Target Energy Expenditure Research Articles

Protonophore treatment augments energy expenditure in mice housed at thermoneutrality.

Sub-thermoneutral housing increases facultative thermogenesis in mice, which may mask the pre-clinical efficacy of anti-obesity strategies that target energy expenditure (EE). Here, we quantified the impact of protonophore treatment on whole-body energetics in mice housed at 30°C. C57BL/6J mice (n = 48, 24M/24F) were housed at 24°C for 2weeks; 32 (16M/16F) were then transitioned to 30°C for a further 4weeks. Following 2weeks acclimation at 30°C, mice (n = 16 per group, 8M/8F) received either normal (0mg/L; Control) or supplemented (400mg/L; 2,4-Dinitrophenol [DNP]) drinking water. Mice were singly housed in metabolic cages to determine total EE (TEE) and its components via respiratory gas exchange. Mitochondrial respiratory function of permeabilized liver tissue was determined by high-resolution respirometry. Transitioning mice from 24°C to 30°C reduced TEE and basal EE (BEE) by 16% and 41%, respectively (both P < 0.001). Compared to 30°C controls, TEE was 2.6kcal/day greater in DNP-treated mice (95% CI: 1.6-3.6kcal/day, P < 0.001), which was partly due to a 1.2kcal/day higher BEE in DNP-treated mice (95% CI: 0.6-1.7kcal/day, P < 0.001). The absolute TEE of 30°C DNP-treated mice was lower than that of mice housed at 24°C in the absence of DNP (DNP: 9.4 ± 0.7kcal/day vs. 24°C control: 10.4 ± 1.5kcal/day). DNP treatment reduced overall body fat of females by 2.9 percentage points versus sex-matched controls (95% CI: 1.3%-4.5%, P < 0.001), which was at least partly due to a reduction in inguinal white fat mass. Protonophore treatment markedly increases EE in mice housed at 30°C. The magnitude of change in TEE of mice receiving protonophore treatment at 30°C was smaller than that brought about by transitioning mice from 24°C to 30°C, emphasizing that housing temperature must be considered when assessing anti-obesity strategies that target EE in mice.

Beyond appetite regulation: Targeting energy expenditure, fat oxidation, and lean mass preservation for sustainable weight loss.

New appetite‐regulating antiobesity treatments such as semaglutide and agents under investigation such as tirzepatide show promise in achieving weight loss of 15% or more. Energy expenditure, fat oxidation, and lean mass preservation are important determinants of weight loss and weight‐loss maintenance beyond appetite regulation. This review discusses prior failures in clinical development of weight‐loss drugs targeting energy expenditure and explores novel strategies for targeting energy expenditure: mitochondrial proton leak, uncoupling, dynamics, and biogenesis; futile calcium and substrate cycling; leptin for weight maintenance; increased sympathetic nervous system activity; and browning of white fat. Relevant targets for preserving lean mass are also reviewed: growth hormone, activin type II receptor inhibition, and urocortin 2 and 3. We endorse moderate modulation of energy expenditure and preservation of lean mass in combination with efficient appetite reduction as a means of obtaining a significant, safe, and long‐lasting weight loss. Furthermore, we suggest that the regulatory guidelines should be revisited to focus more on the quality of weight loss and its maintenance rather than the absolute weight loss. Commitment to this research focus both from a scientific and from a regulatory point of view could signal the beginning of the next era in obesity therapies.

Digestion-Specific Acupuncture Effect on Feeding Intolerance in Critically Ill Post-Operative Oral and Hypopharyngeal Cancer Patients: A Single-Blind Randomized Control Trial.

