Short Sleep Duration Disrupts Glucose Metabolism: Can Exercise Turn Back the Clock?

Short sleep duration is prevalent in modern society and may be contributing to type 2 diabetes prevalence. This review will explore the effects of sleep restriction on glycemic control, the mechanisms causing insulin resistance, and whether exercise can offset changes in glycemic control. Chronic sleep restriction may also contribute to a decrease in physical activity leading to further health complications.

The effects of 6 wk of resistance training on the gut microbiome and cardiometabolic health in young adults with overweight and obesity.

Obesity is a known risk factor for the development of insulin resistance and other cardiometabolic disorders. Recently, the gut microbiome has been associated with obesity and subsequent health complications. Exercise has been regularly utilized as a therapeutic intervention to treat obesity and its associated comorbidities. This study examined the effects of a 6-wk resistance training exercise program (RT) on the diversity, composition, and metabolic pathways of the gut microbiome. Sedentary young adults (age 18-35 yr) with overweight and obesity (BMI 25-45 kg/m2) were recruited to participate in this randomized controlled trial. Participants were randomized to RT (n = 16), a 6-wk resistance training program (3 days/wk), or control (CT) (n = 16), a nonexercising control. Main outcomes of the study included gut microbiome measures (taxa abundances, diversity, and predicted function) and cardiometabolic outcomes [blood pressure (BP) and glucoregulation]. Increased abundances of Roseburia, a short-chain fatty acid (SCFA) producer were observed over 6 wk (W6) with RT compared with CT (group × week, P < 0.05, q < 0.25). RT also induced marginal alterations in predicted microbial metabolic and cell motility pathways compared with CT (group × week, P < 0.05, q < 0.25). However, RT did not significantly impact overall microbial diversity. Furthermore, RT resulted in higher quantitative insulin-sensitivity check index (QUICKI) and lower diastolic BP at W6 compared with CT [baseline (BL)-adjusted P < 0.05]. RT had mixed effects on the gut microbiome. Although RT increased abundances of Roseburia and induced minor changes in microbial pathways, it is important to consider these changes in the context of the overall stability observed in the microbiome composition.NEW & NOTEWORTHY Resistance training induces mixed changes in the gut microbiome, including an increase in the abundances of the Roseburia genus and minor alterations in microbial pathways. However, it is vital to interpret these changes in light of the broader context, where we observe stability in the overall microbiome composition. This stability may be attributed to the microbiome's resilience, demonstrating its capacity to withstand short-term physiological stressors.

Temporal optimization of exercise to lower fasting glucose levels.

Exercise stimulates glucose uptake and increases insulin sensitivity acutely. Temporally optimizing exercise timing may minimize the nocturnal rise in glucose levels. This study examined the effect of exercise timing on evening and overnight glucose concentrations in individuals who were non-obese with normal fasting glucose levels (Non-Ob; n = 18) and individuals with obesity (OB) with impaired fasting glucose levels (OB+IFG) and without (n = 16 and n = 18, respectively). Subjects were studied on three occasions (no exercise (NOEX)), morning exercise (AMEX; 0700 h) and evening exercise (PMEX; 2000 h). The evening meal was provided (1800 h) and blood samples were taken from 1740 to 0700 h and morning endogenous glucose production (EGP) was measured. Glucose and insulin concentrations increased with the dinner meal with peak concentrations being higher in OB+IFG than in OB and Non-Ob (P = 0.04). In OB+IFG, evening glucose concentrations rose above baseline levels at about 2300 h, with the glucose concentrations staying somewhat lower with AMEX and PMEX until ∼0500 h than with NOEX. In OB+IFG, insulin concentrations decreased following the dinner meal and waned throughout the night, despite the rising glucose concentrations. In the OB and Non-Ob individuals following the dinner meal, no increase in glucose concentrations occurred in the evening period and insulin levels mirrored this. No difference was observed in the morning fasting glucose levels between study days or between groups. Regardless of time of day, exercise delays the evening rise in glucose concentrations in adults with OB+IFG but does not lower morning fasting glucose levels or improve the synchrony between glucose and insulin concentrations. KEY POINTS: Insulin resistance and type 2 diabetes have been linked to disturbances of the core clock, and glucose tolerance demonstrates a diurnal rhythm in healthy humans with better glucose tolerance in the morning than in the afternoon and evening. Skeletal muscle is a primary site for insulin resistance in people with impaired glucose tolerance. In individuals with obesity and impaired fasting glucose levels (OB+IFG), following a dinner meal, glucose concentrations started to rise and continues throughout the night, resulting in elevated glucose levels, while concomitantly, insulin levels are waning. Exercise, regardless of the time of day, suppressed the rise in glucose levels in OB+IFG for many hours during the night but did not lower morning fasting glucose levels. Morning exercise was not quite as effective as evening exercise.

