Metabolic Expenditure Research Articles

Brain regulation of hunger and motivation: The case for integrating homeostatic and hedonic concepts and its implications for obesity and addiction

Obesity and other eating disorders are marked by dysregulations to brain metabolic, hedonic, motivational, and sensory systems that control food intake. Classic approaches in hunger research have distinguished between hedonic and homeostatic processes, and have mostly treated these systems as independent. Hindbrain structures and a complex network of interconnected hypothalamic nuclei control metabolic processes, energy expenditure, and food intake while mesocorticolimbic structures are though to control hedonic and motivational processes associated with food reward. However, it is becoming increasingly clear that hedonic and homeostatic brain systems do not function in isolation, but rather interact as part of a larger network that regulates food intake. Incentive theories of motivation provide a useful route to explore these interactions. Adapting incentive theories of motivation can enable researchers to better understand how motivational systems dysfunction during disease. Obesity and addiction are associated with profound alterations to both hedonic and homeostatic brain systems that result in maladaptive patterns of consumption. A subset of individuals with obesity may experience pathological cravings for food due to incentive sensitization of brain systems that generate excessive ‘wanting’ to eat. Further progress in understanding how the brain regulates hunger and appetite may depend on merging traditional hedonic and homeostatic concepts of food reward and motivation.

Protein metabolism, body composition and oxygen consumption in young bulls divergent in residual feed intake offered two contrasting forage-based diets

Protein metabolism and body composition have been identified as major determinants of residual feed intake (RFI) in beef cattle fed high-starch fattening diets. This study aimed to evaluate if these two identified RFI determinants in beef cattle are the same across two contrasting silage-based diets. During two consecutive years, an 84-day feed efficiency test (Test A) immediately followed by a second 112-day feed efficiency test (Test B) was carried out using a total of 100 animals offered either one of two diets (either corn silage- or grass silage-based) over 196 days. At the end of Test A, the 32 animals most divergent for RFI (16 extreme RFI animals per diet, eight low RFI and eight high RFI) were identified and evaluated during Test B for their i) N use efficiency (NUE; N retention/N intake) calculated either from a 10-d nitrogen balance trial or from estimations based on body composition changes occurring during the whole experiment (Test A and Test B; 196 days), ii) carcass and whole-body protein turnover rates analysed through the 3-methyl-histidine urinary excretion and the N isotopic turnover rates of urine, respectively, and iii) body composition measured at the slaughterhouse at the end of Test B. Oxygen consumption was measured during Test B for the 100 animals by two GreenFeed systems. Irrespective of the diet, efficient RFI animals tended (P = 0.08) to improve their NUE when N retention was estimated for 196 days or when considering their lower urinary urea-N to total N ratio (P = 0.03). In contrast, NUE calculated during the 10-d N balance showed no differences (P = 0.65) across RFI groups suggesting that this method may not be suitable to capture small NUE differences. Efficient RFI individuals presented higher dressing percentage and muscle deposition in the carcass (P = 0.003) but lighter rumen (P = 0.001), and a trend for lower oxygen consumption (P = 0.08) than inefficient RFI animals irrespective of the diet. Lower protein degradation rates of skeletal muscle and lower protein synthesis rates of plasma proteins were found in efficient RFI cattle but only with the corn silage-based diet (RFI × Diet; P = 0.02). The higher insulinaemia associated with the corn silage-based diet (P = 0.001) seemed to be a key metabolic feature explaining the positive association between protein turnover and RFI only in this diet. Feed N was more efficiently used for growth by efficient RFI animals regardless of the diet but lower protein turnover rates in efficient RFI animals were only observed with corn silage-based diets.

Methylmalonic Acid Impairs Cell Respiration and Glutamate Uptake in C6 Rat Glioma Cells: Implications for Methylmalonic Acidemia.

