Deletion of the Cold Thermoreceptor TRPM8 Increases Heat Loss and Food Intake Leading to Reduced Body Temperature and Obesity in Mice.

The coupling of energy homeostasis to thermoregulation is essential to maintain homeothermy in changing external environments. We studied the role of the cold thermoreceptor TRPM8 in this interplay in mice of both sexes. We demonstrate that TRPM8 is required for a precise thermoregulation in response to cold, in fed and fasting. Trpm8-/- mice exhibited a fall of 0.7°C in core body temperature when housed at cold temperatures, and a deep hypothermia (<30°C) during food deprivation. In both situations, TRPM8 deficiency induced an increase in tail heat loss. This, together with the presence of TRPM8-sensory fibers innervating the main tail vessels, unveils a major role of this ion channel in tail vasomotor regulation. Finally, TRPM8 deficiency had a remarkable impact on energy balance. Trpm8-/- mice raised at mild cold temperatures developed late-onset obesity and metabolic dysfunction, with daytime hyperphagia and reduction of fat oxidation as plausible causal factors. In conclusion, TRPM8 fine-tunes eating behavior and fuel utilization during thermoregulatory adjustments to mild cold. Persistent imbalances in these responses result in obesity.SIGNIFICANCE STATEMENT The thermosensitive ion channel TRPM8 is required for a precise thermoregulatory response to cold and fasting, playing an important role in tail vasoconstriction, and therefore heat conservation, as well as in the regulation of ingestive behavior and metabolic fuel selection upon cooling. Indeed, TRPM8-deficient mice, housed in a mild cold environment, displayed an increase in tail heat loss and lower core body temperature, associated with the development of late-onset obesity with glucose and lipid metabolic dysfunction. A persistent diurnal hyperphagia and reduced fat oxidation constitute plausible underlying mechanisms in the background of a deficient thermoregulatory adjustment to mild cold ambient temperatures.

Higher rate of fat oxidation during rowing compared with cycling ergometer exercise across a range of exercise intensities.

The relative contribution of carbohydrate and fat oxidation to energy expenditure during exercise is dependent on variables including exercise intensity, mode, and recruited muscle mass. This study investigated patterns of substrate utilization during two non-weightbearing exercise modalities, namely cycling and rowing. Thirteen young, moderately trained males performed a continuous incremental (3-min stages) exercise test to exhaustion on separate occasions on an electronically braked cycle (CYC) ergometer and an air-braked rowing (ROW) ergometer, respectively. On two further occasions, participants performed a 20-min steady-state exercise bout at ∼50%VO2peak on the respective modalities. Despite similar oxygen consumption, rates of fat oxidation (FATox ) were ∼45% higher during ROW compared with CYC (P < 0.05) across a range of power output increments. The crossover point for substrate utilization occurred at a higher relative exercise intensity for ROW than CYC (57.8 ± 2.1 vs 42.1 ± 3.6%VO2peak , P < 0.05). During steady-state submaximal exercise, the higher FATox during ROW compared with CYC was maintained (P < 0.05), but absolute FATox were 42% (CYC) and 28% (ROW) lower than during incremental exercise. FATox is higher during ROW compared with CYC exercise across a range of exercise intensities matched for energy expenditure, and is likely as a consequence of larger muscle mass recruited during ROW.

Functional Impact of Alternative Metabolic Substrates in Failing Human Cardiomyocytes.

Recent studies suggest that metabolic dysregulation in patients with heart failure might contribute to myocardial contractile dysfunction. To understand the correlation between function and energy metabolism, we studied the impact of different fuel substrates on human nonfailing or failing cardiomyocytes. Consistent with the concept of metabolic flexibility, nonfailing myocytes exhibited excellent contractility in all fuels provided. However, impaired contractility was observed in failing myocytes when carbohydrates alone were used but was improved when additional substrates were added. This study demonstrates the functional significance of fuel utilization shifts in failing human cardiomyocytes.

The Molecular Mechanisms of Fuel Utilization during Exercise.

