Detrimental Changes in Health during Menopause: The Role of Physical Activity.

Midlife women experience changes in cardiometabolic, physical, and psychosocial health during menopause that negatively impacts their overall quality of life. Factors that contribute to these increases in cardiometabolic risk include weight gain as well as increases in fat mass (particularly abdominal adiposity), insulin resistance, and vascular dysfunction. Other deleterious changes in physical health (e. g. reduced sleep health, bone density, and balance) as well as changes in psychosocial health (e. g. mood, anxiety, and depression) often coincide and are linked to these increases in cardiometabolic risk. Physical activity and exercise are important lifestyle components that have been demonstrated to improve cardiometabolic, physical, and psychosocial health, yet physical activity and exercise is known to decline during perimenopause and into the postmenopausal years. In this narrative review, we summarize these changes in overall health during menopause as well as how declining physical activity contributes to these changes. Additionally, we discuss how incorporating physical activity and exercise during menopause can potentially ameliorate health declines. We conclude that there exists a significant, positive impact of physical activity on cardiometabolic, physical, and psychological health among midlife women, particularly if undertaken during the perimenopausal and postmenopausal years.

Effect of watermelon supplementation on exercise performance, muscle oxygenation, and vessel diameter in resistance-trained men.

INTRODUCTION: Watermelon shows promise as an ergogenic aid due to its high concentration of L-citrulline, vitamins, minerals, and antioxidants. PURPOSE: The purpose of this study was to examine the effect of watermelon supplementation on exercise performance, muscle oxygenation, and vessel diameter. METHODS: In a crossover design fashion, 15 resistance-trained men (22.4 ± 2.9 years; 177.5 ± 7.1 cm; 82.7 ± 11.2 kg) were randomly assigned to supplement with either watermelon juice concentrate (WM; 2.2 g·day-1 L-citrulline) or placebo (PL) for 7 days prior to completing an experimental trial consisting of an isometric mid-thigh pull test and acute bench press protocol. Participants completed two sets of two repetitions at 75% 1 repetition maximum (1-RM) with maximum ballistic intent followed by five repetition-maximum (RM) sets at the same load. Barbell velocity and power were measured via linear position transducer during the first two sets, while volume load and muscle oxygenation were quantified during RM sets. Brachial artery diameter and subjective perception measures were assessed at baseline and immediately pre- and post-exercise. RESULTS: Except for a greater percent change in skeletal muscle oxygenation during WM compared to PL on average and across sets (mean difference = + 4.1%, p = 0.033, BF10 = 2.2-54.5), separate traditional and Bayesian analyses of variance with repeated measures, as well as paired-samples t tests for calculated summary measures, revealed no evidence favoring conditional differences in any measure of performance, perception, or muscle oxygenation. CONCLUSION: Short-term watermelon supplementation does not appear to enhance isometric force production, bench press performance, blood vessel diameter, or muscle oxygenation parameters compared to PL in resistance-trained men.

Supplemental Watermelon Juice Attenuates Acute Hyperglycemia-Induced Macro-and Microvascular Dysfunction in Healthy Adults.