Methylmalonic acidemia is an organic acidemia caused by deficient activity of L-methylmalonyl-CoA mutase or its cofactor cyanocobalamin and it is biochemically characterized by an accumulation of methylmalonic acid (MMA) in tissue and body fluids of patients. The main clinical manifestations of this disease are neurological and observable symptoms during metabolic decompensation are encephalopathy, cerebral atrophy, coma, and seizures, which commonly appear in newborns. This study aimed to investigate the toxic effects of MMA in a glial cell line presenting astrocytic features. Astroglial C6 cells were exposed to MMA (0.1-10mM) for 24 or 48h and cell metabolic viability, glucose consumption, and oxygen consumption rate, as well as glutamate uptake and ATP content were analyzed. The possible preventive effects of bezafibrate were also evaluated. MMA significantly reduced cell metabolic viability after 48-h period and increased glucose consumption during the same period of incubation. Regarding the energy homeostasis, MMA significantly reduced respiratory parameters of cells after 48-h exposure, indicating that cell metabolism is compromised at resting and reserve capacity state, which might influence the cell capacity to meet energetic demands. Glutamate uptake and ATP content were also compromised after exposure to MMA, which can be influenced energy metabolism impairment, affecting the functionality of the astroglial cells. Our findings suggest that these effects could be involved in the pathophysiology of neurological dysfunction of this disease. Methylmalonic acid compromises mitochondrial functioning leading to reduced ATP production and reduces glutamate uptake by C6 astroglial cells.

Antibiotic Resistance Carriage Causes a Lower Survivability Due to Stress Associated with High-Pressure Treatment among Strains from Starter Cultures.

Simple SummaryHigh-pressure processing is one of the most promising novel food preservation methods that is increasingly used in the food industry. It is applied in various food products such as dairy, meat, juices, and jams to improve safety and shelf-life by the inactivation of microorganisms and preserving of quality attributes. It is reported that the level of antibiotic resistance may influence the ability of strains to survive stress conditions. In this study, it was investigated if carrying antibiotic resistance genes affects the survival of lactic acid bacteria (Lactococcus and the former Lactobacillus) strains during high-pressure treatment. It was demonstrated that carrying antibiotic resistance genes strains showed a lower survival in response to pressure than strains carrying up to one resistance gene. The same observations were made for both genera. Appropriately selected parameters of high-pressure treatment may help in the elimination of antibiotic-resistant strains.High-pressure processing is one of the most promising novel food preservation methods that is increasingly used in the food industry. Its biggest advantage is that it is a nonthermal method that ensures the microbiological safety of the product while maintaining other features, including nutritional value. If products made with starter cultures are subjected to high-pressure treatment, the process parameters should be selected so as not to eliminate all microorganisms in the product. The aim of the study was to investigate if carrying antibiotic resistance genes affects the survival of lactic acid bacteria (Lactococcus and the former Lactobacillus) strains during high-pressure treatment. Survival was assessed using the plate count method. It was shown that the strains carrying antibiotic resistance genes showed a lower survival to high pressure. This might be explained by the phenomenon of fitness cost, consisting in a reduced adaptation of antibiotic-resistant strains related to metabolic expenditure. The obtained results indicate the need for further research in this field and the need to select food processing parameters depending on the strains intentionally included in the food.

Nicotinamide Riboside Supplementation Attenuates Obesity-Induced Adipose Tissue Fibrosis and Inflammation in Female Mouse Model