Exercise is widely recognized for its positive impact on human health and well-being. The process of utilizing substrates in skeletal muscle during exercise is intricate and governed by complex mechanisms. Carbohydrates and lipids serve as the primary fuel sources for skeletal muscle during exercise. It is now understood that fuel selection during exercise is not solely determined by physical activity itself but is also influenced by the overall metabolic state of the body. The balance between lipid and carbohydrate utilization significantly affects exercise capacity, including endurance, fatigue, and overall performance. Therefore, comprehensively understanding the regulation of substrate utilization during exercise is of utmost importance. The aim of this review is to provide an extensive overview of the current knowledge regarding the pathways involved in the regulation of substrate utilization during exercise. By synthesizing existing research, we can gain a holistic perspective on the intricate relationship between exercise, metabolism, and fuel selection. This advanced understanding has the potential to drive advancements in the field of exercise science and contribute to the development of personalized exercise strategies for individuals looking to optimize their performance and overall health.

The impact of natural menstrual cycle and oral contraceptive pill phase on substrate oxidation during rest and acute submaximal aerobic exercise.

Previous research has identified sex differences in substrate oxidation during submaximal aerobic exercise including a lower respiratory exchange ratio (RER) in females compared with males. These differences may be related to differences in sex hormones. Our purpose was to examine the impact of the natural menstrual cycle (NAT) and second- and third-generation oral contraceptive pill (OCP2 and OCP3) cycle phases on substrate oxidation during rest and submaximal aerobic exercise. Fifty female participants (18 NAT, 17 OCP2, and 15 OCP3) performed two experimental trials that coincided with the low (i.e., nonactive pill/early follicular) and the high hormone (i.e., active pill/midluteal) phase of their cycle. RER and carbohydrate and lipid oxidation rates were determined from gas exchange measurements performed during 10 min of supine rest, 5 min of seated rest, and two 8-min bouts of submaximal cycling exercise at ∼40% and ∼65% of peak oxygen uptake (V̇o2peak). For all groups, there were no differences in RER between the low and high hormone phases during supine rest (0.73 ± 0.05 vs. 0.74 ± 0.05), seated rest (0.72 ± 0.04 vs. 0.72 ± 0.04), exercise at 40% (0.77 ± 0.04 vs. 0.78 ± 0.04), and 65% V̇o2peak (0.85 ± 0.04 vs. 0.86 ± 0.03; P > 0.19 for all). Similarly, carbohydrate and lipid oxidation rates remained largely unchanged across phases during both rest and exercise, apart from higher carbohydrate oxidation in NAT vs. OCP2 at 40% V̇o2peak (P = 0.019) and 65% V̇o2peak (P = 0.001). NAT and OCPs do not appear to largely influence substrate oxidation at rest and during acute submaximal aerobic exercise.NEW & NOTEWORTHY This study was the first to examine the influence of NAT and two generations of OCPs on substrate oxidation during rest and acute submaximal aerobic exercise. We reported no differences across cycle phases or groups on RER, and minimal impact on carbohydrate or lipid oxidation apart from an increase in carbohydrate oxidation in NAT compared with OCP2 during exercise. Based on these findings, NAT/OCP phase controls may not be necessary in studies investigating substrate oxidation.

Similar fat and carbohydrate oxidation in response to arm cycling exercise in persons with spinal cord injury versus able-bodied.

CONTEXT: Persons with spinal cord injury (SCI) present with low fat oxidation that is associated with poor cardiometabolic health. This study compared changes in fat and carbohydrate (CHO) oxidation during moderate intensity continuous exercise in persons with SCI and able-bodied adults (AB). DESIGN: Repeated measures, within-subjects study. SETTING: University laboratory in San Diego, CA. PARTICIPANTS: Nine men and women with SCI (age and time since injury = 32 ± 11 yr and 7 ± 6 yr) and 10 AB adults (age = 25 ± 8 yr). INTERVENTIONS: To assess peak oxygen uptake (VO2peak) and peak power output (PPO), participants performed progressive arm ergometry to volitional exhaustion. Subsequently, they completed 25 min of continuous exercise at 45%PPO. OUTCOME MEASURES: Respiratory exchange ratio (RER), fat and CHO oxidation, and blood lactate concentration (BLa) were assessed. RESULTS: Data showed a similar RER (P = 0.98) during exercise in SCI (0.97 ± 0.04) versus AB (0.97 ± 0.03) reflecting high CHO use and no differences in BLa (3.5 ± 1.1 and 3.0 ± 0.9 vs. mM, P = 0.56) or fat and CHO oxidation between groups (P > 0.05). However, participants with SCI exercised at a higher relative intensity (P < 0.01, 84 ± 7 vs. 75 ± 7%HRpeak) versus AB. CONCLUSION: Data confirm high reliance on CHO during arm ergometry in persons with SCI. To better compare substrate utilization to AB adults, we recommend that exercise be prescribed according to peak heart rate due to differences in cardiorespiratory fitness between groups.

