has emerged as a promising therapeutic approach to restore lost respiratory (and non-respiratory) function in people with spinal cord injury and other clinical disorders that compromise movement. In anesthetized rats during the rest phase, AIH-induced phrenic long-term facilitation is enhanced when the AIH consists of short (1-min) versus longer (5-min) moderate hypoxic episodes (PaO2 ~40-50 mmHg), even with the same cumulative duration of hypoxia (15-min). However, since respiratory plasticity is influenced by a variety of behavioral and physiological factors such as sensory feedback, lung/chest wall mechanics and arousal state, the effectiveness of specific AIH protocols may differ when implemented in unanesthetized rats. Since it is unknown how hypoxic episode duration impacts ventilatory long-term facilitation (vLTF) in unanesthetized rats during the rest phase, we initially tested the hypothesis that short (1-min) hypoxic episodes (FIO2 = 0.09) elicit vLTF in young male Sprague-Dawley rats via whole-body plethysmography; metabolic CO2 production was also assessed. Following 15, 1-min hypoxic episodes, significant vLTF was observed, and this effect was more pronounced when ventilation was normalized to metabolic rate ( i.e. VE/VCO2; p < 0.05). AIH-induced vLTF was accompanied by hypometabolism and a post-hypoxic temperature decrease (p < 0.01), consistent with previous work. Additional studies will be performed to compare these results with “traditional” AIH protocols ( i.e., 5-min hypoxic episodes), and across the rats’ rest versus active phase. In perspective, these results set the stage for future investigations concerning the optimization of AIH protocols in unanesthetized rodent models, including rodent models of injury or disease. NIH HL148030 & 147554 (Mitchell). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effects of sludge retention time on sludge reduction by ultrasound treatment: Sludge characteristics, microbial community, and metabolism

Both ultrasound and sludge retention time (SRT) enable the in-situ sludge reduction during wastewater treatment, but the influence of SRT on ultrasonic lysis – cryptic growth is unclear. This paper researched the influence of different SRTs on sludge lysis - cryptic growth using a sequential bio-reactor (SBR), then explained in details the changes of microorganisms in the SBR. The best SRT for sludge reduction was 30 d, and 47.29% reduction in sludge was achieved. The different SRTs changed the organic matter removal in the wastewater, and the removal rate decreased when SRT exceeded 60 d. The size of the sludge particles varied depending on the SRT, with the smallest size at SRT of 10d being 45.6 μm and the largest size at SRT of 90d being 110.0 μm. SEM showed that the sludge surface changed rough at longer SRT. FTIR and XPS showed notable effect in sludge functional group strength at SRT of 30 d. Extracellular polymeric substance (EPS) reduced the most at SRT of 30 d. The microbial communities of sludge varied with the SRT, and the unique main genus at SRT of 5, 15, 30 and 90 d were C10-SB1A, Lactococcus, Propioniciclava, Lactococcus, respectively. Furthermore, the SRT changed relative abundance of enzymes concerned with metabolism of carbon, nitrogen, and phosphorus. Similarly, SRT changed the metabolic rate, and the metabolic rate of carbon, nitrogen and phosphorus was best at SRT of 30 d.

Na/K-ATPase α1/Src Signaling Regulates Mitochondrial Metabolic Function and ROS Production in Human iPSC-derived Cardiomyocytes

Through an isoform specific mechanism, the Na/K-ATPase (NKA) α1 polypeptide-mediated regulation of Src kinase has emerged as a novel regulator of mitochondrial function in various cell types. Mitochondrial metabolism ensures adequate myocardial performance and adaptation to physiological demand. It is also a critical cellular determinant of cardiac repair and remodeling. To investigate the importance of the proposed NKA/Src regulatory signaling on cardiac mitochondrial metabolic function independently from the classic Na/K-ATPase enzymatic function, we used a gene targeting approach in cardiomyocytes. Human induced pluripotent stem cells (hiPSC) expressing a Src-signaling null mutant (A420P) form of NKA α1 were generated using CRISPR/Cas9-mediated genome editing. NKA isoform protein expression and enzymatic activity remained unchanged. However, baseline levels of Src and ERK1/2 phosphorylation were decreased by 55% and 80%, respectively in the A420P hiPSC (n=3, p<0.05). Both the WT and A420P hiPSC differentiated into cardiomyocytes (iCM) as assessed by morphology, spontaneous cell contraction, marker gene expression, and subcellular striations. Cell metabolism assessed by Seahorse extracellular flux analysis revealed significant reductions in basal and maximal rates of mitochondrial respiration (50%), spare respiratory capacity (50%), ATP production (60%), and coupling effciency (20%) (n=4, p<0.05). ROS production was monitored in live cells by measuring the oxidation of the CM-H2DCFDA dye using a fluorescence microscope. The slope of the ROS production rate curve was dramatically reduced in A420P iCM (80%, n=3, p<0.05). Protein carbonylation levels, analyzed by ELISA as markers of oxidative damage, were also decreased in A420P iCM (n=4, p<0.05). Taken together, these data provide genetic evidence for a role of NKA α1/Src in the tonic stimulation of basal mitochondrial metabolism and ROS production in human cardiac myocytes. This has potential significance in cardiometabolic diseases and suggests that targeting the NKA α1/Src signaling axis may offer a novel approach to address mitochondrial dysfunction. NIH Grant R15 HL145666, NIH Grant P20GM103434 to the West Virginia IDeA Network of Biomedical Research Excellence, and American Heart Association Postdoctoral Fellowship — 22POST917776 — to Marco T. Pessoa. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Comparing the Contributions of Cutaneous and Respiratory Evaporative Water Loss to Cooling in Anna’s Hummingbirds (Calypte anna) Under Fasted and Fed Conditions