ObjectivesNicotinamide riboside (NR) is a nicotinamide adenine dinucleotide (NAD+) precursor. We previously reported that in male diet-induced obesity mice, NR supplementation attenuated liver fibrosis by inhibiting the activation of hepatic stellate cells. However, whether NR elicits a similar effect in females has not been studied. Therefore, in this study, we investigated whether NR consumption can prevent the development of inflammation and fibrosis and improve NAD + metabolism in the liver and white adipose tissue (WAT) in female mice with diet-induced obesity MethodsFemale C57BL/6J mice were fed a high-fat/high-sucrose/high-cholesterol control (HF), or a HF diet supplemented with NR (HF-NR; 400 mg/kg/day) for 20 weeks. The effects of NR on fibrosis and inflammation were assessed by biochemical, molecular, and histological analyses in the liver and gonadal WAT (gWAT). Metabolic rates, energy expenditure, and physical activity of mice were analyzed using indirect calorimetry. ResultsThe body weight of mice fed HF-NR was significantly lower than HF. Also, HF-NR showed reductions in fat mass, glucose intolerance, and serum cholesterol levels compared with HF. In the liver, NAD + content tended toward an increase in the HF-NR, but NR supplementation did not significantly alter liver steatosis and fibrosis, along with no changes in serum alanine aminotransferase levels. In gWAT, the HF-NR group displayed decreased weight and adipocyte size compared with HF. In addition, the numbers of crown-like structures, a marker of inflammation, were markedly reduced in the gWAT of HF-NR compared to the HF. Consistently, NR supplementation decreased the expression of macrophage and proinflammatory M1 macrophage markers. Mice fed HF-NR also exhibited decreased gWAT fibrosis, evidenced by less fibrogenic gene expression and collagen accumulation than HF. Metabolic rates, physical activity, and energy expenditure were significantly higher in the HF-NR group than in HF. ConclusionsNR supplementation increased metabolic rates, energy expenditure, and physical activity, preventing obesity and its-associated inflammation and fibrosis in the WAT of female mice. The data suggest that NR may have sex-dependent effects on tissue-specific inhibition of obesity-induced inflammation and fibrosis. Funding SourcesThis study was supported by NIH 3R01DK108254-04S1.

Preclinical Efficacy of INST3399, a Synthetic Novel PKCbeta Inhibitor, for the Treatment of Obesity and Fatty Liver Disease

ObjectivesThe prevalence of obesity has increased over the last few decades reaching epidemic proportions. Clearly, public health efforts and anti obesity agents presently in use are inadequate for curbing the obesity epidemic. Currently existing FDA-approved anti-obesity drugs are specific receptor-targeted drugs that focus on reducing energy intake. Energy intake reduction is equivalent to calorie-restricted dieting and is prone to weight cycling because it decreases muscle mass, leading to reduced metabolic function and energy expenditure. Hence, long-term weight loss is difficult to achieve. In consideration of the aforementioned hurdles, a promising anti-obesity drug should consist of multi-functional effects leading to energy expenditure. We previously demonstrated that mice with systemic PKCβ deficiency displayed many of the features one would desire in individuals treated with an ideal anti-obesity drug; elevated metabolic rate, which contribute to protection from diet-induced obesity, hepatic steatosis, and insulin-resistance (Hepatology 49:1525,2009; J. Lipid Res. 286:22,795,2011). We recently reported that depletion of hepatocyte-specific PKCβ recapitulates many of the beneficial features of systemic PKCbeta deficient mice (Mol. Metab. 44: e101133,2021; JCI Insight 6: e149023,2021). These results provide compelling evidence that PKCβ is an important therapeutic target for the treatment of obesity, as well as its related metabolic complications.MethodsOur aim is to evaluate therapeutic effects of a novel PKCβ inhibitor, INST3399 to treat obesity and fatty liver disease in a high-fat diet-induced obese C57BL/6J mouse model.ResultsINST3399 is a novel PKCβ inhibitor, which inhibits this kinase by a mechanism different from a well-known alternative ruboxistaurin. INST3399 inhibits PKCβ in the basal state, about >5-times more potent than ruboxistaurin and exhibit more than >100-fold selectivity for PKCβ versus PKCα. Our data demonstrate that INST3399 is safe and able to decrease the degree of obesity and fatty liver disease.ConclusionsINST3399 is a promising novel drug candidate for the pharmacological treatment of obesity and associated comorbidities. Moreover, INST3399 could further evolve as a novel treatment to manage other metabolic conditions with excessive PKCβ expression.Funding SourcesNIH HL138198; Instacare Funds.