Effects of sprint interval training on substrate oxidation in adults living with and without obesity: The i-FLEX study.

Metabolic flexibility is the ability to adapt substrate oxidation according to metabolic demand. Exercise increases fat oxidation responses in individuals living with obesity; however, limited research exists on the relationship between substrate oxidation and insulin sensitivity after sprint interval training (SIT). The primary objective was to investigate changes in substrate oxidation at rest and during submaximal exercise, and in insulin sensitivity after 4 weeks of SIT in individuals living with or without obesity. The secondary objective was to investigate correlations between changes in substrate oxidation and insulin sensitivity following SIT. Adults living with obesity (n = 16, body mass index (BMI) = 34.1 kg/m2  ± 3.8) and without obesity (n = 18, BMI = 22.9 kg/m2  ± 1.6) took part in a 4-week SIT intervention. Participants completed three sessions of SIT per week, consisting of repeated sets of a 30-s Wingate separated by 4 m of active recovery. Substrate oxidation at rest and during submaximal exercise was measured using VCO2 /VO2 . Insulin sensitivity was calculated using the Matsuda index. No difference in substrate oxidation at rest was observed for either group (p > 0.05), while a significant increase in fat oxidation was observed in individuals living with obesity [F(1,31) = 14.55, p = 0.001] during the submaximal exercise test. A significant decrease in insulin sensitivity was observed among individuals without obesity [F(1,31) = 5.010, p = 0.033]. No correlations were observed between changes in substrate oxidation and insulin sensitivity (p > 0.05). Following SIT, individuals living with obesity increased submaximal fat oxidation compared to individuals without obesity. No correlations were observed between substrate oxidation and insulin sensitivity. Thus, SIT impacts fat oxidation during exercise in individuals living with obesity while having no such influence on insulin sensitivity.

Highly Efficient Magnetic Propulsion of NiFe Nanorod-Based Miniature Swimmers in Three Dimensions.

Magnetically actuated miniature robots have attracted the attention of the scientific community over the past two decades, but the confined workspace of their manipulation system (typically a tri-axial coil or eight electromagnetic coils) and the low efficiency of propulsion have limited their utility. Here, we describe a highly efficient NiFe nanorod-based magnetic miniature swimmer that can be manipulated in 3D spaces using two pairs of coils placed in the x-y horizontal plane. In the new swimmer, the shape symmetry is broken along its body, and the asymmetry in magnetizations is introduced perpendicular to the long axis of its body simultaneously. Such a combined asymmetry design offers favorable controllability in planar magnetic fields, which relaxes the multi-axial coil requirement of the commonly used manipulation system and thus reduces the restriction on the shape and size of the workspaces. The new swimmers display efficient 3D propulsion, with a speed of over 5000 µm s-1 (∼3 body length s-1) and powerful locomotion in biological media such as raw human blood. The fuel utilization efficiency of the swimmer, defined as the ratio of the distance to the net input work in one period, was estimated to be approximately from 10-2 to 10-3 m/J, which is significantly higher than that of magnetic motors with a slender body. Moreover, to provide practical support for further potential use, we demonstrated that the swimmer is able to perform incision operations as a minimally invasive microsurgical tool. Such a swimmer actuation strategy provides a simple and efficient way for 3D manipulation of magnetic miniature robots, offering great potential for future biomedical and other applications.

Resistant Starch Combined with Whey Protein Increases Postprandial Metabolism and Lowers Glucose and Insulin Responses in Healthy Adult Men.