During high-temperature periods, endothermic animals evaporate water from the body surface to cool down. The two primary routes of evaporative water loss are: (1) evaporating water from the skin; and (2) evaporation from the respiratory surfaces during breathing and panting. In smaller avian species like Anna's hummingbirds ( Calypte anna), the higher cutaneous surface area to volume ratio presents an opportunity for the skin to become an important avenue for evaporative cooling, possibly becoming a major site. Additionally, hummingbirds feed on water-rich nectar. As a result, they eliminate surplus water through urination, but significant evaporation can also occur through their skin and respiratory system. Thus, total evaporative water loss could rise significantly for these animals when in a hydrated state. Here, this study investigates the relative importance of the two evaporative water loss routes (cutaneous and respiratory) of Anna's hummingbirds in fed and fasted states. We hypothesize that cutaneous evaporation has a high contribution to total evaporation. Moreover, we predict that evaporative water loss rates are higher under the fed (hydrated) condition relative to fasted states. Metabolic and evaporation rates from the head and the body were measured separately in a partitioned chamber at 30°C. Birds were fed immediately prior to entry into respirometry, and the transition from fed to fasted states was recorded over a two-hour period. Total evaporative water loss nearly doubled in the fed versus fasted condition (1.75 ± 0.85 mg H2O/min and 0.97 ± 0.28 mg H2O/min, respectively), with respiratory water loss being significantly higher in the fed compared to the fasted condition (0.87 ± 0.38 mg H2O/min versus 0.42 ± 0.12 mg H2O/min, respectively). On the other hand, the body had a large, but non-significant, difference in evaporative water loss rates between the fed and fasted conditions (0.88 ± 0.55 mg H2O/min and 0.57 ± 0.17 mg H2O/min, respectively). Importantly, cutaneous evaporative water loss made up half of the total evaporation in both the fed and fasted conditions. These results demonstrate that evaporative water loss is modulated by hydration status at both the respiratory and cutaneous surfaces. Furthermore, cutaneous evaporation makes up approximately the same proportion of total evaporation to other birds at thermoneutral temperatures. Future work manipulating ambient temperature in conjunction with hydration status will further our understanding of the relative importance of cutaneous evaporation for these small-bodied birds. Funded by the Genentech Foundations Scholarship, CSUPERB New Investigator Grant, and San Francisco State University. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Exogenous erythropoietin increases hematological status, fat oxidation, and aerobic performance in males following prolonged strenuous training.

This study investigated the effects of EPO on hemoglobin (Hgb) and hematocrit (Hct), time trial (TT) performance, substrate oxidation, and skeletal muscle phenotype throughout 28 days of strenuous exercise. Eight males completed this longitudinal controlled exercise and feeding study using EPO (50 IU/kg body mass) 3×/week for 28 days. Hgb, Hct, and TT performance were assessed PRE and on Days 7, 14, 21, and 27 of EPO. Rested/fasted muscle obtained PRE and POST EPO were analyzed for gene expression, protein signaling, fiber type, and capillarization. Substrate oxidation and glucose turnover were assessed during 90-min of treadmill load carriage (LC; 30% body mass; 55 ± 5% V̇O2peak) exercise using indirect calorimetry, and 6-6-[2H2]-glucose PRE and POST. Hgb and Hct increased, and TT performance improved on Days 21 and 27 compared to PRE (p < 0.05). Energy expenditure, fat oxidation, and metabolic clearance rate during LC increased (p < 0.05) from PRE to POST. Myofiber type, protein markers of mitochondrial biogenesis, and capillarization were unchanged PRE to POST. Transcriptional regulation of mitochondrial activity and fat metabolism increased from PRE to POST (p < 0.05). These data indicate EPO administration during 28 days of strenuous exercise can enhance aerobic performance through improved oxygen carrying capacity, whole-body and skeletal muscle fat metabolism.