Sleep restriction by sleep timing late night or early wake: The impact on physical activity and dietary intake in adults.

PURPOSE: To date, few studies have assessed whether the timing of sleep restriction impacts physical activity and energy intake patterns. Thus, we aimed to quantify physical activity and energy intake during an early wake (EW) and late sleep (LS) period. METHODS: Fourteen participants who met the inclusion criteria (sleep 7-9 h/night and a BMI of <40 kg/m2) participated in 3 crossover free-living conditions: normal sleep (NS, 7-9 h), EW (2-h early wake-time), and LS (2-h late to sleep) for 4 nights. Sleep duration (via Actiwatch), energy intake (via food diaries), and physical activity (via hip accelerometry) were recorded for 4 days/4 nights throughout each condition. RESULTS: Sleep duration was reduced in both sleep restriction conditions compared to NS (p < 0.001) with no difference between sleep restriction conditions. Daily energy intake tended to increase in the LS condition (p = 0.056) but was unchanged during EW (p = 0.56). Fat (p = 0.031) and sodium (p = 0.039) intake were increased in the LS condition only compared to NS. During the EW condition, fat (p = 0.24) and sodium (p = 0.18) intake were not altered. No changes in carbohydrate or protein intake occurred between conditions. Daily steps tended to increase in the EW condition compared to NS (p = 0.058), while steps during the LS condition were unchanged (p = 0.28), with no differences between sleep restriction conditions. CONCLUSION: The timing of sleep curtailment differentially influences physical activity and EI the following day, such that EW results in increased physical activity, while LS leads to poorer dietary choices.

Effect of physical activity on coronary heart disease risk factors among firefighters: a scoping review protocol.

INTRODUCTION: Physical activity interventions have been used for various health conditions, including cardiovascular disease. However, the literature is still limited regarding the effect of physical activity on coronary heart disease among firefighters. METHODS AND ANALYSIS: The review will be conducted according to recommendations from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) and PRISMA Protocol guidelines. This scoping review will provide a synthesis of current evidence on the effects of physical activity on coronary heart disease among firefighters. Search strategies will be performed in the following databases: Cochrane database, PubMed, Medline, (EbscoHost), Web of Science, Academic Search Complete, CINAHL (EBSCO), SAGE journals, ScienceDirect and Scopus. We will include literature in the English language that are full-text peer-reviewed articles from inception to November 2021. Screening of (titles, abstracts and full text of potential articles) will be done by two independent authors using EndNote V.9 software tool. A standardised data extraction form will be designed for the extraction. Two authors will independently extract the data from the selected articles and all differences will be discussed by an invited third reviewer if a consensus cannot be reached. The primary outcomes will be the impact of physical fitness on firefighters experiencing coronary artery disease. This information can assist policy-makers in decision-making related to the use of physical activity in firefighters experiencing coronary heart disease. ETHICS AND DISSEMINATION: Ethical clearance has been obtained from the University ethics committee and the City of Cape Town. The findings will be disseminated through publications and the physical activity guidelines will be submitted to the Fire Departments within the City of Cape Town. Data analysis will start on 1 April 2023.

Endothelial HSP72 is not reduced in type 2 diabetes nor is it a key determinant of endothelial insulin sensitivity.