BACKGROUND: Acute hyperglycemia reduces NO bioavailability and causes macro- and microvascular dysfunction. Watermelon juice (WMJ) is a natural source of the amino acid citrulline, which is metabolized to form arginine for the NO cycle and may improve vascular function. OBJECTIVES: We examined the effects of 2 weeks of WMJ compared to a calorie-matched placebo (PLA) to attenuate acute hyperglycemia-induced vascular dysfunction. METHODS: In a randomized, placebo-controlled, double-blind, crossover trial, 6 men and 11 women (aged 21-25; BMI, 23.5 ± 3.2 kg/m2) received 2 weeks of daily WMJ (500 mL) or a PLA drink followed by an oral-glucose-tolerance test. Postprandial flow-mediated dilation (FMD) was measured by ultrasound (primary outcome), while postprandial microvascular blood flow (MVBF) and ischemic reperfusion were measured by near-infrared spectroscopy (NIRS) vascular occlusion test (VOT). RESULTS: The postprandial FMD area AUC was higher after WMJ supplementation compared to PLA supplementation (838 ± 459% · 90 min compared with 539 ± 278% · 90 min; P = 0.03). The postprandial MVBF (AUC) was higher (P = 0.01) following WMJ supplementation (51.0 ± 29.1 mL blood · 100 mL tissue-1 · min-1 · 90 min) compared to the PLA (36.0 ± 20.5 mL blood · 100 mL tissue-1 · min-1 · 90 min; P = 0.01). There was a significant treatment effect (P = 0.048) for WMJ supplementation (71.2 ± 1.5%) to increase baseline tissue oxygen saturation (StO2%) when compared to PLA (65.9 ± 1.7%). The ischemic-reperfusion slope was not affected by WMJ treatment (P = 0.83). CONCLUSIONS: Two weeks of daily WMJ supplementation improved FMD and some aspects of microvascular function (NIRS-VOT) during experimentally induced acute hyperglycemia in healthy adults. Preserved postprandial endothelial function and enhanced skeletal muscle StO2% are likely partially mediated by increased NO production (via citrulline conversion into arginine) and by the potential antioxidant effect of other bioactive compounds in WMJ.

Dynamic Glucose Disposal is Driven by Reduced Endogenous Glucose Production in Response to Voluntary Wheel Running: A Stable Isotope Approach.

To resolve both the systems level and molecular mechanisms responsible for exercise induced improvements in glucose tolerance, we sought to test the effect of voluntary wheel running exercise on postprandial glucose dynamics. We utilized a stable isotope labeled oral glucose tolerance test (SI-OGTT) incorporating complimentary deuterium glucose tracers at 1:1 ratio (2-2H-glucose and 6-6 2H-glucose; 2g/kg lean body mass) to distinguish between endogenous glucose production (EGP) and whole-body glucose disposal. SI-OGTT was performed in C57BL/6J mice after 8 weeks on a high fat diet (45% fat). Mice were then randomized to either a wheel running cage (n=13, HFD Ex) or normal cage (n=13, HFD Sed) while maintaining the HFD for 4 weeks prior to performing a SI-OGTT. HFD Ex mice demonstrated improvements in whole blood glucose total AUC that was attributed primarily to a reduction in EGP AUC. Serum insulin levels measured at 0 and 15-minutes post glucose gavage were significantly elevated in the HFD Sed mice, whereas HFD Ex mice demonstrated the expected reduction in insulin at both time points. Overall, exercise improved hepatic insulin sensitivity by reducing postprandial EGP, but also increased whole-body glucose disposal. Finally, these results demonstrate the benefits of exercise on hepatic insulin sensitivity by combining a more physiological route of glucose administration (oral glucose) with the resolution of stable isotope tracers. These novel observations clearly demonstrate that SI-OGTT is a sensitive and cost-effective method to measure exercise adaptations in obese mice with as little as 2 µl of tail blood.

Metabolic and Mechanical Effects of Laddermill Graded Exercise Testing.

Allerton, TD, Earnest, CP, and Johannsen, NM. Metabolic and mechanical effects of laddermill graded exercise testing. J Strength Cond Res 32(1): 195-200, 2018-The purpose of this study was to compare the metabolic responses and mechanical impact forces during a maximal graded exercise test (GXT) on a laddermill (LM) vs. a standard treadmill (TM). Twenty college-aged men (n = 10) and women completed a GXT on the TM and LM in random order. During the GXT, expired gases (V[Combining Dot Above]O2 and V[Combining Dot Above]CO2), heart rate, accelerometer data, blood lactate (BLa), and rating of perceived exertion (RPE) were collected in the last minute of each stage. Data were analyzed by paired t-tests and presented herein as mean ± SD. Treadmill exercise resulted in a higher V[Combining Dot Above]O2peak than LM exercise (45.6 ± 7.5 vs. 41.2 ± 5.6 ml·kg·min, p < 0.001). Blood lactate threshold was similar (p = 0.2) between LM (62 ± 17% V[Combining Dot Above]O2peak) and TM (68 ± 1% V[Combining Dot Above]O2peak). The average activity level experienced during LM (0.14 ± 0.04 vector magnitude unit [VMU]) exercise was lower (p < 0.0001) vs. TM (0.67 ± 0.01 VMU). Additionally, impact forces were reduced (p < 0.005) from the vertical plane during LM (-0.46 ± 0.12g) compared with TM (-0.81 ± 0.06g) exercise. Our results suggest that the nature of LM exercise does not elicit the same V[Combining Dot Above]O2peak response observed during TM exercise. However, impact forces were reduced and energy expenditure remained higher during LM testing, whereas RPE was similar between modalities. LM exercise may provide an alternative to individuals seeking to incur a negative energy balance, but to whom higher impact forces are detrimental.