Perspective: Obesity—an unexplained epidemic

ABSTRACTSince 1980, obesity prevalence among US adults has soared from 14% to 42%. The commonly accepted explanation is pervasive overeating: ever-increasing energy intake as the population gains weight, year after year. However, evidence does not support this hypothesis. National data on energy intake and energy availability show increases between 1961 and 2000, during modern industrialization of food; but a plateau or declines thereafter—even as obesity continued rising—and while physical activity modestly increased. Thus, Americans appear to be eating relatively less since 2000, for ever-increasing body sizes, as time has progressed. Although both energy intake and energy availability are measured with error, such errors would have to be new since 2000 and systematically increasing over time for these 2 separate, independent measures. Given the tremendous societal consequences of obesity, and failure to date of energy balance–focused interventions to stem the tide, it is critical for the scientific community to consider and test alternative hypotheses. Growing evidence suggests complex, interrelated biological interactions between food processing (including acellular nutrients, depleted prebiotics, additives), gut microbial composition and function, host metabolic expenditure, and intergenerational transmission of risk (including epigenetics, noncoding RNAs, microbial species). In this paradigm, whereas increasing energy intake may have contributed to rising obesity in earlier years, today pervasive adiposity and its physiologic adaptations have created a biological milieu which interacts with industrialized foods to promote escalating obesity, even with stable energy intake—a self-sustaining, difficult-to-reverse cycle. These scientific hypotheses must be rigorously evaluated, because even partial confirmation would dramatically shift and expand current prevention and treatment strategies. Urgent new investment in research is required. Simultaneously, uncertain evidence on the obesity epidemic's primary drivers does not mean there is no evidence on actions that can help, and existing science must be more rapidly translated and refined into clinical, public health, and policy interventions.

Nicotinamide riboside supplementation exerts an anti–obesity effect and prevents inflammation and fibrosis in white adipose tissue of female diet-induced obesity mice

Nicotinamide riboside (NR) is a nicotinamide adenine dinucleotide (NAD+) precursor. We previously reported that NR supplementation prevented the development of liver fibrosis in male mice. However, whether NR exerts a similar effect in females is unknown. Therefore, we determined whether NR supplementation can prevent obesity-induced inflammation and fibrosis in the liver and white adipose tissue (WAT) by providing NAD+ in obese female mice. Female C57BL/6J mice at the age of 8 weeks (young) and 16 weeks (old) were fed a high-fat/high-sucrose/high-cholesterol diet (HF) or HF diet supplemented with NR at 400 mg/kg/d for 20 weeks. While NR had minor effects in young female mice, it significantly reduced body weight gain, fat mass, glucose intolerance, and serum cholesterol levels compared to the HF group in old females. Hepatic NAD+ level tended toward an increase in the NR group (P=.054), but NR did not attenuate serum alanine aminotransferase levels, steatosis, and liver fibrosis in old female mice. However, NR decreased weight and adipocyte size in gonadal WAT (gWAT) of old females. NR also reduced the number of crown-like structures and the expression of inflammatory genes, along with decreases in fibrogenic gene expression and collagen accumulation in gWAT compared with the HF group. Also, old mice fed NR showed increased metabolic rates, physical activity, and energy expenditure compared with the HF. Thus, our results indicated that NR supplementation exerted an anti–obesity effect and prevented the development of inflammation and fibrosis in the WAT of old, but not young, female mice with diet-induced obesity.

Brown Adipose Tissue and Novel Management Strategies for Polycystic Ovary Syndrome Therapy.

Brown adipose tissue (BAT), a unique tissue, plays a key role in metabolism and energy expenditure through adaptive nonshivering thermogenesis. It has recently become a therapeutic target in the treatment of obesity and metabolic diseases. The thermogenic effect of BAT occurs through uncoupling protein-1 by uncoupling adenosine triphosphate (ATP) synthesis from energy substrate oxidation. The review discusses the recent developments and progress associated with the biology, function, and activation of BAT, with a focus on its therapeutic potential for the treatment of polycystic ovary syndrome (PCOS). The endocrine activity of brown adipocytes affects the energy balance and homeostasis of glucose and lipids, thereby affecting the association of BAT activity and the metabolic profile. PCOS is a complex reproductive and metabolic disorder of reproductive-age women. Functional abnormalities of adipose tissue (AT) have been reported in patients with PCOS. Numerous studies have shown that BAT could regulate the features of PCOS and that increases in BAT mass or activity were effective in the treatment of PCOS through approaches including cold stimulation, BAT transplantation and compound activation in various animal models. Therefore, BAT may be used as a novel management strategy for the patients with PCOS to improve women’s health clinically. It is highly important to identify key brown adipokines for the discovery and development of novel candidates to establish an efficacious therapeutic strategy for patients with PCOS in the future.

