Exercise training and cold exposure trigger distinct molecular adaptations to inguinal white adipose tissue.

Exercise training and cold exposure both improve systemic metabolism, but the mechanisms are not well established. Here, we tested the hypothesis that inguinal white adipose tissue (iWAT) adaptations are critical for these beneficial effects and determined the impact of exercise-trained and cold-exposed iWAT on systemic glucose metabolism and the iWAT proteome and secretome. Transplanting trained iWAT into sedentary mice improves glucose tolerance, while cold-exposed iWAT transplantation shows no such benefit. Compared to training, cold leads to more pronounced alterations in the iWAT proteome and secretome, downregulating >2,000 proteins but also boosting the thermogenic capacity of iWAT. In contrast, only training increases extracellular space and vesicle transport proteins, and only training upregulates proteins that correlate with favorable fasting glucose, suggesting fundamental changes in trained iWAT that mediate tissue-to-tissue communication. This study defines the unique exercise training- and cold exposure-induced iWAT proteomes, revealing distinct mechanisms for the beneficial effects of these interventions on metabolic health.

Exercise Training and Cold Exposure Trigger Distinct Molecular Adaptations to Inguinal White Adipose Tissue.

Exercise training and cold exposure both improve systemic metabolism, but the mechanisms are not well-established. We tested the hypothesis that adaptations to inguinal white adipose tissue (iWAT) are critical for these beneficial effects by determining the impact of exercise-trained and cold-exposed iWAT on systemic glucose metabolism and the iWAT proteome and secretome. Transplanting trained iWAT into sedentary mice improved glucose tolerance, while cold-exposed iWAT transplantation showed no such benefit. Compared to training, cold led to more pronounced alterations in the iWAT proteome and secretome, downregulating >2,000 proteins but also boosting iWAT's thermogenic capacity. In contrast, only training increased extracellular space and vesicle transport proteins, and only training upregulated proteins that correlate with favorable fasting glucose, suggesting fundamental changes in trained iWAT that mediate tissue-to-tissue communication. This study defines the unique exercise training- and cold exposure-induced iWAT proteomes, revealing distinct mechanisms for the beneficial effects of these interventions on metabolic health.

Moderate-intensity endurance training improves late phase ß-cell function in adults with type 2 diabetes.

Physical activity is important for type 2 diabetes treatment, yet the underlying mechanisms for these beneficial effects of exercise are not fully understood. Here, we investigated the effects of exercise training on biphasic ß-cell insulin secretory function, a key factor regulating blood glucose. Adults with type 2 diabetes (7F/3M, age 49 ± 5 years, BMI 30 ± 3 kg/m2) completed a 10-week moderate-intensity exercise program and multiple components of glucose homeostasis were measured. Training improved glycemic control, insulin sensitivity, and processing of proinsulin-to-insulin. Training increased late phase ß-cell function by 38% (p = 0.01), which was correlated with changes in VO2peak suggesting training response-dependent effects. Ras-Responsive Element Binding Protein 1 (RREB1) concentrations, a protein postulated to increase type 2 diabetes risk, were inversely correlated with increases in training-induced late-phase disposition index, consistent with an inhibitory role of RREB1 on insulin secretion. Moderate-intensity exercise training improves late-phase ß-cell function and glycemic control in adults with type 2 diabetes.

Association of Timing of Moderate-to-Vigorous Physical Activity With Changes in Glycemic Control Over 4 Years in Adults With Type 2 Diabetes From the Look AHEAD Trial.

OBJECTIVE: We aimed to determine the association of the time-of-day of bout-related moderate-to-vigorous physical activity (bMVPA) with changes in glycemic control across 4 years in adults with overweight/obesity and type 2 diabetes. RESEARCH DESIGN AND METHODS: Among 2,416 participants (57% women; mean age, 59 years) with 7-day waist-worn accelerometry recording at year 1 or 4, we assigned bMVPA timing groups based on the participants' temporal distribution of bMVPA at year 1 and recategorized them at year 4. The time-varying exposure of bMVPA (≥10-min bout) timing was defined as ≥50% of bMVPA occurring during the same time period (morning, midday, afternoon, or evening), <50% of bMVPA in any time period (mixed), and ≤1 day with bMVPA per week (inactive). RESULTS: HbA1c reduction at year 1 varied among bMVPA timing groups (P = 0.02), independent of weekly bMVPA volume and intensity. The afternoon group had the greatest HbA1c reduction versus inactive (-0.22% [95%CI -0.39%, -0.06%]), the magnitude of which was 30-50% larger than the other groups. The odds of discontinuation versus maintaining or initiating glucose-lowering medications at year 1 differed by bMVPA timing (P = 0.04). The afternoon group had the highest odds (odds ratio 2.13 [95% CI 1.29, 3.52]). For all the year-4 bMVPA timing groups, there were no significant changes in HbA1c between year 1 and 4. CONCLUSIONS: bMVPA performed in the afternoon is associated with improvements in glycemic control in adults with diabetes, especially within the initial 12 months of an intervention. Experimental studies are needed to examine causality.