High-fat diet differentially regulates metabolic parameters in obesity-resistant S5B/Pl rats and obesity-prone Osborne-Mendel rats.

The current experiment tested the hypothesis that consumption of a high-fat diet (HFD) would differentially affect metabolic parameters in obesity-prone Osborne-Mendel (OM) and obesity-resistant S5B/Pl (S5B) rats. In OM rats consuming a HFD, an increase in HFD intake, body mass, and percent fat mass, and a HFD-induced decrease in metabolic rate and energy expenditure were demonstrated. In S5B rats consuming a HFD, no change in percent body fat or HFD intake was demonstrated and HFD increased metabolic rate and energy expenditure. To assess whether HFD differentially altered skeletal muscle markers of metabolism in OM and S5B rats, the expression of the transporters, CD36 and GLUT4, and the energy sensors, AMPK and PPARγ, in the gastrocnemius muscle was measured. Oxidation and lipid accumulation in the gastrocnemius muscle was histologically determined. Consumption of a HFD decreased phosphorylated AMPK and PPARγ expression in the skeletal muscle of obesity-prone OM rats. Lipid accumulation in skeletal muscle was significantly higher in OM rats fed a HFD. Overall, these data suggest that the differential response to HFD on metabolic rate, energy expenditure, and phosphorylated AMPK and PPARγ in OM and S5B rats, may partially account for differences in the susceptibility to develop obesity.

Chronic binge alcohol consumption alters myogenic gene expression and reduces in vitro myogenic differentiation potential of myoblasts from rhesus macaques.

Chronic alcohol abuse is associated with skeletal muscle myopathy. Previously, we demonstrated that chronic binge alcohol (CBA) consumption by rhesus macaques accentuates skeletal muscle wasting at end-stage of simian immunodeficiency virus (SIV) infection. A proinflammatory, prooxidative milieu and enhanced ubiquitin proteasome activity were identified as possible mechanisms leading to loss of skeletal muscle. The possibility that impaired regenerative capacity, as reflected by the ability of myoblasts derived from satellite cell (SCs) to differentiate into myotubes has not been examined. We hypothesized that the inflammation and oxidative stress in skeletal muscle from CBA animals impair the differentiation capacity of myoblasts to form new myofibers in in vitro assays. We isolated primary myoblasts from the quadriceps femoris of rhesus macaques that were administered CBA or isocaloric sucrose (SUC) for 19 mo. Proliferation and differentiation potential of cultured myoblasts were examined in vitro. Myoblasts from the CBA group had significantly reduced PAX7, MYOD1, MYOG, MYF5, and MEF2C expression. This was associated with decreased myotube formation as evidenced by Jenner-Giemsa staining and myonuclei fusion index. No significant difference in the proliferative ability, cell cycle distribution, or autophagy was detected between myoblasts isolated from CBA and SUC groups. Together, these results reflect marked dysregulation of myoblast myogenic gene expression and myotube formation, which we interpret as evidence of impaired skeletal muscle regenerative capacity in CBA-administered macaques. The contribution of this mechanism to alcoholic myopathy warrants further investigation.