CTRP11 contributes modestly to systemic metabolism and energy balance.

C1q/TNF‐related proteins (CTRP1‐15) constitute a conserved group of secreted proteins of the C1q family with diverse functions. In vitro studies have shown that CTRP11/C1QL4 can inhibit adipogenesis, antagonize myoblast fusion, and promote testosterone synthesis and secretion. Whether CTRP11 is required for these processes in vivo remains unknown. Here, we show that knockout (KO) mice lacking CTRP11 have normal skeletal muscle mass and function, and testosterone level, suggesting that CTRP11 is dispensable for skeletal muscle development and testosterone production. We focused our analysis on whether this nutrient‐responsive secreted protein plays a role in controlling sugar and fat metabolism. At baseline when mice are fed a standard chow, CTRP11 deficiency affects metabolic parameters in a sexually dimorphic manner. Only Ctrp11‐KO female mice have significantly higher fasting serum ketones and reduced physical activity. In the refeeding phase following food withdrawal, Ctrp11‐KO female mice have reduced food intake and increased metabolic rate and energy expenditure, highlighting CTRP11’s role in fasting–refeeding response. When challenged with a high‐fat diet to induce obesity and metabolic dysfunction, CTRP11 deficiency modestly exacerbates obesity‐induced glucose intolerance, with more pronounced effects seen in Ctrp11‐KO male mice. Switching to a low‐fat diet after obesity induction results in greater fat loss in wild type relative to KO male mice, suggesting impaired response to obesity reversal and reduced metabolic flexibility in the absence of CTRP11. Collectively, our data provide genetic evidence for novel sex‐dependent metabolic regulation by CTRP11, but note the overall modest contribution of CTRP11 to systemic energy homeostasis.

Variability of regional glucose metabolism and the topology of functional networks in the human brain

The brain consumes the most energy per relative mass amongst the organs in the human body. Theoretical and empirical studies have shown that behavioral processes are relatively inexpensive metabolically, and that most energy goes to maintaining the status quo, i.e., the balance of cell membranes’ resting potentials and subthreshold spontaneous activity. Spontaneous activity fluctuates across brain regions in a correlated fashion that defines multi-scale hierarchical networks called resting-state networks (RSNs). Different regions of the brain display different metabolic consumption, but the relationship between regional brain metabolism and RSNs is still under investigation.Here, we examine the variability of glucose metabolism across brain regions, measured with the relative standard uptake value (SUVR) using 18F-FDG PET, and the topology of RSNs, measured through graph analysis applied to fMRI resting-state functional connectivity (FC).We found a moderate linear relationship between the strength (STR) of pairwise regional FC and metabolism. Moreover, the linear correlation between SUVR and STR grew stronger as we considered more connected regions (hubs). Regions connecting different RSNs, or connector hubs, showed higher SUVR than regions connecting nodes within the same RSN, or provincial hubs. Our results show that functional connections as probed by fMRI are related to glucose metabolism, especially in a system of provincial and connector hubs.

Metabolic syndrome and alcohol consumption as risk factors for liver disease: which border?

Metabolic syndrome and alcohol consumption as risk factors for liver disease: which border?

Impact of Aerobic High-Intensity Interval Training Intervention and Mediterranean Diet Recommendations on Health-Related Quality of Life and Lifestyle Modification in Post-Myocardial Infarction Patients: Results From the INTERFARCT Surveys.