Endurance training and essential amino acid intervention synergize to ameliorate fructose-induced metabolic dysfunction in mice

Purpose: Excessive fructose (FRU) consumption can rapidly produce multiple features of metabolic syndrome, including dysregulation of systemic metabolism, insulin resistance, and diabetes. Essential amino acids (EAAs) and endurance exercise training (ET) improve abnormal metabolism in various disease conditions, yet their combined effect and metabolic mechanism remain unclear. Thus, the current study aimed to investigate metabolic kinetic mechanism and the combined effect of EAA and ET on fructose-induced metabolic dysfunction. Materials and methods: Mice were randomly divided into 5 groups with an 8-week intervention: normal chow (CON), FRU, FRU+ET, FRU+EAA or FRU+ET+ EAA, followed by stable isotope tracer infusions ([U-13C16]palmitate, [D2]glucose, and [D5]glycerol) or D2O administration to determine substrate metabolic flux rates and their contribution to TCA cycle flux and protein synthesis rates of various organs, respectively. Summary of results: FRU-induced adverse changes in body weight and physical function were reversed by ET, EAA, or ET+EAA. In stable isotope tracing analysis, ET and ET+EAA alleviated hyperglycemia by suppressing hepatic glucose production rate, while EAA and ET+EAA normalized palmitate turnover and contribution to TCA cycle in various organs. Additionally, the altered protein synthesis measured using a D2O labeling method was normalized by ET and ET+EAA. Conclusion:These findings suggest that the combined treatment of dietary EAAs and ET more effectively mitigates fructose-induced metabolic dysfunction by normalizing hepatic glucose production rate, protein synthesis rates, and fatty acid metabolism. This research was supported by a grant of the Korea Health Technology R&amp;D Project through the Korea Health industry Development Institute (KHIDI), funded by the Ministry of Health &amp; Welfare, Republic of Korea (HI22C2208), and the National Research Foundation of Korea (NRF), funded by the Korea government (MSIT) (No. 2021R1A2C3005801), and partially funded by MYOCARE INC. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Sexual Dimorphism in Substrate Metabolism During Exercise

During aerobic exercise, women oxidize significantly more lipids and less carbohydrates than men. This sexual dimorphism in substrate metabolism has been attributed, in part, to the observed differences in epinephrine and glucagon levels between men and women during exercise. To identify the underpinning candidate physiological mechanisms for these sex differences, we developed a sex-specific multi-scale mathematical model that relates cellular metabolism in the organs to whole-body responses during exercise. We conducted simulations to test the hypothesis that sex differences in the exercise-induced changes to epinephrine and glucagon would result in the sexual dimorphism of hepatic metabolic flux rates via the glucagon-to-insulin ratio (GIR). Indeed, model simulations indicate that the shift towards lipid metabolism in the female model is primarily driven by the liver. The female model liver exhibits resistance to GIR-mediated glycogenolysis, which helps maintain hepatic glycogen levels. This decreases arterial glucose levels and promotes the oxidation of free fatty acids. Furthermore, in the female model, skeletal muscle relies on plasma free fatty acids as the primary fuel source, rather than intramyocellular lipids, whereas the opposite holds true for the male model. This work was supported by the Canadian Institutes of Health Research (CIHR) and the Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery award. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Target for lipid-to-carbohydrate intake minimizes cost of growth.

Many theoretical treatments of foraging use energy as currency, with carbohydrates and lipids considered interchangeable as energy sources. However, herbivores must often synthesize lipids from carbohydrates since they are in short supply in plants, theoretically increasing the cost of growth. We tested whether a generalist insect herbivore (Locusta migratoria) can improve its growth efficiency by consuming lipids, and whether these locusts have a preferred caloric intake ratio of carbohydrate to lipid (C : L). Locusts fed pairs of isocaloric, isoprotein diets differing in C and L consistently selected a 2C : 1L target. Locusts reared on isocaloric, isoprotein 3C : 0L diets attained similar final body masses and lipid contents to locusts fed the 2C : 1L diet, but they ate more and had a ~12% higher metabolic rate, indicating an energetic cost for lipogenesis. These results demonstrate that some animals can selectively regulate carbohydrate-to-lipid intake and that consumption of dietary lipids can improve growth efficiency.