Impact of low-load resistance exercise with and without blood flow restriction on muscle strength, endurance, and oxidative capacity: A pilot study.

Low-load resistance exercise (LLRE) to failure can increase muscle mass, strength, endurance, and mitochondrial oxidative capacity (OXPHOS). However, the impact of adding blood flow restriction to low-load resistance exercise (LLBFR) when matched for volume on these outcomes is incompletely understood. This pilot study examined the impact of 6 weeks of single-legged LLBFR and volume-matched LLRE on thigh bone-free lean mass, strength, endurance, and mitochondrial OXPHOS. Twenty (12 males and 8 females) untrained young adults (mean ± SD; 21 ± 2 years, 168 ± 11 cm, 68 ± 12 kg) completed 6 weeks of either single-legged LLBFR or volume-matched LLRE. Participants performed four sets of 30, 15, 15, and 15 repetitions at 25% 1-RM of leg press and knee extension with or without BFR three times per week. LLBFR increased knee extension 1-RM, knee extension endurance, and thigh bone-free lean mass relative to control (all p < 0.05). LLRE increased leg press and knee extension 1-RM relative to control (p = 0.012 and p = 0.054, respectively). LLRE also increased mitochondrial OXPHOS (p = 0.047 (nonparametric)). Our study showed that LLBFR increased muscle strength, muscle endurance, and thigh bone-free lean mass in the absence of improvements in mitochondrial OXPHOS. LLRE improved muscle strength and mitochondrial OXPHOS in the absence of improvements in thigh bone-free lean mass or muscle endurance.

Adjunctive therapy with an oral H2S donor provides additional therapeutic benefit beyond SGLT2 inhibition in cardiometabolic heart failure with preserved ejection fraction.

BACKGROUND AND PURPOSE: Sodium glucose cotransporter 2 inhibitors (SGLT2i) have emerged as a potent therapy for heart failure with preserved ejection fraction (HFpEF). Hydrogen sulphide (H2S), a well-studied cardioprotective agent, could be beneficial in HFpEF. SGLT2i monotherapy and combination therapy involving an SGLT2i and H2S donor in two preclinical models of cardiometabolic HFpEF was investigated. EXPERIMENTAL APPROACH: Nine-week-old C57BL/6N mice received L-NAME and a 60% high fat diet for five weeks. Mice were then randomized to either control, SGLT2i monotherapy or SGLT2i and H2S donor, SG1002, for five additional weeks. Ten-week-old ZSF1 obese rats were randomized to control, SGLT2i or SGLT2i and SG1002 for 8 weeks. SG1002 monotherapy was investigated in additional animals. Cardiac function (echocardiography and haemodynamics), exercise capacity, glucose handling and multiorgan pathology were monitored during experimental protocols. KEY RESULTS: SGLT2i treatment improved E/e' ratio and treadmill exercise in both models. Combination therapy afforded increases in cardiovascular sulphur bioavailability that coincided with improved left end-diastolic function (E/e' ratio), exercise capacity, metabolic state, cardiorenal fibrosis, and hepatic steatosis. Follow-up studies with SG1002 monotherapy revealed improvements in diastolic function, exercise capacity and multiorgan histopathology. CONCLUSIONS AND IMPLICATIONS: SGLT2i monotherapy remediated pathological complications exhibited by two well-established HFpEF models. Adjunctive H2S therapy resulted in further improvements of cardiometabolic perturbations beyond SGLT2i monotherapy. Follow-up SG1002 monotherapy studies inferred an improved phenotype with combination therapy beyond either monotherapy. These data demonstrate the differing effects of SGLT2i and H2S therapy while also revealing the superior efficacy of the combination therapy in cardiometabolic HFpEF.