This study aims to determine the impact of 2 (low vs high volume) high-intensity interval training (HIIT) programs with Mediterranean diet (MedDiet) recommendations on health-related quality of life (HRQoL) and lifestyle modification, and to examine the relationships between the changes in anxiety and depression with HRQoL and lifestyle variables after myocardial infarction (MI). Participants (n = 80) were randomized to attention control or one of the two supervised HIIT groups (2d/weeks). Surveys before and after intervention (16weeks): HRQoL (SF-36), anxiety and depression (HADS), MedDiet adherence (MEDAS), and physical activity (PA) and sedentary behavior (SB) levels. After intervention, there were improvements (P < .05) in HRQoL, HADS scores, and MedDiet adherence, with higher PA level in both HIIT groups with no between-HIIT group differences. The HADS score decline correlated (P < .05) with both the increase in physical component of SF-36 (r = .42), the overall metabolic expenditure (r = .26), and adherence to the MedDiet (r = .24), and the reduction in the SB (r = .35). HIIT exercise intervention with MedDiet recommendations improved HRQoL, along with reduced anxiety and depression symptoms, and a healthier lifestyle after MI. Better mental health was related to higher values of PA and MedDiet adherence.

Phosphoproteomics reveals that camel and goat milk improve glucose homeostasis in HDF/STZ-induced diabetic rats through activation of hepatic AMPK and GSK3-GYS axis

Diabetes is a serious public health problem with global implications. Among many diabetes management therapies, non-pharmacological therapies such as those that focus on diet and exercise are gradually becoming more acceptable to patients. Within dietary management options, dairy products such as camel and goat milk are valued for their specific health benefits. The aim of this study was therefore to investigate the effect of camel and goat milk consumption on glucose homeostasis in high-fat diet and streptozotocin (HFD/STZ) induced diabetic rats. HFD/STZ-induced diabetic rats were fed with different milk for 35 days. Parameters related to glucose homeostasis, as well as hepatic proteome and phosphoproteome were investigated. The results of which showed that camel and goat milk consumption improved fasting glucose levels, glucose tolerance, and indicators related to lipid metabolism, while bovine and sheep milk consumption did not work. In addition, the hepatic phosphoproteome suggests that the ameliorative effect of both camel and goat milk was associated with the activation of AMPK. However, camel milk consumption further elevated the phosphorylation level of hepatic ACC, while goat milk consumption activated GSK3-GYS axis-related proteins. The present study investigated the possible mechanisms by which camel and goat milk consumption improves glucose homeostasis in HFD/STZ-induced diabetic rats and revealed their differences in the mechanism of antidiabetic effect.

Improved heat coefficients for joint-space metabolic energy expenditure model during level, uphill, and downhill walking.

A previously developed joint-space metabolic energy expenditure (MEE) model includes subject-specific parameters and was validated using level walking gait data. In this work, we determine how well this joint-space model performs during various walking grades (-8%, 0%, and 8%) at 0.8 m·s ⁻1 and 1.3 m·s ⁻1 using published gait data in the literature. In response to those results, we formulate an optimization problem and solve it through the particle swam method plus fmincon function in MATLAB to identify a new optimal weighting parameter set for each grade that produces more accurate predicted MEE and we compare our new findings with seven other MEE models in the literature. The current study matched the measured MEE the best with the lowest RMSE values for level (0.45 J·kg ⁻1·m ⁻1) and downhill (0.82 J·kg ⁻1·m ⁻1) walking and the third lowest RMSE value for uphill (1.56 J·kg ⁻1·m ⁻1) walking, where another MEE model, Looney et al., had the lowest RMSE for uphill (1.27 J·kg ⁻1·m ⁻1) walking. Bland-Altman plots and three independent-samples t-tests show that there was no statistical significant difference between experimentally measured MEE and estimated MEE during the three walking conditions, meaning that the three new optimal weighting parameter sets can be used with 6 degree of freedom (DOF) lower extremity motion data to better estimate whole body MEE in those scenarios. We believe that this work is a step towards identifying a single robust parameter set that allows for accurate estimation of MEE during any task, with the potential to mitigate a limitation of indirect calorimetry requiring lengthy steady state motion.

Independent and Interactive Effects of Genetic Background and Sex on Tissue Metabolomes of Adipose, Skeletal Muscle, and Liver in Mice.