Impaired endothelial insulin signaling and consequent blunting of insulin-induced vasodilation is a feature of type 2 diabetes (T2D) that contributes to vascular disease and glycemic dysregulation. However, the molecular mechanisms underlying endothelial insulin resistance remain poorly known. Herein, we tested the hypothesis that endothelial insulin resistance in T2D is attributed to reduced expression of heat shock protein 72 (HSP72). HSP72 is a cytoprotective chaperone protein that can be upregulated with heating and is reported to promote insulin sensitivity in metabolically active tissues, in part via inhibition of JNK activity. Accordingly, we further hypothesized that, in individuals with T2D, 7 days of passive heat treatment via hot water immersion to waist level would improve leg blood flow responses to an oral glucose load (i.e., endogenous insulin stimulation) via induction of endothelial HSP72. In contrast, we found that: 1) endothelial insulin resistance in T2D mice and humans was not associated with reduced HSP72 in aortas and venous endothelial cells, respectively; 2) after passive heat treatment, improved leg blood flow responses to an oral glucose load did not parallel with increased endothelial HSP72; and 3) downregulation of HSP72 (via small-interfering RNA) or upregulation of HSP72 (via heating) in cultured endothelial cells did not impair or enhance insulin signaling, respectively, nor was JNK activity altered. Collectively, these findings do not support the hypothesis that reduced HSP72 is a key driver of endothelial insulin resistance in T2D but provide novel evidence that lower-body heating may be an effective strategy for improving leg blood flow responses to glucose ingestion-induced hyperinsulinemia.

Hepatocyte-specific eNOS deletion impairs exercise-induced adaptations in hepatic mitochondrial function and autophagy.

OBJECTIVE: Endothelial nitric oxide synthase (eNOS) is a potential mediator of exercise-induced hepatic mitochondrial adaptations. METHODS: Here, male and female hepatocyte-specific eNOS knockout (eNOShep-/- ) and intact hepatic eNOS (eNOSfl/fl ) mice performed voluntary wheel-running exercise (EX) or remained in sedentary cage conditions for 10 weeks. RESULTS: EX resolved the exacerbated hepatic steatosis in eNOShep-/- male mice. Elevated hydrogen peroxide emission (~50% higher in eNOShep-/- vs. eNOSfl/fl mice) was completely ablated with EX. Interestingly, EX increased [1-14 C] palmitate oxidation in eNOSfl/fl male mice, but this was blunted in the eNOShep-/- male mice. eNOShep-/- mice had lower markers of the energy sensors AMP-activated protein kinase (AMPK)/phospho- (p)AMPK and mammalian target of rapamycin (mTOR) and p-mTOR, as well as the autophagy initiators serine/threonine-protein kinase ULK1 and pULK1, compared with eNOSfl/fl mice. Females showed elevated electron transport chain protein content and markers of mitochondrial biogenesis (transcription factor A, mitochondrial, peroxisome proliferator-activated receptor-gamma coactivator 1α). CONCLUSIONS: Collectively, this study demonstrates for the first time, to the authors' knowledge, the requirement of eNOS in hepatocytes in the EX-induced increases in hepatic fatty acid oxidation in male mice. Deletion of eNOS in hepatocytes also appears to impair the energy-sensing ability of the cell and inhibit the activation of the autophagy initiating factor ULK1. These data uncover the important and novel role of hepatocyte eNOS in EX-induced hepatic mitochondrial adaptations.

Exercise/Physical Activity in Individuals with Type 2 Diabetes: A Consensus Statement from the American College of Sports Medicine.

ABSTRACT: This consensus statement is an update of the 2010 American College of Sports Medicine position stand on exercise and type 2 diabetes. Since then, a substantial amount of research on select topics in exercise in individuals of various ages with type 2 diabetes has been published while diabetes prevalence has continued to expand worldwide. This consensus statement provides a brief summary of the current evidence and extends and updates the prior recommendations. The document has been expanded to include physical activity, a broader, more comprehensive definition of human movement than planned exercise, and reducing sedentary time. Various types of physical activity enhance health and glycemic management in people with type 2 diabetes, including flexibility and balance exercise, and the importance of each recommended type or mode are discussed. In general, the 2018 Physical Activity Guidelines for Americans apply to all individuals with type 2 diabetes, with a few exceptions and modifications. People with type 2 diabetes should engage in physical activity regularly and be encouraged to reduce sedentary time and break up sitting time with frequent activity breaks. Any activities undertaken with acute and chronic health complications related to diabetes may require accommodations to ensure safe and effective participation. Other topics addressed are exercise timing to maximize its glucose-lowering effects and barriers to and inequities in physical activity adoption and maintenance.

Home-Based Arm Cardiac Rehabilitation in Disabled Veterans: A Pilot Study.