Malnourishment is prevalent in patients suffering from head and neck cancer. The postoperative period is crucial in terms of nutritional support, especially after composite resection and reconstruction surgery. These patients present with a number of risk factors that aggravate feeding intolerance, including postoperative status, prolonged immobility, decreased head elevation, mechanical ventilation, and applied sedative agents. Routine management protocols for feeding intolerance include prokinetic drug use and post-pyloric tube insertion, which could be both limited and accompanied by detrimental adverse events. This single-blind clinical trial aimed to investigate the effects of acupuncture in postoperative feeding intolerance in critically ill oral and hypopharyngeal cancer patients. Twenty-eight patients were randomized into two groups: Intervention group and Control group. Interventions were administered daily over three consecutive postoperative days. The primary outcome revealed that the intervention group reached 70% and 80% of target energy expenditure (EE) significantly earlier than the control group (4.00 ± 1.22 versus 6.69 ± 3.50 days, p = 0.012), accompanied by higher total calorie intake within the first postoperative week (10263.62 ± 1086.11 kcals versus 8384.69 ± 2120.05 kcals, p = 0.004). Furthermore, the intervention group also needed less of the prokinetic drug (Metoclopramide, 20.77 ± 48.73 mg versus 68.46 ± 66.56 mg, p = 0.010). In conclusion, digestion-specific acupuncture facilitated reduced postoperative feeding intolerance in oral and hypopharyngeal cancer patients.

Targeting Energy Expenditure-Drugs for Obesity Treatment.

Obesity and overweight are associated with lethal diseases. In this context, obese and overweight individuals infected by COVID-19 are at greater risk of dying. Obesity is treated by three main pharmaceutical approaches, namely suppressing appetite, reducing energy intake by impairing absorption, and increasing energy expenditure. Most compounds used for the latter were first envisaged for other medical uses. However, several candidates are now being developed explicitly for targeting obesity by increasing energy expenditure. This review analyzes the compounds that show anti-obesity activity exerted through the energy expenditure pathway. They are classified on the basis of their development status: FDA-approved, Withdrawn, Clinical Trials, and Under Development. The chemical nature, target, mechanisms of action, and description of the current stage of development are described for each one.

Relationship Between Percentages of Heart Rate Reserve and Oxygen Uptake Reserve During Cycling and Running: A Validation Study.

Guimarães, GC, Farinatti, PTV, Midgley, AW, Vasconcellos, F, Vigário, P, and Cunha, FA. Relationship between percentages of heart rate reserve and oxygen uptake reserve during cycling and running: a validation study. J Strength Cond Res 33(7): 1954-1962, 2019-This study investigated the relationship between percentages of heart rate reserve (%HRR) and oxygen uptake reserve (%VO2R) during a cardiopulmonary exercise test (CPET) and discrete bouts of isocaloric cycling and treadmill running. Thirty men visited the laboratory 3 times for anthropometrical and resting VO2 assessments, and perform cycling and running CPETs. Ten men visited the laboratory twice more to investigate the validity of the %HRR-%VO2R relationships during isocaloric bouts of cycling and running at 75% VO2R with energy expenditures of 400 kcals. The %HRR was significantly higher than the %VO2R during both CPETs at all exercise intensities (p < 0.001). During isocaloric exercise bouts, mean %HRR-%VO2R differences of 6.5% and 7.0% were observed for cycling and running, respectively (p = 0.007-p < 0.001). The %HRR and %VO2R increased over time (p < 0.001), the rate of which was influenced by exercise modality (p < 0.001). On average, heart rate was 5 (p = 0.007) and 8 (p < 0.001) b·min higher than predicted from the second energy expenditure quartile for cycling and running, respectively; however, observed VO2 was lower than predicted during all quartiles for cycling, and the first quartile for running. Consequently, time to achieve the target energy expenditure was greater than predicted (p < 0.01). In conclusion, the %HRR-%VO2R relationship observed during CPET data did not accurately transpose to prolonged isocaloric bouts of cycling and running. In addition, power outputs and speeds defined by the American College of Sports Medicine equations for cycling and running, respectively, overestimated VO2 and energy expenditure.

The Root of Atractylodes macrocephala Koidzumi Prevents Obesity and Glucose Intolerance and Increases Energy Metabolism in Mice.

Targeting energy expenditure offers a strategy for treating obesity more effectively and safely. In previous studies, we found that the root of Atractylodes macrocephala Koidzumi (Atractylodis Rhizoma Alba, ARA) increased energy metabolism in C2C12 cells. Here, we investigated the effects of ARA on obesity and glucose intolerance by examining energy metabolism in skeletal muscle and brown fat in high-fat diet (HFD) induced obese mice. ARA decreased body weight gain, hepatic lipid levels and serum total cholesterol levels, but did not modify food intake. Fasting serum glucose, serum insulin levels and glucose intolerance were all improved in ARA treated mice. Furthermore, ARA increased peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α) expression, and the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) in skeletal muscle tissues, and also prevented skeletal muscle atrophy. In addition, the numbers of brown adipocytes and the expressions of PGC1α and uncoupling protein 1 (UCP1) were elevated in the brown adipose tissues of ARA treated mice. Our results show that ARA can prevent diet-induced obesity and glucose intolerance in C5BL/6 mice and suggests that the mechanism responsible is related to the promotion of energy metabolism in skeletal muscle and brown adipose tissues.