Resistant starch (RS) and/or protein consumption favorably influence energy metabolism, substrate utilization, and weight management. The current study administered four different versions of a pancake breakfast containing waxy maize or RS with and without whey protein (WP) and measured postprandial thermogenesis (TEM), fuel utilization, and circulating satiation and appetite factors for 180 min in a group of healthy, adult men. On four separate visits to the laboratory, eight participants were administered four different pancake breakfast meal challenges using a single-blind, randomized crossover design: (1) waxy maize starch (WMS) control; (2) WMS and WP (WMS + WP); (3) RS; or (4) RS and WP (RS + WP). TEM (kcals/180 min) was significantly greater (p < 0.05) in RS + WP (45.11; confidence interval (CI), 33.81-56.41) compared to WMS (25.61; CI, 14.31-36.91), RS (29.44; CI, 18.14-40.74), and WMS + WP (24.64; CI, 13.34-35.94), respectively. Fat oxidation was enhanced (p < 0.05) after RS + WP compared to RS at 60 min (+23.10%), WMS at 120 min (+27.49%), and WMS and WMS + WP at 180 min (+35.76%; +17.31%, respectively), and RER was decreased with RS + WP versus the other three meals (mean differences: ≥-0.021). Insulin concentrations were decreased (p < 0.05) following RS + WP compared to WMS, whereas both RS (-46.19%) and RS + WP (-53.05%) insulin area under the curve (AUC) were greatly reduced (p < 0.01) compared to WMS. While limited by sample size, meals containing both RS and WP increased postprandial thermogenesis and fat oxidation, and lowered insulin response compared to isocaloric meals without this combination. Therefore, RS + WP may favorably impact energy metabolism and thus weight control and body composition under chronic feeding conditions.

High-Fructose, High-Fat Diet Alters Muscle Composition and Fuel Utilization in a Juvenile Iberian Pig Model of Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is a serious metabolic condition affecting millions of people worldwide. A "Western-style diet" has been shown to induce pediatric NAFLD with the potential disruption of skeletal muscle composition and metabolism. To determine the in vivo effect of a "Western-style diet" on pediatric skeletal muscle fiber type and fuel utilization, 28 juvenile Iberian pigs were fed either a control diet (CON) or a high-fructose, high-fat diet (HFF), with or without probiotic supplementation, for 10 weeks. The HFF diets increased the total triacylglycerol content of muscle tissue but decreased intramyocellular lipid (IMCL) content and the number of type I (slow oxidative) muscle fibers. HFF diets induced autophagy as assessed by LC3I and LC3II, and inflammation, as assessed by IL-1α. No differences in body composition were observed, and there was no change in insulin sensitivity, but HFF diets increased several plasma acylcarnitines and decreased expression of lipid oxidation regulators PGC1α and CPT1, suggesting disruption of skeletal muscle metabolism. Our results show that an HFF diet fed to juvenile Iberian pigs produces a less oxidative skeletal muscle phenotype, similar to a detraining effect, and reduces the capacity to use lipid as fuel, even in the absence of insulin resistance and obesity.

A Handheld Metabolic Device (Lumen) to Measure Fuel Utilization in Healthy Young Adults: Device Validation Study.

BACKGROUND: Metabolic carts measure the carbon dioxide (CO2) produced and oxygen consumed by an individual when breathing to assess metabolic fuel usage (carbohydrates versus fats). However, these systems are expensive, time-consuming, and only available in health care laboratory settings. A small handheld device capable of determining metabolic fuel usage via CO2 from exhaled air has been developed. OBJECTIVE: The aim of this study is to evaluate the validity of a novel handheld device (Lumen) for measuring metabolic fuel utilization in healthy young adults. METHODS: Metabolic fuel usage was assessed in healthy participants (n=33; mean age 23.1 years, SD 3.9 years) via respiratory exchange ratio (RER) values obtained from a metabolic cart as well as % CO2 from the Lumen device. Measurements were performed at rest in two conditions: fasting, and after consuming 150 grams of glucose, in order to determine changes in metabolic fuel usage. Reduced major axis regression and simple linear regression were performed to test for agreement between RER and Lumen % CO2. RESULTS: Both RER and Lumen % CO2 significantly increased after glucose intake (P<.001 for both) compared with fasting conditions, by 0.089 and 0.28, respectively. Regression analyses revealed an agreement between the two measurements (F1,63=18.54; P<.001). CONCLUSIONS: This study shows the validity of Lumen for detecting changes in metabolic fuel utilization in a comparable manner with a laboratory standard metabolic cart, providing the ability for real-time metabolic information for users under any circumstances.

Function of Nr4a Orphan Nuclear Receptors in Proliferation, Apoptosis and Fuel Utilization Across Tissues.