Exercise training remodels inguinal white adipose tissue through adaptations in innervation, vascularization, and the extracellular matrix.

Inguinal white adipose tissue (iWAT) is essential for the beneficial effects of exercise training on metabolic health. The underlying mechanisms for these effects are not fully understood, and here, we test the hypothesis that exercise training results in a more favorable iWAT structural phenotype. Using biochemical, imaging, and multi-omics analyses, we find that 11 days of wheel running in male mice causes profound iWAT remodeling including decreased extracellular matrix (ECM) deposition and increased vascularization and innervation. We identify adipose stem cells as one of the main contributors to training-induced ECM remodeling, show that the PRDM16 transcriptional complex is necessary for iWAT remodeling and beiging, and discover neuronal growth regulator 1 (NEGR1) as a link between PRDM16 and neuritogenesis. Moreover, we find that training causes a shift from hypertrophic to insulin-sensitive adipocyte subpopulations. Exercise training leads to remarkable adaptations to iWAT structure and cell-type composition that can confer beneficial changes in tissue metabolism.

Single-cell dissection of the obesity-exercise axis in adipose-muscle tissues implies a critical role for mesenchymal stem cells.

Exercise training is critical for the prevention and treatment of obesity, but its underlying mechanisms remain incompletely understood given the challenge of profiling heterogeneous effects across multiple tissues and cell types. Here, we address this challenge and opposing effects of exercise and high-fat diet (HFD)-induced obesity at single-cell resolution in subcutaneous and visceral white adipose tissue and skeletal muscle in mice with diet and exercise training interventions. We identify a prominent role of mesenchymal stem cells (MSCs) in obesity and exercise-induced tissue adaptation. Among the pathways regulated by exercise and HFD in MSCs across the three tissues, extracellular matrix remodeling and circadian rhythm are the most prominent. Inferred cell-cell interactions implicate within- and multi-tissue crosstalk centered around MSCs. Overall, our work reveals the intricacies and diversity of multi-tissue molecular responses to exercise and obesity and uncovers a previously underappreciated role of MSCs in tissue-specific and multi-tissue beneficial effects of exercise.

Post-graduate medical education in the time of COVID-19: Not a remotely simple task.

The COVID-19 pandemic has stimulated a rapid shift towards telemedicine, which has had tremendous repercussions on all domains of the healthcare ecosystem. The effects of the transition to telemedicine on post-graduate medical education and on patient care provided by trainees have not been fully elucidated. Focusing on the multifaceted scope of endocrinology teaching clinics, the experience garnered by endocrinology fellows, preceptors, and patients through the adoption of virtual visits has shed new light on relevant challenges that require specific attention. First, we identified a divergent trend in glycated hemoglobin in people with type 1 diabetes according to their use of continuous glucose monitoring (CGM). Second, the patient's perspective highlighted positive aspects, including expanded options for clinical care, but also limitations in communication with clinicians for people without access to videoconferencing tools or EHR-based portals. Finally, regarding medical training evaluation and skills-based learning, academic centers, professional organizations, and clinical educators should develop new teaching curricula suitable for a telemedicine-based environment. While simultaneously facing numerous pressures, fellows can potentially spearhead new models of care delivery and innovative approaches to clinical education leveraging telemedicine.

Changes in mood and health-related quality of life in Look AHEAD 6 years after termination of the lifestyle intervention.

OBJECTIVE: The Action for Health in Diabetes (Look AHEAD) study previously reported that intensive lifestyle intervention (ILI) reduced incident depressive symptoms and improved health-related quality of life (HRQOL) over nearly 10 years of intervention compared with a control group (the diabetes support and education group [DSE]) in participants with type 2 diabetes and overweight or obesity. The present study compared incident depressive symptoms and changes in HRQOL in these groups for an additional 6 years following termination of the ILI in September 2012. METHODS: A total of 1,945 ILI participants and 1,900 DSE participants completed at least one of four planned postintervention assessments at which weight, mood (via the Patient Health Questionnaire-9), antidepressant medication use, and HRQOL (via the Medical Outcomes Scale, Short Form-36) were measured. RESULTS: ILI participants and DSE participants lost 3.1 (0.3) and 3.8 (0.3) kg [represented as mean (SE); p = 0.10], respectively, during the 6-year postintervention follow-up. No significant differences were observed between groups during this time in incident mild or greater symptoms of depression, antidepressant medication use, or in changes on the physical component summary or mental component summary scores of the Short Form-36. In both groups, mental component summary scores were higher than physical component summary scores. CONCLUSIONS: Prior participation in the ILI, compared with the DSE group, did not appear to improve subsequent mood or HRQOL during 6 years of postintervention follow-up.

Placental superoxide dismutase 3 mediates benefits of maternal exercise on offspring health.