Atractylenolide III Enhances Energy Metabolism by Increasing the SIRT-1 and PGC1α Expression with AMPK Phosphorylation in C2C12 Mouse Skeletal Muscle Cells.

Targeting energy expenditure provides a potential alternative strategy for achieving energy balance to combat obesity and the development of type 2 diabetes mellitus (T2DM). In the present study, we investigated whether atractylenolide III (AIII) regulates energy metabolism in skeletal muscle cells. Differentiated C2C12 myotubes were treated with AIII (10, 20, or 50 µM) or metformin (2.5 mM) for indicated times. The levels of glucose uptake, the expressions of key mitochondrial biogenesis-related factors and their target genes were measured in C2C12 myotubes. AIII significantly increased the glucose uptake levels, and significantly increased the expressions of peroxisome proliferator-activated receptor coactivator-1α (PGC1α) and mitochondrial biogenesis-related markers, such as, nuclear respiratory factor-1 (NRF-1), and mitochondrial transcription factor A (TFAM) and mitochondrial mass and total ATP contents. In addition, AIII significantly increased the phosphorylation of AMP-activated protein kinase (AMPK) and the expression of sirtuin1 (SIRT1). These results suggest that AIII may have beneficial effects on obesity and T2DM by improving energy metabolism in skeletal muscle.

Do the speeds defined by the American College of Sports Medicine metabolic equation for running produce target energy expenditures during isocaloric exercise bouts?

The accuracy of the American College of Sports Medicine (ACSM) equations for producing predicted values of heart rate reserve (HRR) and oxygen uptake reserve (VO2R) and consequently, target energy expenditure (EE) during exercise are yet to be established. This study investigated whether speeds defined by the ACSM metabolic equation for running correctly estimate the EEs during isocaloric exercise bouts. Twenty-eight men performed a ramp-incremental maximal exercise test to determine HRmax and VO2max. Two continuous exercise bouts at 60 and 80% VO2R and target EE of 400 kcal were then performed. In the 60% VO2R exercise the observed VO2R and EE were lower than predicted only during the first time quartile of the bout (t = 6.5, p < 0.001), whereas at 80% VO2R it was lower during the first (t = 15.3, p < 0.001), second (t = 5.4, p < 0.001) and third (t = 3.1, p = 0.025) quartiles. The observed HR was lower than predicted in the first time quartile of the 60% [Formula: see text] (t = 5.6, p < 0.001) and 80% VO2R bouts (t = 10.7, p < 0.001), whereas no significant differences occurred for any other time quartiles (p ≥ 0.23). In conclusion, the running speed defined by the ACSM metabolic equation overestimated VO2R and EE within exercise performed at 60 and 80% VO2R especially in higher intensities.