A living lab to develop smart home services for the residential welfare of older adults

Owing to the decline in the physical and social functions of older adults, the residential environment substantially impacts the psychological and emotional stability and life satisfaction for older adults. Recently, there has been a growing interest in providing residential welfare services related to the health and independent living of the older adults. The primary objective of this research was to identify the needs and perceptions of older adults regarding smart home services and associated sensors and evaluate the indoor environment conditions of older adults through a living lab. Survey results indicate that older adults felt the burden of electricity bills in summer and winter and had relatively high safety-related smart home service needs. Focus group interviews with the participants in the living lab confirmed that older adults positively perceived the benefits and privacy of the living-lab sensors. In addition, the analysis of indoor environment data over one year from a case-study household showed that approximately 66.4% during the winter season and 13.1% during the summer season have fallen within the neutral thermal comfort range according to the proposed approach (i.e., predicted mean vote (PMV) calculated using heart rate). This study adopted the proposed PMV method (hereafter PMV-P) that takes into account personal factors (e.g., metabolic rate of older adults that can be calculated using heart rate) and environmental factors (e.g., temperature, humidity) by using the real-time data collected from IoT-based sensors. Furthermore, this study proposed a new home energy management system (EMS) algorithm on the basis of model predictive control for reducing heating energy consumption while satisfying the thermal comfort. The new EMS was demonstrated to achieve 5 – 12% heating energy savings depending on the thermal comfort preferences of occupants. Overall, the results of multidisciplinary research not only provided the preliminary evidence regarding the needs and perceptions of older adults toward IoT-based sensors but also showcased the development of IoT-based smart home service system through the living lab.

Physical inactivity following volumetric muscle loss results in a divergence between whole-body and cellular metabolic dysfunction

Volumetric muscle loss (VML) is the frank loss of muscle due to injury or surgery and is characterized by whole-body and cellular metabolic dysfunction. Following VML, prolonged bedrest and life-long disability may worsen metabolic dysfunction. This work aimed to elucidate the impact of VML and physical inactivity on the whole-body, cellular, and metabolomic environment of the remaining uninjured muscle. Adult male C57BI/6J mice (n=40) underwent unilateral VML to the posterior hindlimb compartment or served as age-matched injury naïve controls, then were randomized to standard or restricted activity cages for 8-wks. Physical activity, whole-body metabolism, and glucose tolerance were evaluated at 6- and 7-wks post-VML, respectively. Small molecule metabolites and lipids were measured using liquid chromatography-couple and flow injection tandem mass spectrometry. Differences were evaluated by two-way ANOVA with Tukey’s HSD post hoc. Inactivity following VML resulted in ~7% decrease in 24-hr metabolic rate compared to VML alone (p=0.032). Regardless of injury, 24-hr RER was ~5% greater following inactivity (p=0.001). Over 24 hrs, carbohydrate oxidation was ~23% greater with injury and inactivity (p=0.001); lipid oxidation was largely unchanged (p≥0.068). Change in RER (ΔRER) was ~93% greater in VML-injured mice (p=0.030). Physical activity can influence whole-body metabolism, and inactivity post-VML results in greater whole-body carbohydrate usage. Regardless of activity, blood glucose levels were lower following injury (p&lt;0.001). Adiponectin was greater in VML-injured muscles (p&lt;0.001), which may explain enhanced whole-body glucose tolerance post-VML. Protein expression of localized metabolic signals revealed muscle GLUT4, fatty acid binding protein 4, acetyl-CoA carboxylase (ACC), phosphorylated ACC (pACC) and liver fatty acid synthase (FAS) were unaffected by injury and inactivity (p≥0.117). Muscles of inactive, VML-injured mice exhibited a greater pACC:ACC ratio (p=0.046), suggesting decreased fatty acid synthesis. No effect of injury or inactivity was observed in circulating leptin (p≥0.188). Beta-hydroxyacyl CoA dehydrogenase activity was decreased following injury, suggesting a diminished capacity to oxidize fatty acids (p=0.033). Inactivity alone did not alter the metabolome. Injury resulted in 54 significantly expressed metabolites and/or ratios. The combination of injury and inactivity produced a similar response as VML alone, with 91% of metabolites and/or ratios commonly expressed between groups. Similar metabolite expressions following VML with and without inactivity indicate VML injury alone is regulating an altered metabolome. Collectively, although there was no substantial impact of inactivity on whole-body metabolic dysfunction above VML alone, metabolic changes in VML-injured muscles suggests functional alterations in fatty acid metabolism with inactivity. If the ability to oxidize fatty acids is exhausted following VML, resulting accumulation of triglycerides may contribute to metabolic disease often observed with physical inactivity. Continued work to elucidate mechanisms and functional aspects of fatty acid oxidation following VML is needed. W81XWH-20-1-0885 and R01-AR078903 to JAC &amp; SMG. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Critical Environmental Limits for Middle-Aged Adults (PSU HEAT Project)