Early Renal Denervation Attenuates Cardiac Dysfunction in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: The renal sympathetic nervous system modulates systemic blood pressure, cardiac performance, and renal function. Pathological increases in renal sympathetic nerve activity contribute to the pathogenesis of heart failure with preserved ejection fraction (HFpEF). We investigated the effects of renal sympathetic denervation performed at early or late stages of HFpEF progression. METHODS AND RESULTS: Male ZSF1 obese rats were subjected to radiofrequency renal denervation (RF-RDN) or sham procedure at either 8 weeks or 20 weeks of age and assessed for cardiovascular function, exercise capacity, and cardiorenal fibrosis. Renal norepinephrine and renal nerve tyrosine hydroxylase staining were performed to quantify denervation following RF-RDN. In addition, renal injury, oxidative stress, inflammation, and profibrotic biomarkers were evaluated to determine pathways associated with RDN. RF-RDN significantly reduced renal norepinephrine and tyrosine hydroxylase content in both study cohorts. RF-RDN therapy performed at 8 weeks of age attenuated cardiac dysfunction, reduced cardiorenal fibrosis, and improved endothelial-dependent vascular reactivity. These improvements were associated with reductions in renal injury markers, expression of renal NLR family pyrin domain containing 3/interleukin 1ß, and expression of profibrotic mediators. RF-RDN failed to exert beneficial effects when administered in the 20-week-old HFpEF cohort. CONCLUSIONS: Our data demonstrate that early RF-RDN therapy protects against HFpEF disease progression in part due to the attenuation of renal fibrosis and inflammation. In contrast, the renoprotective and left ventricular functional improvements were lost when RF-RDN was performed in later HFpEF progression. These results suggest that RDN may be a viable treatment option for HFpEF during the early stages of this systemic inflammatory disease.

Preference for linoleic acid in obesity-prone and obesity-resistant rats is attenuated by the reduction of CD36 on the tongue.

Differential sensing of dietary fat and fatty acids by the oral cavity is proposed to regulate the susceptibility to obesity. In the current experiments, animals that differ in their susceptibility to obesity were used to investigate the influence of the oral cavity on the preference for the polyunsaturated fatty acid, linoleic acid. In experiment 1, the preference for differing concentrations of linoleic acid was determined in obesity-prone Osborne-Mendel (OM) and obesity-resistant S5B/Pl (S5B) rats. The preference threshold for linoleic acid was lower in S5B rats, compared with OM rats. To determine whether differences in linoleic acid preference threshold were related to innate strain differences in the fatty acid receptors on the tongue, the expression of GPR120, GPR40, and CD36 on the circumvallate papillae were assessed in OM and S5B rats. Results indicated that the expression of CD36, GPR40, and GPR120 did not differ between these two strains. Numerous studies have examined the role of CD36 on fat intake; therefore, in experiment 3, RNA interference was used to decrease the expression of CD36 on the tongues of OM and S5B rats, and the effect of decreased CD36 expression on linoleic acid preference was determined. CD36 siRNA attenuated linoleic acid preference for the most preferred concentration in both OM and S5B rats. Overall, these data indicate that there are innate differences in the preference threshold for linoleic acid in obesity-prone and obesity-resistant rats. Experimentally reducing the expression of CD36 on the circumvallate papillae attenuated the preference for linoleic acid in both strains.

The Effect of Watermelon Juice Supplementation on Heart Rate Variability and Metabolic Response during an Oral Glucose Challenge: A Randomized, Double-Blind, Placebo-Controlled Crossover Trial.

Heart rate variability (HRV) provides a simple method to evaluate autonomic function in health and disease. A reduction in HRV may indicate autonomic dysfunction and is strongly associated with aspects of cardiometabolic disease, including hyperglycemia. Reduced nitric oxide (NO) bioavailability is also implicated in the development of cardiometabolic disease and autonomic dysfunction. Watermelons are natural sources of L-arginine and L-citrulline, substrates used for NO synthesis. Watermelon consumption can improve NO bioavailability. We conducted a randomized, double-blind, placebo-controlled crossover trial to test the effects of 2 weeks of daily watermelon juice (WMJ) supplementation on HRV in response to an oral glucose challenge (OGC) in healthy young adults. We also performed indirect calorimetry to assess if our intervention altered the metabolic response to the OGC. WMJ supplementation preserved high-frequency power (HF) (treatment effect, p = 0.03) and the percentage of successive differences that differ by more than 50 ms (pNN50) (treatment effect, p = 0.009) when compared to the placebo treatment. There was no difference in resting energy expenditure or substate oxidation according to treatment. We report that WMJ supplementation attenuates OGC-induced reductions in HRV. Future work should emphasize the importance of NO bioavailability in autonomic dysfunction in cardiometabolic disease.