Targeting energy expenditure via fuel switching and beyond

Since over-nutrition accelerates the development of obesity, progression to type 2 diabetes, and the associated co-morbidity and mortality, there has been a keen interest in therapeutic interventions targeting mechanisms that may curb appetite, increase energy expenditure or at least attenuate insulin resistance. Over the past decade, numerous peri-mitochondrial targets in the de novo lipid synthesis pathway have been linked to an increase in energy expenditure and the drug development industry has pursued the gene products involved as candidates to develop drugs against. The basis of this link, and specifically the premise that lowering tissue and cellular malonyl-CoA can increase energy expenditure, is scrutinised here. The argument presented is that fuel switching as effected by changes in cellular malonyl-CoA concentrations will not trigger the mitochondria to increase energy expenditure because: (1) an increase in beta-oxidation by lowering respiratory exchange ratio (indicative of the metabolic fuel consumed) does not equal an increase in energy expenditure (how rapidly fuel is consumed); (2) the ATP:oxygen ratios (i.e. ATP energy made:oxygen required for the reaction) are similar when metabolising lipids (2.8) vs glucose (3.0); (3) substrate availability (NEFA) does not drive energy expenditure in vivo; and (4) the availability of ADP in the mitochondrial matrix determines the rate of energy expenditure, not the availability of fuel to enter the mitochondrial matrix. To increase mitochondrial energy expenditure, work must be done (exercise) and/or the mitochondrial proton leak must be enhanced, both of which increase availability of ADP. In fact, despite the historic taboo of chemical uncoupling, this mechanism validated in humans is closest on task to increasing whole-body energy expenditure. Chemical uncoupling mimics the naturally occurring phenomenon of proton leak, accelerating the metabolism of glucose and lipids. However, it is completely non-genomic (i.e. the target is a location, not a gene product) and is not associated with addiction or mood alterations common to satiety agents. A significant hurdle for drug development is to discover a safe mitochondrial uncoupler and to formulate it potentially as a pro-drug and/or oral pump, to avoid the issue of overdosing experienced in the 1930s. The potential therapeutic impact of such a compound for an over-nutritioned patient population could be profound. If effective, the mitochondrial uncoupler mechanism could resolve many of the associated diseases such as type 2 diabetes, hypertension, obesity, depression, sleep apnoea, non-alcoholic steatohepatitis, insulin resistance and hyperlipidaemia, therefore becoming a 'disease-modifying therapy'.

Targeting energy expenditure in muscle as a means of combating obesity

1. To date, an effective therapeutic agent that induces weight loss in obese subjects remains elusive. In order to establish a successful means to combat obesity, it is imperative that we identify novel targets that regulate energy balance. 2. Exciting new data have created resurgence in interest in the role of thermogenesis in energy balance. Recently, it has been demonstrated that functional brown adipocytes are present in adult humans and that brown adipocytes and myocytes are derived from a similar cell lineage and are thus likely to have similar physiological functions. 3. Recent work in the sheep has demonstrated that diffuse fat beds and skeletal muscle exhibit thermogenic properties. Furthermore, in sheep, central administration of leptin markedly increases postprandial thermogenesis in both fat and muscle tissues. This demonstrates that thermogenic processes in skeletal muscle can be manipulated in a similar way to thermogenesis in brown fat. 4. Given that skeletal muscle comprises a significant portion of bodyweight, approximately 30-40% of total body mass, we predict that energy expended by this tissue is likely to have significant ramifications for the regulation of bodyweight. 5. We propose that manipulation of skeletal muscle thermogenesis may provide a novel avenue for the development of anti-obesity therapies.

The energetic and cardiovascular response to treadmill walking and cycle ergometer exercise in obese women

Physical activity is essential in obesity management, but exercise capacity is compromised in obese individuals due to the excessive body mass, impacting on body movement's energetics, and to the dysfunctions of regulatory mechanisms, affecting cardiovascular responses. This study aims to compare the energetics and cardiovascular responses of walking and cycling in obese women, and to formulate recommendations regarding the most suitable type of exercise for obesity. Fifteen obese (OB) and six normal weight (NW) women exercised on treadmill (TM) and cycle ergometer (CE). During both exercise modalities, metabolic rate was higher in OB than in NW and correlated with measures of body mass. Leg movement metabolic rate during cycling depended upon individual adiposity, and when accounted for, mechanical efficiency was similar in the two groups. When accounting for extra mass, differences in metabolic rate among groups are abolished for CE, indicating no obesity impairment of muscle efficiency, but not for TM, suggesting that differences in biomechanics may explain the higher net cost of transport of OB. In both groups, HR was higher during CE than TM at the same oxygen uptake (VO(2)), but in OB the HR increment over VO(2) was greater for CE than for TM. Therefore, due to different cardiovascular responses to TM and CE in OB, walking is more convenient, enabling OB to attain target energy expenditure at lower HR or in a shorter time.