One of the cornerstones of treatment after acute coronary syndromes is cardiac rehabilitation (CR). However, traditional CR remains underused in the United States due to comorbidities and geographical limitations. To evaluate feasibility and safety of our individually tailored CR program, we evaluated twelve weeks of tele-monitored home-based arm ergometer and weight training exercises in seven Veterans. Prior to beginning our CR program, all Veterans underwent an arm ergometer stress test and training in the proper techniques for arm exercises and weight training. Seattle Angina Questionnaire (SAQ) and the MacNew Heart Disease Health-related Quality of Life (MacNew) questionnaire were administered at the beginning and conclusion of the program. Six patients completed the study. One withdrew due to generalized weakness. There were no adverse events during the study period. There was a perceived improvement in heart disease related global (4.47 to 4.61), physical, emotional, and social well-being by the MacNew questionnaire. The SAQ showed improvement in physical limitation, angina frequency, treatment satisfaction, and overall quality of life (36.1 to 51.7) after completion of our tailored CR program. There was a decrease in average blood pressure and patients were able to exercise seven minutes longer and workload increased eight additional watts. This pilot study demonstrates the safety and feasibility of a home-based arm cardiac rehabilitation program. These tailored programs may improve quality of life in coronary artery disease patients with disabilities.

Effects of diurnal exercise timing on appetite, energy intake and body composition: A parallel randomized trial.

OBJECTIVE: To determine the effect of diurnal exercise timing on appetite, energy intake and body composition in individuals with overweight or obesity. METHODS: Forty sedentary, individuals with overweight or obesity (17 males, 23 females; age: 51 ± 13 years; BMI: 30.9 ± 4.2 kg/m2) were randomly allocated to complete a 12-week supervised multi-modal exercise training program performed either in the morning (amEX) or evening (pmEX). Outcome measures included appetite in response to a standardised test meal, daily energy intake (EI), body weight and body composition. Measures of dietary behaviour were assessed at baseline and post-intervention, along with habitual physical activity, sleep quality and sleep quantity. Significance was set at p ≤ .05 and Hedge's g effect sizes were calculated. RESULTS: Regardless of timing, exercise training increased perceived fullness (AUC; g = 0.82-1.67; both p < .01), decreased daily EI (g = 0.73-0.93; both p < .01) and body-fat (g = 0.29-0.32; both p <. 01). The timing of exercise did not change the daily EI or body-fat response to training (all p ≥ .27), however, perceived fullness increased in the amEX group (p ≤ .01). DISINHIBITION: (g = 0.35-1.95; p ≤ .01) and Hunger (g = 0.05-0.4; p = .02) behaviours decreased following exercise training, with Disinhibition demonstrating greater improvements in the pmEX group (p = .01). Objective and subjective sleep quantity increased with training (all p ≤ .01), but sleep quality was not reported to change. CONCLUSIONS: Multi-modal exercise training improved body composition and some appetite outcomes, although changes were inconsistent and largely independent of exercise-timing. In the absence of dietary manipulation, the effect of diurnal exercise timing on appetite and body composition appear trivial compared to the overall benefits of exercise participation.

Leg Fidgeting During Prolonged Sitting Improves Postprandial Glycemic Control in People with Obesity.

OBJECTIVE: Studies have shown that fidgeting augments metabolic demand and increases blood flow to the moving limbs, whereas prolonged sitting suppresses these factors and exacerbates postprandial glucose excursions. Therefore, the hypothesis of this study was that leg fidgeting during prolonged sitting would improve postprandial glycemic control. METHODS: Adults with obesity (n = 20) participated in a randomized crossover trial in which blood glucose and insulin concentrations were measured during a 3-hour sitting period following the ingestion of a glucose load (75 g). During sitting, participants either remained stationary or intermittently fidgeted both legs (2.5 minutes off and 2.5 minutes on). Accelerometer counts, oxygen consumption, and popliteal-artery blood flow were also measured during the sitting period. RESULTS: As expected, fidgeting increased accelerometer counts (P < 0.01), oxygen consumption (P < 0.01), and blood flow through the popliteal artery (P < 0.05). Notably, fidgeting lowered both glucose (P < 0.01) and insulin (P < 0.05) total area under the curve (AUC) and glucose incremental AUC (P < 0.05). Additionally, there was a strong negative correlation between fidgeting-induced increases in blood flow and reduced postprandial glucose AUC within the first hour (r = -0.569, P < 0.01). CONCLUSIONS: Leg fidgeting is a simple, light-intensity physical activity that enhances limb blood flow and can be incorporated during prolonged sitting to improve postprandial glycemic control in people with obesity.

Modest sleep restriction does not influence steps, physical activity intensity or glucose tolerance in obese adults.