Genetics play an important role in the development of metabolic diseases. However, the relative influence of genetic variation on metabolism is not well defined, particularly in tissues, where metabolic dysfunction that leads to disease occurs. We used inbred strains of laboratory mice to evaluate the impact of genetic variation on the metabolomes of tissues that play central roles in metabolic diseases. We chose a set of four common inbred strains that have different levels of susceptibility to obesity, insulin resistance, and other common metabolic disorders. At the ages used, and under standard husbandry conditions, these lines are not overtly diseased. Using global metabolomics profiling, we evaluated water-soluble metabolites in liver, skeletal muscle, and adipose from A/J, C57BL/6J, FVB/NJ, and NOD/ShiLtJ mice fed a standard mouse chow diet. We included both males and females to assess the relative influence of strain, sex, and strain-by-sex interactions on metabolomes. The mice were also phenotyped for systems level traits related to metabolism and energy expenditure. Strain explained more variation in the metabolite profile than did sex or its interaction with strain across each of the tissues, especially in liver. Purine and pyrimidine metabolism and pathways related to amino acid metabolism were identified as pathways that discriminated strains across all three tissues. Based on the results from ANOVA, sex and sex-by-strain interaction had modest influence on metabolomes relative to strain, suggesting that the tissue metabolome remains largely stable across sexes consuming the same diet. Our data indicate that genetic variation exerts a fundamental influence on tissue metabolism.

Dual endothelin receptor antagonism increases resting energy expenditure in people with increased adiposity.

Increased adiposity is associated with dysregulation of the endothelin system, both of which increase the risk of cardiovascular disease (CVD). Preclinical data indicate that endothelin dysregulation also reduces resting energy expenditure (REE). The objective was to test the hypothesis that endothelin receptor antagonism will increase REE in people with obesity compared with healthy weight individuals. Using a double blind, placebo-controlled, crossover design, 32 participants [healthy weight (HW): n = 16, BMI: 21.3 ± 2.8 kg/m2, age: 26 ± 7 yr and overweight/obese (OB): n = 16, BMI: 33.5 ± 9.5 kg/m2, age: 31 ± 6 yr] were randomized to receive either 125 mg of bosentan (ETA/B antagonism) or placebo twice per day for 3 days. Breath-by-breath gas exchange data were collected and REE was assessed by indirect calorimetry. Venous blood samples were analyzed for concentrations of endothelin-1 (ET-1). Treatment with bosentan increased plasma ET-1 in both OB and HW groups. Within the OB group, the changes in absolute REE (PLA: -77.6 ± 127.6 vs. BOS: 72.2 ± 146.6 kcal/day; P = 0.046). The change in REE was not different following either treatment in the HW group. Overall, absolute plasma concentrations of ET-1 following treatment with bosentan were significantly associated with kcal/day of fat (r = 0.488, P = 0.005), percentage of fat utilization (r = 0.415, P = 0.020), and inversely associated with the percentage of carbohydrates (r = -0.419, P = 0.019), and respiratory exchange ratio (r = -0.407, P = 0.023). Taken together, these results suggest that modulation of the endothelin system may represent a novel therapeutic approach to increase both resting metabolism and caloric expenditure, and reduce CVD risk in people with increased adiposity.NEW & NOTEWORTHY Findings from our current translational investigation demonstrate that dual endothelin A/B receptor antagonism increases total REE in overweight/obese individuals. These results suggest that modulation of the endothelin system may represent a novel therapeutic target to increase both resting metabolism and caloric expenditure, enhance weight loss, and reduce CVD risk in seemingly healthy individuals with elevated adiposity.