The influence of 30 minutes of light to moderate intensity cycling on postprandial lipemia

Elevated postprandial lipemia is an independent risk factor for coronary heart disease, and bouts of moderate intensity exercise of 60 min or more are often reported to lower postprandial lipemia. Information on moderate intensity exercise bouts of shorter duration corresponding to the current recommendations of health-maintaining exercise (i.e. 30 min or energy expenditure of approximately 630 kJ), however, is scarce. Therefore, we searched for the lowest exercise intensity during 30 min of light to moderate intensity cycling that still reduced postprandial lipemia. We employed a repeated measures cross-over design. Twelve healthy, not endurance trained, young men performed three activity trials (30 min cycling with a target energy expenditure of 420, 630 and 840 kJ) before ingestion of two mixed meals with a macronutrient composition corresponding to current recommendations and a control trial (no physical activity before meal ingestion). Capillary triacylglycerol was measured in the fasting state and hourly for 6 h after the first meal. Respiratory gases were analyzed in the fasting state, and 3 and 6 h after the first meal. Triacylglycerol and respiratory responses between the trials were compared with analyses of variance. Postprandial lipemia and the incremental area under the triacylglycerol curve were not significantly different with the activity trials compared with the control trial. The postprandial respiratory exchange ratio was also not significantly affected by activity. Thirty minutes of light to moderate intensity cycling did not reduce postprandial lipemia after two mixed meals with a moderate fat content in healthy, not endurance trained, young men.

The influence of 30 minutes of light to moderate intensity cycling on postprandial lipemia

Elevated postprandial lipemia is an independent risk factor for coronary heart disease, and bouts of moderate intensity exercise of 60 min or more are often reported to lower postprandial lipemia. Information on moderate intensity exercise bouts of shorter duration corresponding to the current recommendations of health-maintaining exercise (i.e. 30 min or energy expenditure of approximately 630 kJ), however, is scarce. Therefore, we searched for the lowest exercise intensity during 30 min of light to moderate intensity cycling that still reduced postprandial lipemia.We employed a repeated measures cross-over design.Twelve healthy, not endurance trained, young men performed three activity trials (30 min cycling with a target energy expenditure of 420, 630 and 840 kJ) before ingestion of two mixed meals with a macronutrient composition corresponding to current recommendations and a control trial (no physical activity before meal ingestion). Capillary triacylglycerol was measured in the fasting state and hourly for 6 h after the first meal. Respiratory gases were analyzed in the fasting state, and 3 and 6 h after the first meal. Triacylglycerol and respiratory responses between the trials were compared with analyses of variance.Postprandial lipemia and the incremental area under the triacylglycerol curve were not significantly different with the activity trials compared with the control trial. The postprandial respiratory exchange ratio was also not significantly affected by activity.Thirty minutes of light to moderate intensity cycling did not reduce postprandial lipemia after two mixed meals with a moderate fat content in healthy, not endurance trained, young men.

Effects of exercise intensity on cardiovascular fitness, total body composition, and visceral adiposity of obese adolescents

Little is known about how the intensity of exercise influences cardiovascular fitness and body composition, especially in obese adolescents. Our goal was to determine the effects of physical training intensity on the cardiovascular fitness, percentage of body fat (%BF), and visceral adipose tissue (VAT) of obese adolescents. Obese 13-16-y-olds (n = 80) were assigned to 1) biweekly lifestyle education (LSE), 2) LSE + moderate-intensity physical training, or 3) LSE + high-intensity physical training. The intervention lasted 8 mo. Physical training was offered 5 d/wk, and the target energy expenditure for all subjects in physical training groups was 1047 kJ (250 kcal)/session. Cardiovascular fitness was measured with a multistage treadmill test, %BF with dual-energy X-ray absorptiometry, and VAT with magnetic resonance imaging. The increase in cardiovascular fitness in the high-intensity physical training group, but not in the moderate-intensity group, was significantly greater than that in the LSE alone group (P = 0.009); no other comparisons of the 3 groups were significant. Compared with the LSE alone group, a group composed of subjects in both physical training groups combined who attended training sessions >or=2 d/wk showed favorable changes in cardiovascular fitness (P < 0.001), %BF (P = 0.001), and VAT (P = 0.029). We found no evidence that the high-intensity physical training was more effective than the moderate-intensity physical training in enhancing body composition. The cardiovascular fitness of obese adolescents was significantly improved by physical training, especially high-intensity physical training. The physical training also reduced both visceral and total-body adiposity, but there was no clear effect of the intensity of physical training.