Critical environmental limits are the combinations of temperature and humidity above which heat balance cannot be maintained for a given metabolic heat production. Our lab has previously established critical environmental limits for young and older adults; however, these limits have yet to be established for middle-aged adults. The purpose of the present study was to (1) identify critical environmental limits for middle-aged adults, and (2) investigate age-related differences in critical environmental limits at a low metabolic rate reflecting activities of daily living across the adult age spectrum. Twenty-six older (71±5 yrs, 14F/12M), 36 middle aged (51±9 yrs, 26F/10M), and 27 young adults (23±3 yrs, 13F/14M) were exposed to progressive heat stress in a controlled environmental chamber during minimal activity. Progressive heat stress for the determination of critical environmental limits comprised either (1) constant dry-bulb (Tdb) temperature at 34°C with progressively increasing water vapor pressure (Pa) by 1 mmHg every 5 minutes (Pcrit trial), or (2) constant Pa at 12 mmHg with progressively increasing Tdb by 1°C every 5 minutes (Tcrit trial). Critical environmental limits in hot-dry environments were higher in young compared to middle aged (49.3±2.3 °C vs. 45.4±4.0 °C; p = 0.002) and older adults (49.3±2.3°C vs. 43.2±4.0°C; p &lt; 0.001), but were not different between middle aged and older adults (45.4±4.0 °C vs. 43.2±4.0°C; p = 0.125). Critical environmental limits in warm-humid conditions were lower in older adults compared to young (23.1±6.1 mmHg vs 31.7±1.5 mmHg, p &lt; 0.001) and middle aged (23.1±6.1 mmHg vs 29.0±5.1 mmHg, p = 0.004), but were not different between the young and middle aged (31.7±1.5 mmHg vs 29.0±5.1 mmHg, p = 0.220). Age was correlated with critical environmental limits in Tcrit (R2 = 0.34; p &lt; 0.001) and Pcrit (R2 = 0.51; p &lt; 0.001) trials based on linear and curvilinear regression, respectively. Critical environmental limits for middle aged adults performing minimal activity in warm-humid and hot-dry environments are intermediate to young and older adults. These data demonstrate an age-related decline in critical environmental limits that can be characterized by linear decline in hot-dry environments and by curvilinear decline in warm-humid environments. Supported by NIH Grant R01 AG067471. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Intermittent Fasting Alters O2 Consumption and Body Composition in Young Rats: Comparative Analysis between Females and Males

Objectives: Intermittent Fasting (IF), time-restrictive food intake, has been shown to improve cognitive functions and reduce age-related behavioral impairments in rodent models. Our prior studies have found that IF intervention has significantly reduced body weights and food intake in male Fsher-344 rats; however, females did not display IF-induced declines in body weights and food intake. The exact mechanism for the sex differences in body weight and food intake during IF is not fully understood. Factors such as shifts in body composition and metabolic demand may contribute to variations in body weight shifts and food consumption. We hypothesized that changes in body composition and metabolic shifts may contribute to sex differences in body weight and food consumption in response to IF. Methods: Thirty-six, two-month-old male and female Fisher-344 rats were randomly assigned to four groups: ad libitum (AL) male, IF males, AL females, IF females. The AL group had 24/7 access to food and water while the IF group had 24/7 access to water and full access to food on an every-other-day basis for four weeks. After four weeks of IF intervention, rats were introduced to a metabolic rate (respiratory gas analyzer) and a grip strength test. In addition, body scans were performed using a Lunar Piximus rodent densitometer, (GE Lunar corporation). Group differences were analyzed with two-way ANOVA per Prism Graph Pad software. Following body scans, animals were euthanized, and tissues were sectioned, weighted, and stored for future analysis (brain, skeletal muscles, and adipose tissues). Results: IF intervention resulted in reduced body mass in males (vs. AL males, p&lt;0.0001) but not in females. Average daily food intake tended to be lowered in IF groups compared to their AL counterparts. Densitometry results revealed that the IF males had a decreased lean mass (vs. AL males, p&lt;0.0001) and fat mass (vs. AL males, p&lt;0.0001). Neither lean mass nor fat mass were changed in females as a result of IF. After two weeks of IF, O2 consumption was lowered in IF females compared to AL (P=0.0215 fed-state, P=0.0030 fast-state); however, no significant effect was seen in males. Grip strength was not significant among groups. Conclusions: In the present study, IF males significantly reduced body weights, as well as both fat and lean mass while females did not exhibit IF-induced changes. Interestingly, IF females displayed declines in oxygen consumption while males did not change. The decrease in oxygen consumption (slower metabolism) in IF females can be seen as a compensatory mechanism by the body to conserve energy and maintain body weights and composition shifts. The sexual dimorphic effect of body composition shifts is intriguing and the metabolic adaptations in skeletal muscle/fat tissues will be the focus of follow-up investigations. Funding source: P20GM113109 Cognitive and Neurobiological Approaches to Plasticity (CNAP) center. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Brown Adipose Tissue-Derived GDF15 Mediates Energy Homeostasis in a Sex-Dependent Manner