Glucagon-like peptide-1/glucagon receptor agonism associates with reduced metabolic adaptation and higher fat oxidation: A randomized trial.

OBJECTIVE: This study tested the hypothesis that treatment with the glucagon-like peptide-1/glucagon receptor agonist SAR425899 would lead to a smaller decrease in sleeping metabolic rate (SMR; kilocalories/day) than expected from the loss of lean and fat mass (metabolic adaptation). METHODS: This Phase 1b, double-blind, randomized, placebo-controlled study was conducted at two centers in inpatient metabolic wards. Thirty-five healthy males and females with overweight and obesity (age = 36.5 ± 7.1 years) were randomized to a calorie-reduced diet (-1000 kcal/d) and escalating doses (0.06-0.2 mg/d) of SAR425899 (n = 17) or placebo (n = 18) for 19 days. SMR was measured by whole-room calorimetry. RESULTS: Both groups lost weight (-3.68 ± 1.37 kg placebo; -4.83 ± 1.44 kg SAR425899). Those treated with SAR425899 lost more weight, fat mass, and fat free mass (p < 0.05) owing to a greater achieved energy deficit than planned. The SAR425899 group had a smaller reduction in body composition-adjusted SMR (p = 0.002) as compared with placebo, but not 24-hour energy expenditure. Fat oxidation and ketogenesis increased in both groups, with significantly greater increases with SAR425899 (p < 0.05). CONCLUSIONS: SAR425899 led to reduced selective metabolic adaptation and increased lipid oxidation, which are believed to be beneficial for weight loss and weight-loss maintenance.

Loss of Adipocyte STAT5 Confers Increased Depot-Specific Adiposity in Male and Female Mice That Is Not Associated With Altered Adipose Tissue Lipolysis.

STATs (Signal Transducers and Activators of Transcription) 5A and 5B are induced during adipocyte differentiation and are primarily activated by growth hormone (GH) and prolactin in fat cells. Previous studies in mice lacking adipocyte GH receptor or STAT5 support their roles in lipolysis-mediated reduction of adipose tissue mass. Male and female mice harboring adipocyte-specific deletion of both STAT5 genes (STAT5AKO) exhibit increased subcutaneous or inguinal adipose tissue mass, but no changes in visceral or gonadal fat mass. Both depots display substantial increases in adipocyte size with no changes in lipolysis in adipose tissue explants. RNA sequencing analysis of subcutaneous adipose tissue and indirect calorimetry experiments reveal sex-dependent differences in adipose gene expression and whole-body energy expenditure, respectively, resulting from the loss of adipocyte STAT5.

Exercise reduced the formation of new adipocytes in the adipose tissue of mice in vivo.

Exercise has beneficial effects on metabolism and health. Although the skeletal muscle has been a primary focus, exercise also mediates robust adaptations in white adipose tissue. To determine if exercise affects in vivo adipocyte formation, fifty-two, sixteen-week-old C57BL/6J mice were allowed access to unlocked running wheels [Exercise (EX) group; n = 13 males, n = 13 females] or to locked wheels [Sedentary (SED) group; n = 13 males, n = 13 females] for 4-weeks. In vivo adipocyte formation was assessed by the incorporation of deuterium (2H) into the DNA of newly formed adipocytes in the inguinal and gonadal adipose depots. A two-way ANOVA revealed that exercise significantly decreased new adipocyte formation in the adipose tissue of mice in the EX group relative to the SED group (activity effect; P = 0.02). This reduction was observed in male and female mice (activity effect; P = 0.03). Independent analysis of the depots showed a significant reduction in adipocyte formation in the inguinal (P = 0.05) but not in the gonadal (P = 0.18) of the EX group. We report for the first time that exercise significantly reduced in vivo adipocyte formation in the adipose tissue of EX mice using a physiologic metabolic 2H2O-labeling protocol.