Deep Learning Enables Exoboot Control to Augment Variable-Speed Walking

Ankle exoskeletons have the potential to improve mobility, but common controllers are often inflexible to variations in tasks, such as changes in walking speed. To enable effective variable-speed exoboot control, we developed and validated a two-headed convolutional neural network trained to (1) classify stance versus swing and (2) predict the phase during stance, which was then mapped to a desired exoboot torque. This Machine Learning Estimator (MLE) was trained from nine participants walking at three speeds and four exoboot assistance levels. A Time-Based Estimator (TBE) that predicted gait phase from the two previous stride durations was used to apply realistic torques during MLE training and served as a within&#x2013;participant control condition. The MLE was validated online with three new participants walking at a range of speeds and torques, both interpolating within and extrapolating outside the training set. Online validation accuracy (RMSE) across tested speeds and torque levels was 3.9&#x0025;. On a simple walking task in which treadmill speed was varied sinusoidally between 1.1 and 1.6 m&#x002F;s with a 30 s period, the three participants exhibited a mean 5.2&#x0025; decrease in metabolic expenditure with the MLE compared to no-exo (boots only), but exhibited a 5.4&#x0025; increase when walking with the TBE. The MLE more accurately predicted heel strike and toe off events (heel strike Mean Absolute Error: 9.6 ms; toe off MAE: 13.2 ms) than the TBE (heel strike MAE: 19.1 ms; toe off MAE: 34 ms). These positive results validated the potential of using a deep learning model for gait state estimation to effectively control an ankle exoskeleton across variable walking speeds.

Effects of Gradient and Speed on Uphill Running Gait Variability.

The aim of this study was to investigate the effects of gradient and speed on running variability (RV) and local dynamic stability (LDS) during uphill running. (1) Both gradient and speed increase metabolic effort, in terms of heart rate (HR) and perceived exertion (CR10), in line with the contemporary literature, and (2) gradient increases RV and impairs LDS. "Crossover" observational design. Level 3. A total of 25 runners completed 10-minute running trials in 3 different conditions and in a randomized order: gradient at 0% (0CON), 2% (2CON), and 2% at isoefficiency speed (2IES). 0CON and 2CON speeds were calculated as the "best 10-km race performance" minus 1 km·h-1, whereas 2IES speed was adjusted to induce the same metabolic expenditure as 0CON. HR and perceived exertion as well as running kinematic variables were collected across all trials and conditions. Running variability was calculated as the standard deviation of the mean stride-to-stride intervals over 100 strides, while LDS was expressed by the Lyapunov exponent (LyE) determined on running cycle time over different running conditions. Increases in HR and CR10 were observed between 0CON and 2CON (P < 0.001) and between 2IES and 2CON (P < 0.01). Higher RV was found in 2CON compared with 0CON and 2IES (both P < 0.001). Finally, the largest LyE was observed in 2IES compared with 0CON and 2CON (P = 0.02 and P = 0.01, respectively). Whereas RV seems to be dependent more on metabolic effort, LDS is affected by gradient to a greater extent. Running variability could be used to monitor external training load in marathon runners.

Metabolic cost of flight and aerobic efficiency in the rose chafer, Protaetia cuprea (Cetoniinae).

Rose chafer beetles (Protetia cuprea) are pollinators as well as agricultural pests, flying between flowers and trees while foraging for pollen and fruits. Calculating the energy they expend on flying during foraging activity faces the challenge of measuring the metabolic rate (MR) of free-flying insects in an open space. We overcame this challenge by using the bolus injection of 13 C Na-bicarbonate technique to measure their metabolic energy expenditure while flying in a large flight arena. Concurrently, we tracked the insects with high-speed cameras to extract their flight trajectory, from which we calculated the mechanical power invested in flying for each flight bout. We found that the chemical (metabolic) energy input converted to mechanical flight energy output at a mean efficiency of 10.4%±5.2%, with a trend of increased efficiency in larger conspecifics (efficiency scaled with body mass to the power of 1.4). The transition in the summer from a diet of pollen to that of fruits may affect the energy budget available for foraging. Starved P. cuprea, feeding on apples ad libitum, increased their body mass by an average of 6% in 2h. According to our calculations, such a meal can power a 630-m flight (assuming a carbohydrate assimilation efficiency of 90%). Pollen, with a low water and carbohydrate content but rich in proteins and lipids, has a higher caloric content and should assimilate differently when converting food to flight fuel. The high cost of aerial locomotion is inherent to the foraging behavior of rose chafers, explaining their short flight bouts followed by prolonged feeding activity.