Growth differentiation factor 15 (GDF15) is a distant member of the transforming growth factor-β (TGFβ) superfamily that can be expressed in several tissues. Studies have shown that in response to prolonged high-fat feeding and cold stress GDF15 can be induced in brown adipocytes. Importantly, administration of recombinant GDF15 in rodents and non-human primates (Xiong, Y. et al. Long-acting MIC-1/GDF15 molecules to treat obesity: Evidence from mice to monkeys. Sci. Transl. Med. 9, eaan8732 (2017) reduces food intake and body mass. Indeed, we have recently shown that in a model of mitochondrial stress, brown adipose tissue (BAT)-derived GDF15 is required to maintain energy homeostasis and cold-induced thermogenesis in mice. Nonetheless, the role of BAT-derived GDF15 during physiological stress is not known. In the present study, we tested the hypothesis that BAT-derived GDF15 is required to regulate cold-induced thermogenesis and energy homeostasis in high-fat fed mice. To test this hypothesis, we generated mice selectively lacking GDF15 in thermogenic adipocytes (brown and beige) (GDF15 BKO). GDF15 BKO male and female mice had normal body weight, body composition and glucose homeostasis under baseline conditions. In response to 4 hours of cold exposure following fasting, the decline in core body temperature in GDF15 BKO female mice was similar to that observed in their wild type (WT) counterparts. Conversely, GDF15 BKO male mice became hypothermic. Surprisingly, after 12 weeks on a high-fat diet (HFD), GDF15 BKO female mice weighed significantly less and had reduced fat mass relative to their WT controls, while male mice had increased body weight and fat accumulation. Furthermore, resistance to DIO in female mice was associated with increased energy expenditure, while food intake and locomotor activity were unchanged. When ovariectomized, GDF15 BKO females experienced similar weight gain and fat accumulation as WT mice and no longer had increased energy expenditure. Of note, estrogen receptor alpha ( Esr1) expression in BAT was significantly repressed in GDF15 BKO male mice fed high-fat diet but was maintained in female mice relative to their respective WT controls. Taken together, our data suggest that GDF15 expression in BAT is dispensable for thermoregulation in female mice but is required to regulate core body temperature in males. Furthermore, while GDF15 BKO male mice are susceptible, female mice are resistant to DIO via mechanisms likely involving sex hormones and increased resting metabolic rates. NIH DK125405 to R.O.P.; Diabetes Research Training Program funded by the NIH (T32 DK112751) to JJ and by the NIH 1R25GM116686 to L.M.G.P. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Age-Related Differences in the Onset of Cardiovascular Drift during Progressive Heat Stress (PSU HEAT Project)