EXERCISE DOSE FOR CARDIOVASCULAR HEALTH OF OBESE YOUTHS

Heart rate variability (HRV), analysis of beat-to-beat variation on a continuous ECG, provides a non-invasive method of assessing parasympathetic activity (PSA) and sympathetic neural activity (SNA) of the heart. The effect on HRV and CV health of lifestyle education (LSE) alone versus LSE+physical training (PT) at moderate and high intensities was investigated in obese youths. Subjects were 81 obese teenagers (14.9 ± 1.3 yr) assigned to: (1) biweekly LSE only; (2) LSE+moderate-intensity PT; or (3) LSE+high-intensity PT for 8 months, 5 days/week. The target energy expenditure (EE) for all subjects in both PT groups was 1047 kJ (250 kcal)/session. HRV parameters included two indices of PSA (root mean square of successive differences, RMSSD, and high frequency power, HFP) and an index of SNA (LFP/HFP ratio). CV fitness was measured using a treadmill test (VO2-170) and visceral adipose tissue (VAT) was measured with magnetic resonance imaging. Although the PT had favorable effects on VAT and VO2-170 (p's < 0.05), it did not lead to significant group differences in HRV parameters (p > 0.05). Within the PT group, those youths who maintained higher HR (r = 0.42, P < 0.01) and higher EE (r = 0.48, P < 0.01) during the PT tended to show increases in RMSSD from pre- to post-PT. Similarly, HFP tended to increase more in youths with higher EE (r = 0.36, P < 0.05) during PT. Those with higher attendance tended to have reductions in the change of LFP/HFP ratio (r = 0.32, P < 0.05). Thus, no experimental evidence was provided that those in the PT group improved significantly more than those in the LSE-alone group. However, within the groups that were assigned to PT, those who attended more regularly and exercised at a higher intensity showed more favorable changes in cardiac autonomic activity. Supported by NIH HL55564.

EXERCISE DOSE FOR CARDIOVASCULAR HEALTH OF OBESE YOUTHS

The effect on cardiovascular (CV) health of lifestyle education (LSE) alone vs LSE+physical training (PT) at moderate and high intensities was investigated in obese youths. Subjects were 81 obese 13–16 y olds assigned to: (1) biweekly lifestyle education; (2) LSE+ moderate- intensity PT; or (3) LSE+high-intensity PT. The 8-mo PT intervention was offered 5 d/wk. The target energy expenditure for all PT subjects was 1047 kJ (250 kcal)/session. Pre- and post-PT measures included plasma fibrinogen (FIB), plasminogen activator inhibitor-1 (PAI-1), D-dimer and C-reactive protein (CRP); sub-maximal CV fitness (VO2-170; treadmill test), percent body fat (%BF;DXA), and visceral adipose tissue (VAT; MRI). Pre-PT, FIB and CRP were correlated with %BF (r = 0.51, p ≤ 0.01; r = 0.61, p ≤ 0.01), VAT (r = 0.27, p ≤ 0.05; r = 0.47, p ≤ 0.01) and VO2-170 (r = 0.39, p ≤ 0.001; r = 0.43, p ≤ 0.01); PAI-1 was correlated with %BF (r = 0.30, p ≤ 0.01) and VAT (r = 0.48, p ≤ 0.01); D-dimer was correlated with VO2-170 (r = −0.24, p ≤ 0.05). There were no within or between group differences in the pre- to post-PT changes for FIB, PAI-1, D-dimer and CRP (p > 0.05). Correlations with pre-PT levels, and changes in VO2-170, %BF, VAT, and PT process variables (attendance, average heart rate, energy expenditure) were performed to explore inter-individual variation in the response to the PT. The PT process variables were not correlated with any of the hemostatic or inflammatory markers. The change in PAI-1 was correlated with the change in %BF (r = 0.31, p ≤ 0.05) but not with the change in VAT or fitness (p > 0.05). The changes in FIB, D-dimer and CRP were not correlated with the changes in fitness or adiposity. The change in FIB was not correlated with its pre-PT level (p > 0.05). In conclusion, individuals with lower fitness and higher adiposity had higher levels of hemostatic and inflammatory markers, putting them at risk for future CV disease. No evidence was provided that PT had a direct influence on these markers, or that the PT intensities differed in effectiveness or efficacy. However, individuals who decreased most in %BF were those who had the greatest decrease in PAI-1, indicating that a beneficial effect of PT on adiposity may lead to a beneficial effect on some hemostatic factors. Supported by NIH HL55564.