Reliability of measurements of energy expenditure and substrate oxidation using whole-room indirect calorimetry.

OBJECTIVE: This analysis aimed to measure the intraparticipant reliability-the intraclass correlation coefficient-of all the components of daily energy expenditure (EE) (24-hour EE, sleep EE, resting EE, basal EE, and thermic effect of food) over a period of 3 consecutive days in 35 study participants. METHODS: The components of daily EE and substrate use (respiratory exchange ratio) were measured over 3 consecutive days before and after a 3-week 1,000-kcal/d caloric restriction/weight-loss intervention. RESULTS: There was a high degree of reliability for sleep EE (96.8%), 24-hour EE (97.8%), basal EE (90.6%), and resting EE (93.2%) during the run-in period. The intraclass correlation coefficient for the follow-up period after weight loss (3.67 ± 1.10 kg) remained high for sleep EE (95.6%), 24-hour EE (100%), basal EE (96.1%), and resting EE (92.5%). The minimal detectable differences in EE were reduced by 30% for both 24-hour EE and sleep EE when comparing 2 days versus 1 day spent in the whole-room indirect calorimeter. CONCLUSIONS: The reliability of the daily components of EE is very high both prior to and after a weight-loss intervention. We here provide instrumental data for investigators to adequately power studies investigating energy metabolism using whole-room indirect calorimetry.

An Ethanolic Extract of Artemisia dracunculus L. Enhances the Metabolic Benefits of Exercise in Diet-induced Obese Mice.

PURPOSE: The purpose of this study was to determine the effect of an ethanolic extract of Artemisia dracunculus L. (5011) combined with exercise on in vivo glucose and fat metabolism in diet-induced obese male mice. METHODS: After 8 wk of high-fat diet (HFD) feeding, 52 mice were randomly allocated to a voluntary wheel running group (HFD Ex), a 5011 + HFD sedentary group (5011 Sed), a 5011 + HFD Ex (5011 Ex), or an HFD sedentary group (HFD Sed) for 4 wk. Real-time energy expenditure and substrate utilization were measured by indirect calorimetry. A stable isotope glucose tolerance test was performed before and after the 4-wk wheel running period to determine changes in endogenous glucose production and glucose disposal. We also performed an analysis of genes and proteins associated with the early response to exercise and exercise adaptations in skeletal muscle and liver. RESULTS: When compared with HFD Ex mice, 5011 Ex mice had increased fat oxidation during speed- and distance-matched wheel running bouts. Both HFD Ex and 5011 Ex mice had reduced endogenous glucose during the glucose tolerance test, whereas only the 5011 Sed and the 5011 Ex mice had improved glucose disposal after the 4-wk experimental period when compared with HFD Sed and HFD Ex mice. 5011 Ex mice had increased Pgc1-α and Tfam expression in skeletal muscle when compared with HFD Ex mice, whereas Pdk4 expression was reduced in the liver of HFD Ex and 5011 Ex mice. CONCLUSIONS: Our study demonstrates that 5011, an ethanolic extract of A. dracunculus L., with a history of medicinal use, enhances the metabolic benefits of exercise to improve in vivo fat and glucose metabolism.

Adaptive Fat Oxidation Is Coupled with Increased Lipid Storage in Adipose Tissue of Female Mice Fed High Dietary Fat and Sucrose.