As a result of the increasing duration, frequency, and severity of heat waves, older men and women are at greater risk for heat-related morbidity and mortality, with the majority of excess heat-related deaths attributed to increased cardiovascular strain associated with heat stress. PURPOSE: To (1) identify the environmental conditions (ambient temperature (Tdb) and humidity (rh)) at which heart rate (HR) begins to increase from equilibrium (i.e., the onset of cardiovascular drift), and (2) compare the environments in which cardiovascular drift begins relative to those at which a continuous rise in core temperature (Tc) is observed in young (Y), middle (MA), and older (O) adults. Methods: 26 Y (10 F; 19-29 yrs), 27 MA (21F; 40-64 yrs), and 19 O (7 F; 65-76 yrs) subjects were exposed to progressive heat stress in an environmental chamber at a low metabolic rate reflecting activities of daily living (159 ± 34 W) in a warm-humid (WH, 34-36°C, 50-80% rh) and a hot-dry (HD, 38°C-52°C, &lt;30% rh) environment. The environmental thresholds above which HR and Tc equilibrium could no longer be maintained were identified. Results: In WH environments, sustained increases in HR preceded the Tc inflection point in Y (73±5% rh vs. 81±5% rh; p&lt;0.001), MA (67±11% rh vs. 73±12% rh; p&lt;0.001), and O adults (53±11% rh vs. 57±12% rh; p=0.041). Similarly, in HD (15-20% rh) environments, the onset of cardiovascular drift preceded the Tc inflection point in Y (47±3°C vs. 49±3°C; p=0.004), MA (44±4°C vs. 46±4°C; p&lt;0.001), and O adults (42±5°C vs. 44±4°C; p=0.007). Additionally, in WH environments, cardiovascular drift began at lower combinations of Tdb and rh in O vs. Y subjects (34°C, 53±11% rh vs. 34°C, 73±5% rh; p&lt;0.001) and O vs. MA adults (34°C, 53±11% rh vs. 34°C, 67±11% rh; p=0.008). In HD environments, cardiovascular drift began at lower environments in MA vs. Y (44±4°C, 18% rh vs. 47±3°C, 15% rh; p=0.044) and O vs. Y (42±5°C, 20% rh vs. 47±3°C, 15% rh; p=0.006) CONCLUSION: These data suggest that cardiovascular drift, indicating increases in cardiovascular strain, occurs during compensable heat stress at metabolic rates reflecting activities of daily living in Y, MA, and O adults. Further, there is an age-associated shift in the onset of cardiovascular drift toward lower combinations of Tdb and rh. SIGNIFICANCE/NOVELTY: These results are the first to identify the specific environmental conditions at which increases in cardiovascular strain occur across the adult age spectrum. These findings provide concrete data for the development of safety guidelines and policy decisions to mitigate cardiovascular-related morbidity and mortality during impending heat events. Supported by NIA Grant T32 AG049676 (to R.M.C.) and NIH Grant R01 AG067471 (to W.L.K.). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Hernandezine acts as a CDK4 suppressor inhibiting tumor growth by the CDK4/PKM2/NRF2 axis in colon cancer

BackgroundThe cyclin-dependent kinase 4 (CDK4) interacts with its canonical and non-canonical substrates modulating the cell cycle in tumor cells. However, the potential substrates and the beyond-cell-cycle-regulated functions of CDK4 in colon cancer (CC) are still unknown. Hernandezine (HER) is previously verified to induce G0/G1 phase arrest and autophagic cell death in human cancer cells, which implies that HER might target G0/G1 phase-related proteins, including CDK4. PurposeThe present study tried to investigate the glycolytic metabolism and oxidative stress functions of CDK4 in colon cancer. Furthermore, the inhibitory effects and potential binding sites of HER on CDK4, as well as its anti-tumor activity were investigated in CC cells. MethodsThe mass spectrometry assay was performed to identify potential endogenous substrates of CDK4 and the correlation between glycolytic metabolic rate and CDK4 level in COAD patient tissues. Meanwhile, after inhibiting the activity or the expression of CDK4, the binding capacity of CDK4 to PKM2 and NRF2 and the latter two protein distributions in cytoplasm and nucleus were detected in CC cells. In vitro, the regulatory effects of the CDK4-PKM2-NRF2 axis on glycolysis and oxidative stress were performed by ECAR, OCR, and ROS assay. The inhibitory effect of HER on CDK4 activity was explored in CC cells and the potential binding sites were predicted and testified in vitro. Furthermore, tumor growth inhibition of HER by suppressing the CDK4-PKM2-NRF2 axis was also investigated in vitro and in vivo. ResultsPKM2 and NRF2 were identified as endogenous substrates of CDK4 and, high-expressed CDK4 was associated with low-level glycolysis in COAD. In vitro, inactivated CDK4 facilitated CDK4-PKM2-NRF2 complex formation which resulted in 1) inhibited PKM2 activity and retarded the glycolytic rate; 2) cytoplasm-detained NRF2 failed to transcript anti-oxidative gene expressions and induced oxidant stress. Additionally, as a CDK4 inhibitor, HER developed triple anti-tumor effects including induced G0/G1 phase arrest, suppressed glycolysis, and disrupted the anti-oxidative capacity of CC cells. Conclusion: The results first time revealed that CDK4 modulated glycolytic and anti-oxidative capacity of CC cells via bound to its endogenous substrates, PKM2 and NRF2. Additionally, 140Asp145Asn amino acid sites of CDK4 were potential targets of HER. HER exerts anti-tumor activity by inhibited the activity of CDK4, promoted the CDK4-PKM2-NRF2 complex formation in the CC cells.