Sleep restriction (SR) (<6 h) and physical activity (PA) are risk factors for obesity, but little work has examined the inter-related influences of both risk factors. In a free-living environment, 13 overweight/obese adults were sleep restricted for five nights to 6 h time-in-bed each night, with and without regular exercise (45 min/65% VO2 max; counterbalanced design). Two days of recovery sleep followed SR. Subjects were measured during a mixed meal tolerance test (MMT), resting metabolic rate, cognitive testing and fat biopsy (n=8). SR increased peak glucose response (+7.3 mg/dl, p = .04), elevated fasting non-esterified fatty acid (NEFA) concentrations (+0.1 mmol/L, p = .001) and enhanced fat oxidation (p < .001) without modifying step counts or PA intensity. Inclusion of daily exercise increased step count (+4,700 steps/day, p < .001) and decreased the insulin response to a meal (p = .01) but did not prevent the increased peak glucose response or elevated NEFA levels. The weekend recovery period improved fasting glucose (p = .02), insulin (p = .02), NEFA concentrations (p = .001) and HOMA-IR (p < .01) despite reduced steps (p < .01) and increased sedentary time (p < .01). Abdominal adipose tissue (AT) samples, obtained after baseline, SR and exercise, did not differ in lipolytic capacity following SR. Fatty acid synthase protein content tended to increase following SR (p = .07), but not following exercise. In a free-living setting, SR adversely affected circulating NEFAs, fuel oxidation and peak glucose response but did not directly affect glucose tolerance or AT lipolysis. SR-associated metabolic impairments were not mitigated by exercise, yet recovery sleep completely rescued its adverse effects on glucose metabolism.

Role of ERß in adipocyte metabolic response to wheel running following ovariectomy.

Estrogen receptor ß (ERb), one of the two major estrogen receptors, acts via genomic and non-genomic signaling pathways to affect many metabolic functions, including mitochondrial biogenesis and respiration. This study assessed the effect of ERb classical genomic activity on adipocyte-specific and -systemic metabolic responses to wheel running exercise in a rodent model of menopause. Female mice lacking the ERb DNA-binding domain (ERbDBDKO, n = 20) and WT (n = 21) littermate controls were fed a high-fat diet (HFD), ovariectomized (OVX), and randomized to control (no running wheel) and exercise (running wheel access) groups and were followed for 8 weeks. Wheel running did not confer protection against metabolic dysfunction associated with HFD+OVX in either ERbDBDKO or WT mice, despite increased energy expenditure. Unexpectedly, in the ERbDBDKO group, wheel running increased fasting insulin and surrogate measures of insulin resistance, and modestly increased adipose tissue inflammatory gene expression (P ≤ 0.05). These changes were not accompanied by significant changes in adipocyte mitochondrial respiration. It was demonstrated for the first time that female WT OVX mice do experience exercise-induced browning of white adipose tissue, indicated by a robust increase in uncoupling protein 1 (UCP1) (P ≤ 0.05). However, KO mice were completely resistant to this effect, indicating that full ERb genomic activity is required for exercise-induced browning. The inability to upregulate UCP1 with exercise following OVX may have resulted in the increased insulin resistance observed in KO mice, a hypothesis requiring further investigation.

Post Meal Exercise May Lead to Transient Hypoglycemia Irrespective of Glycemic Status in Humans.

During exercise, there is coordination between various hormonal systems to ensure glucoregulation. This study examined if hypoglycemia occurs during moderate-intensity exercise in non-obese and obese individuals with and without type 2 diabetes (T2D). Eighteen non-obese, 18 obese, and 10 obese with T2D completed 2 study days that included a meal at 1,800 h followed by rest (NOEX) or exercise (PMEX; 45 min/55% of VO2 max 2 h post meal). Glucose, insulin, and glucagon concentrations were measured throughout this 5.5 h period. Subjects with T2D had elevated glucose responses to the meal on both study days, compared to non-obese and obese subjects (P < 0.05). During evening exercise (PMEX), subjects with T2D had a greater drop in glucose concentration (-98.4 ± 13.3 mg/dL) compared to obese (-44.8 ± 7.1 mg/dL) and non-obese (-39.3 ± 6.1 mg/dL; P < 0.01) subjects. Glucose levels decreased more so in females than males in both conditions (P < 0.01). Nadir glucose levels <70 mg/dL were observed in 33 subjects during NOEX and 39 subjects during PMEX. Obese males had a larger exercise-induced insulin drop than obese females (P = 0.01). During PMEX, peak glucagon concentrations were elevated compared to NOEX (P < 0.001). Male participants with T2D had an increased glucagon response during NOEX and PMEX compared to females (P < 0.01). In conclusion, in individuals with varying glucose tolerance, there is a dramatic drop in glucose levels during moderate-intensity exercise, despite appropriate insulin concentrations prior to exercise, and glucagon levels rising during exercise. Moderate-intensity exercise can result in low glucose concentrations (<60 mg/dL), and yet many of these individuals will be asymptomatic.