Western diets high in fat and sucrose are associated with metabolic syndrome (MetS). Although the prevalence of MetS in women is comparable to that in men, metabolic adaptations in females to Western diet have not been reported in preclinical studies. This study investigates the effects of Western diet on risk factors for MetS in female mice. Based on our earlier studies in male mice, we hypothesized that dietary supplementation with extracts of Artemisia dracunculus L. (PMI5011) and Momordica charantia (bitter melon) could affect MetS risk factors in females. Eight-week-old female mice were fed a 10% kcal fat, 17% kcal sucrose diet (LFD); high-fat, high-sucrose diet (HFS; 45% kcal fat, 30% kcal sucrose); or HFS diet with PMI5011 or bitter melon for three months. Body weight and adiposity in all HFS groups were greater than the LFD. Total cholesterol level was elevated with the HFS diets along with LDL cholesterol, but triglycerides and free fatty acids were unchanged from the LFD. Over the three month period, female mice responded to the HFS diet by adaptive increases in fat oxidation energy in muscle and liver. This was coupled with increased fat storage in white and brown adipose tissue depots. These responses were enhanced with botanical supplementation and confer protection from ectopic lipid accumulation associated with MetS in female mice fed an HFS diet.

Metabolic flexibility is impaired in response to acute exercise in the young offspring of mothers with type 2 diabetes.

We assessed metabolic flexibility (MF) via a mixed meal in a group of young, healthy participants with a positive family history of maternal type 2 diabetes (T2D) (FH+) and those without a family history of T2D (FH-) under three distinct conditions; baseline (BL; no previous exercise), 1-h post high intensity interval exercise (1H), and 48-h post exercise recovery. On separate visits, participants completed a single bout of high intensity interval exercise (HIIE) and repeated the MMTT 1-h (1H) and 48 h (48H) postexercise. FH+ participants were not able to suppress fat oxidation 1-h post exercise (1H) as effectively as FH- participants were, however, this response was improved when measured at the 48H visit. Insulin AUC was significantly lowered at both 1H and 48H when compared to the BL visit. Serum NEFA AUC was elevated 1-h post exercise, when compared to BL, but was significantly reduced at the 48H visit. Young, healthy participants with a maternal history of T2D demonstrate impaired MF (related to the inability to suppress fat oxidation) in response to acute HIIE (1H) that was improved 48H. The overall effect of HIIE showed improved insulin AUC and NEFA AUC up to 48H post that did not differ by FH.

Myoblast mitochondrial respiration is decreased in chronic binge alcohol administered simian immunodeficiency virus-infected antiretroviral-treated rhesus macaques.

Work from our group demonstrated that chronic binge alcohol (CBA)-induces mitochondrial gene dysregulation at end-stage disease of simian immunodeficiency virus (SIV) infection in antiretroviral therapy (ART) naïve rhesus macaques. Alterations in gene expression can disrupt mitochondrial homeostasis and in turn contribute to the risk of metabolic comorbidities characterized by loss of skeletal muscle (SKM) functional mass that are associated with CBA, human immunodeficiency virus (HIV) infection, and prolonged ART. The aim of this study was to examine the interaction of CBA and ART on SKM fiber oxidative capacity and myoblast mitochondrial respiration in asymptomatic SIV-infected macaques. SKM biopsies were obtained and myoblasts isolated at baseline and 11 months post-SIV infection from CBA/SIV/ART+ and from sucrose (SUC)-treated SIV-infected (SUC/SIV/ART+) macaques. CBA and ART decreased succinate dehydrogenase (SDH) activity in type 1 and type 2b fibers as determined by immunohistochemistry. Myoblasts isolated from CBA/SIV/ART+ macaques showed decreased maximal oxygen consumption rate (OCR) compared to myoblasts from control macaques. Maximal OCR was significantly increased in control myoblasts following incubation with formoterol, a beta adrenergic agonist, and this was associated with increased PGC-1α expression and mtDNA quantity. Additionally, formoterol treatment of myoblasts isolated from CBA/SIV/ART+ macaques partially restored maximal OCR to levels not significantly different from control. These results show that CBA in combination with ART impairs myoblast mitochondrial homeostasis in SIV-infected macaques. Moreover, our findings suggest that adrenergic agonists can potentially ameliorate mitochondrial dysfunction. Future studies will elucidate whether physical exercise in HIV patients with alcohol use disorder can improve mitochondrial health.