Comparative anoxia responses of hatchling and juvenile western painted turtles (Chrysemys picta bellii)

The western painted turtle ( Chrysemys picta bellii) is the most anoxia-tolerant tetrapod known, with adults capable of surviving anoxia for more than 170 days at 3°C. However, hatchling painted turtles are known to have an anoxia tolerance of just 40 days at 3°C. It is believed that the reduced mineralization of the hatchling shell likely limits their buffering capacity, but other aspects of their physiology, such as anaerobic metabolic rate and glycogen stores could be limiting as well. We hypothesize that one year-old juveniles, with more mineralized shells, would tolerate anoxia longer than recently hatched turtles. Thirty-five juvenile and hatchling turtles were gradually cold-acclimated from 20°C to 3°C and then placed inside individual cages. Three aquaria (37.85L) each contained eight juvenile and eight hatchling turtles. Eleven control juvenile and hatchling turtles were sampled and flash-frozen for future analysis of tissue glycogen, lactate, and carbonate. The remaining turtles were then submerged in anoxic water and their limb withdrawal reflex tested daily for a loss of response. When half of each developmental group became unresponsive, the remaining responsive turtles were then sampled. The hatchling and juvenile turtles lost their withdrawal reflex after 39.3 ±1.2 days and 42.3 ±2.6 days, respectively, indicating there was no significant difference in anoxia tolerance between the developmental groups. Powdered whole-body turtle samples showed similar total glucose and glycogen levels in juveniles (30.484 μmol/g tissue and 4.875 μmol/g tissue) and hatchlings (27.301 μmol/g tissue μmol/g tissue and 4.718 μmol/g tissue), respectively. Plasma samples showed that juveniles tended to have slightly higher free glucose and lactate (15.160 mmol/L and 6.317 mmol/L) compared to hatchlings (11.118 mmol/L and 5.531 mmol/L), respectively. There was no interaction between anoxia tolerance and life stage. These results suggest that tissue glycogen stores, and not buffering capacity, limits the anoxia tolerance of young turtles. NSF CAREER grant to DEW. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Dynamics of epigenetic regulation in Dryophytes versicolor skeletal muscle: Lysine methylation and acetylation involvement in metabolic rate depression

For the breadth of the winter, Dryophytes versicolor can survive full body freezing utilizing a phenomenon known as metabolic rate depression (MRD). Epigenetic transcriptional control on gene expression, such as histone methylation and acetylation, can aid in implementing a balance between permissive and restricted chromatin required to endure this stress. As such, this study explores the interplay between histone lysine methyl and acetyl transferases (HKMTs, HATs), as well as the abundance of various acetyl-lysine and methyl-lysine moieties on histone H3 and H4. Results showing that overexpression of transcriptionally repressive marks, and under expression of active ones, suggest a negative effect on overall gene transcription in skeletal muscle tissue.

Variation in Resting Metabolic Rate Affects Identification of Metabolic Change in Geographically Distinct Cohorts of Patients With ALS.

Variation in Resting Metabolic Rate Affects Identification of Metabolic Change in Geographically Distinct Cohorts of Patients With ALS.

Changes in microRNA expression related to ischemia-reperfusion injury in the kidney of the thirteen-lined ground squirrel during torpor

During the hibernation season, the thirteen-lined ground squirrel undergoes cyclical torpor and arousal periods. The decrease and restoration of metabolic rate and oxygen delivery during torpor and arousal, respectively, may cause reperfusion-ischemia injury in the kidneys. In order to maintain the structural integrity of the kidneys necessary for renal function resumption during arousal, the thirteen-lined ground squirrel has developed adaptive methods to prevent and repair kidney injury. In this present study, computational methods were used to clean and analyze sequenced kidney RNA samples. Significantly differentially expressed microRNAs and enriched gene sets were also determined. From the gene set analysis, the results showed an increase in ubiquitin-related processes and p53 signaling pathways which suggested the occurrence of kidney damage during torpor. There was also an observed increase in cell cycle processes and the anchoring junction cellular compartment which may lend to the prevention of kidney injury. From the differentially expressed microRNAs, miR-27a (log2FC= 1.639; p-value= 0.023), miR-129 (log2FC= 2.516; p-value= 0.023), miR-let-7b (log2FC= 2.360; p-value= 0.025), miR-let-7c (log2FC= 2.291; p-value= 0.037) and miR-let-7i (log2FC= 1.564; p-value= 0.039) were found to be significantly upregulated. These biochemical adaptations may allow the thirteen-lined ground squirrel to maintain kidney structure and function during hibernation.