Age, Sex, and Depot-Specific Differences in Adipose-Tissue Estrogen Receptors in Individuals with Obesity.

OBJECTIVE: The aim of this study was to examine the effects of sex and menopausal status on depot-specific estrogen signaling in white adipose tissue (AT) in age-matched men and women with morbid obesity. METHODS: A total of 28 premenopausal women, 16 postmenopausal women, and 27 age-matched men undergoing bariatric surgery were compared for omental (OM) AT (OMAT) and abdominal subcutaneous (SQ) AT (SQAT) genes and proteins. RESULTS: With the exception of fasting nonesterified fatty acids being higher in women (P < 0.01), no differences were found in other indicators of glucose and lipid metabolism. In OMAT, estrogen receptor (ER) beta (ERß) levels were higher in older women than in younger women and older men (sex-age interaction, P < 0.01), and aromatase expression was higher in older men than in older women (P < 0.05). In SQAT, women had lower expression of ERß than men (P < 0.05). Protein content of ER alpha and ERß was highly correlated with the mitochondrial protein uncoupling protein 1 across sexes and ages (P < 0.001). Age increased SQ inflammatory gene expression in both sexes. CONCLUSIONS: In morbid obesity, sex and age affect AT ERs, lipid metabolism, mitochondrial uncoupling protein 1, and inflammatory expression in an AT depot-dependent manner. The SQAT immunometabolic profile is heavily influenced by age and menopause status, more so than OMAT.

Effects of ERß and ERα on OVX-induced changes in adiposity and insulin resistance.

Loss of ovarian hormones leads to increased adiposity and insulin resistance (IR), increasing the risk for cardiovascular and metabolic diseases. The purpose of this study was to investigate whether the molecular mechanism behind the adverse systemic and adipose tissue-specific metabolic effects of ovariectomy requires loss of signaling through estrogen receptor alpha (ERα) or estrogen receptor ß (ERß). We examined ovariectomized (OVX) and ovary-intactwild-type (WT), ERα-null (αKO), and ERß-null (ßKO) female mice (age ~49 weeks; n = 7-12/group). All mice were fed a phytoestrogen-free diet (<15 mg/kg) and either remained ovary-intact (INT) or were OVX and followed for 12 weeks. Body composition, energy expenditure, glucose tolerance, and adipose tissue gene and protein expression were analyzed. INT αKO were ~25% fatter with reduced energy expenditure compared to age-matched INT WT controls and ßKO mice (all P < 0.001). Following OVX, αKO mice did not increase adiposity or experience a further increase in IR, unlike WT and ßKO, suggesting that loss of signaling through ERα mediates OVX-induced metabolic dysfunction. In fact, OVX in αKO mice (i.e., signaling through ERß in the absence of ERα) resulted in reduced adiposity, adipocyte size, and IR (P < 0.05 for all). ßKO mice responded adversely to OVX in terms of increased adiposity and development of IR. Together, these findings challenge the paradigm that ERα mediates metabolic protection over ERß in all settings. These findings lead us to suggest that, following ovarian hormone loss, ERß may mediate protective metabolic benefits.

Changes in nucleus accumbens gene expression accompany sex-specific suppression of spontaneous physical activity in aromatase knockout mice.