The Nr4a family of nuclear hormone receptors is composed of three members-Nr4a1/Nur77, Nr4a2/Nurr1 and Nr4a3/Nor1. While currently defined as ligandless, these transcription factors have been shown to regulate varied processes across a host of tissues. Of particular interest, the Nr4a family impinge, in a tissue dependent fashion, on cellular proliferation, apoptosis and fuel utilization. The regulation of these processes occurs through both nuclear and non-genomic pathways. The purpose of this review is to provide a balanced perspective of the tissue specific and Nr4a family member specific, effects on cellular proliferation, apoptosis and fuel utilization.

The Effect of Acute L-carnitine and Carbohydrate Intake on Cycling Performance.

Chronic supplementation of L-carnitine and carbohydrate has been reported to increase L-carnitine content in skeletal muscle and have positive influences on exercise variables and performance. This study investigated the acute intake of L-carnitine and carbohydrate on the exercise parameters of cycling. A total of 10 males (27.0 ± 4 years) completed two exercise sessions consisting of 40 min of cycling at 65% of VO2peak, followed by cycling to exhaustion at 85% of VO2peak. L-carnitine or a placebo was consumed 3 hours prior to exercise, and beverages consisting of 94 g of carbohydrate were consumed at both 2 hours, and 30 minutes prior to exercise. Repeated measures ANOVAs were used to compare respiratory exchange ratio (RER), blood lactate, and power output across experimental trials and time. A repeated measures t-test was used to analyze differences between conditions and time to exhaustion. RER was significantly lower (p=0.01) at baseline with L-carnitine ingestion (.83 ± .05) compared to the placebo ingestion (.86 ± .06). Blood lactate was significantly lower (p=0.02) after 10 minutes of cycling at 65% of VO2peak with ingestion of L-carnitine (35% change from baseline) compared to placebo ingestion (53% change from baseline). No differences were found for power output or time to exhaustion at 85% of VO2peak. Despite mentioned differences, acute intake of L-carnitine and carbohydrate does not appear to influence exercise parameters, likely due to a lack of sufficient change in the content of L-carnitine in skeletal muscle.

Metabolic characterization of overweight and obese adults.

OBJECTIVES: Traditional evaluations of metabolic health may overlook underlying dysfunction in individuals who show no signs of insulin resistance or dyslipidemia. The purpose of this study was to characterize metabolic health in overweight and obese adults using traditional and non-traditional cardiometabolic variables. A secondary purpose was to evaluate differences between overweight/obese and male/female cohorts, respectively. METHODS: Forty-nine overweight and obese adults (Mean ± SD; Age = 35.0 ± 8.9 yrs; Body mass index = 33.6 ± 5.2 kg·m-2; Percent body fat [%fat] = 36.7 ± 7.9%) were characterized. Body composition (fat mass [FM], lean mass [LM], %fat) was calculated using a 4-compartment model; visceral adipose tissue (VAT) was quantified using B-mode ultrasound. Resting metabolic rate (RMR) and respiratory exchange ratio (RER) were evaluated using indirect calorimetry. Fasted blood and saliva samples were analyzed for total cholesterol (TC), high-density lipoproteins (HDL), low-density lipoproteins (LDL), triglycerides (TRG), glucose (GLUC), insulin, leptin, estradiol, and cortisol. RESULTS: The prevalence of individuals with two or more cardiometabolic risk factors increased from 13%, using traditional risk factors (GLUC, TRG, HDL), to 80% when non-traditional metabolic factors (VAT, LM, RMR, RER, TC, LDL, HOMA-IR) were considered. Between overweight/obese, there were no significant differences in %fat (p = 0.152), VAT (p = 0.959), RER (p = 0.493), lipids/GLUC (p > 0.05), insulin (p = 0.143), leptin (p = 0.053), or cortisol (p = 0.063); obese had higher FM, LM, RMR, and estradiol (p < 0.01). Males had greater LM, RMR, and TRG (p < 0.01); females had greater %fat, and leptin (p < 0.001). There were no significant sex differences in RER, estradiol, insulin, or cortisol (p > 0.05). CONCLUSIONS: Evaluating metabolic health beyond BMI and traditional cardiometabolic risk factors can give significant insights into metabolic status. Due to high variability in metabolic health in overweight and obese adults and inherent sex differences, implementation of body composition and visceral fat measures in the clinical setting can improve early identification and approaches to disease prevention.