Aromatase catalyzes conversion of testosterone to estradiol and is expressed in a variety of tissues, including the brain. Suppression of aromatase adversely affects metabolism and physical activity behavior, but mechanisms remain uncertain. The hypothesis tested herein was that whole body aromatase deletion would cause gene expression changes in the nucleus accumbens (NAc), a brain regulating motivated behaviors such as physical activity, which is suppressed with loss of estradiol. Metabolic and behavioral assessments were performed in male and female wild-type (WT) and aromatase knockout (ArKO) mice. NAc-specific differentially expressed genes (DEGs) were identified with RNAseq, and associations between the measured phenotypic traits were determined. Female ArKO mice had greater percent body fat, reduced spontaneous physical activity (SPA), consumed less energy, and had lower relative resting energy expenditure (REE) than WT females. Such differences were not observed in ArKO males. However, in both sexes, a top DEG was Pts, a gene encoding an enzyme necessary for catecholamine (e.g., dopamine) biosynthesis. In comparing male and female WT mice, top DEGs were related to sexual development/fertility, immune regulation, obesity, dopamine signaling, and circadian regulation. SPA correlated strongly with Per3, a gene regulating circadian function, thermoregulation, and metabolism (r = -0.64, P = .002), which also correlated with adiposity (r = 0.54, P = .01). In conclusion, aromatase ablation leads to gene expression changes in NAc, which may in turn result in reduced SPA and related metabolic abnormalities. These findings may have significance to post-menopausal women and those treated with an aromatase inhibitor.

The Effect of Exercise Timing on Glycemic Control: A Randomized Clinical Trial.

Despite the acknowledgment of exercise as a cornerstone in the management of type 2 diabetes (T2D), the importance of exercise timing has only recently been considered. PURPOSE: This study sought to determine the effect of diurnal exercise timing on glycemic control in individuals enrolled in a 12-wk supervised multimodal exercise training program. A secondary aim was to determine the effect of diurnal exercise timing on the circadian rhythm of wrist skin temperature. METHODS: Forty sedentary, overweight adults (mean ± SD, age = 51 ± 13 yr; body mass index = 30.9 ± 4.2 kg·m; women, n = 23) with and without (n = 20) T2D diagnosis were randomly allocated to either a morning (amEX) or an evening (pmEX) exercise training group. The supervised 12-wk (3 d·wk) program, comprised 30 min of moderate-intensity walking and 4 resistance-based exercises (3 sets, 12-18 repetitions each). Glycemic outcomes (glycated hemoglobin, fasting glucose, postprandial glucose) and wrist skin temperature were assessed at baseline and postintervention. RESULTS: Exercise training improved (main effect of time, all P < 0.01) all glycemic outcomes; however, this was independent of allocation to either the amEX (Hedge's g, 0.23-0.90) or the pmEX (Hedge's g, 0.16-0.90) group. Accordingly, the adopted exercise training program did not alter the circadian rhythm of skin temperature. When only T2D individuals were compared, amEX demonstrated greater effects (all Hedge's g) on glycated hemoglobin (amEX, 0.57; pmEX, 0.32), fasting glucose (amEX, 0.91; pmEX, 0.53), and postprandial glucose (amEX, 1.12; pmEX, 0.71) but was not statistically different. CONCLUSIONS: Twelve weeks of multimodal exercise training improved glycemic control and postprandial glycemic responses in overweight non-T2D and T2D individuals. However, no distinct glycemic benefits or alterations in circadian rhythm were associated with morning versus evening exercise, when performed three times per week in this cohort.

A Thermogenic-Like Brown Adipose Tissue Phenotype Is Dispensable for Enhanced Glucose Tolerance in Female Mice.

The prevailing dogma is that thermogenic brown adipose tissue (BAT) contributes to improvements in glucose homeostasis in obesogenic animal models, though much of the evidence supporting this premise is from thermostressed rodents. Determination of whether modulation of the BAT morphology/function drives changes in glucoregulation at thermoneutrality requires further investigation. We used loss- and gain-of-function approaches including genetic manipulation of the lipolytic enzyme Pnpla2, change in environmental temperature, and lifestyle interventions to comprehensively test the premise that a thermogenic-like BAT phenotype is coupled with enhanced glucose tolerance in female mice. In contrast to this hypothesis, we found that 1) compared to mice living at thermoneutrality, enhanced activation of BAT and its thermogenic phenotype via chronic mild cold stress does not improve glucose tolerance in obese mice, 2) silencing of the Pnpla2 in interscapular BAT causes a brown-to-white phenotypic shift accompanied with inflammation but does not disrupt glucose tolerance in lean mice, and 3) exercise and low-fat diet improve glucose tolerance in obese mice but these effects do not track with a thermogenic BAT phenotype. Collectively, these findings indicate that a thermogenic-like BAT phenotype is not linked to heightened glucose tolerance in female mice.