Poor maternal diet increases the risk of obesity and type 2 diabetes in offspring, adding to the ever-increasing prevalence of these diseases. In contrast, we find that maternal exercise improves the metabolic health of offspring, and here, we demonstrate that this occurs through a vitamin D receptor-mediated increase in placental superoxide dismutase 3 (SOD3) expression and secretion. SOD3 activates an AMPK/TET signaling axis in fetal offspring liver, resulting in DNA demethylation at the promoters of glucose metabolic genes, enhancing liver function, and improving glucose tolerance. In humans, SOD3 is upregulated in serum and placenta from physically active pregnant women. The discovery of maternal exercise-induced cross talk between placenta-derived SOD3 and offspring liver provides a central mechanism for improved offspring metabolic health. These findings may lead to novel therapeutic approaches to limit the transmission of metabolic disease to the next generation.

Exercise Training Promotes Sex-Specific Adaptations in Mouse Inguinal White Adipose Tissue.

Recent studies demonstrate that adaptations to white adipose tissue (WAT) are important components of the beneficial effects of exercise training on metabolic health. Exercise training favorably alters the phenotype of subcutaneous inguinal WAT (iWAT) in male mice, including decreasing fat mass, improving mitochondrial function, inducing beiging, and stimulating the secretion of adipokines. In this study, we find that despite performing more voluntary wheel running compared with males, these adaptations do not occur in the iWAT of female mice. Consistent with sex-specific adaptations, we report that mRNA expression of androgen receptor coactivators is upregulated in iWAT from trained male mice and that testosterone treatment of primary adipocytes derived from the iWAT of male, but not female mice, phenocopies exercise-induced metabolic adaptations. Sex specificity also occurs in the secretome profile, as we identify cysteine-rich secretory protein 1 (Crisp1) as a novel adipokine that is only secreted from male iWAT in response to exercise. Crisp1 expression is upregulated by testosterone and functions to increase glucose and fatty acid uptake. Our finding that adaptations to iWAT with exercise training are dramatically greater in male mice has potential clinical implications for understanding the different metabolic response to exercise training in males and females and demonstrates the importance of investigating both sexes in studies of adipose tissue biology.

Association of Objectively Measured Timing of Physical Activity Bouts With Cardiovascular Health in Type 2 Diabetes.

OBJECTIVE: Moderate- to vigorous-intensity physical activity (MVPA) improves cardiovascular health. Few studies have examined MVPA timing. We examined the associations of timing of bout-related MVPA with cardiorespiratory fitness and cardiovascular risk in adults with type 2 diabetes. RESEARCH DESIGN AND METHODS: Baseline 7-day hip-worn accelerometry data from Look AHEAD participants (n = 2,153, 57% women) were analyzed to identify bout-related MVPA (≥3 METs/min for ≥10 min). Cardiorespiratory fitness was assessed by maximal graded exercise test. Participants were categorized into six groups on the basis of the time of day with the majority of bout-related MVPA (METs × min): ≥50% of bout-related MVPA during the same time window (morning, midday, afternoon, or evening), <50% of bout-related MVPA in any time category (mixed; the reference group), and ≤1 day with bout-related MVPA per week (inactive). RESULTS: Cardiorespiratory fitness was highly associated with timing of bout-related MVPA (P = 0.0005), independent of weekly bout-related MVPA volume and intensity. Importantly, this association varied by sex (P = 0.02). In men, the midday group had the lowest fitness (ß = -0.46 [95% CI -0.87, -0.06]), while the mixed group in women was the least fit. Framingham risk score (FRS) was associated with timing of bout-related MVPA (P = 0.02), which also differed by sex (P = 0.0007). The male morning group had the highest 4-year FRS (2.18% [0.70, 3.65]), but no association was observed in women. CONCLUSIONS: Timing of bout-related MVPA is associated with cardiorespiratory fitness and cardiovascular risk in men with type 2 diabetes, independent of bout-related MVPA volume and intensity. Prospective studies are needed to determine the impacts of MVPA timing on cardiovascular health.

Exercise intensity regulates cytokine and klotho responses in men.

BACKGROUND: Short-term exercise training programs that consist of moderate intensity endurance training or high intensity interval training have become popular choices for healthy lifestyle modifications, with as little as two weeks of training being shown to improve cardiorespiratory fitness and whole-body glucose metabolism. An emerging concept in exercise biology is that exercise stimulates the release of cytokines and other factors into the blood that contribute to the beneficial effects of exercise on metabolism, but whether these factors behave similarly in response to moderate and high intensity short term training is not known. Here, we determined the effects of two short-term exercise training programs on the concentrations of select secreted cytokines and Klotho, a protein involved in anti-aging. METHODS: Healthy, sedentary men (n = 22) were randomized to moderate intensity training (MIT) or sprint intensity training (SIT) treatment groups. SIT consisted of 6 sessions over 2 weeks of 6 × 30 s all out cycle ergometer sprints with 4 min of recovery between sprints. MIT consisted of 6 sessions over 2 weeks of cycle ergometer exercise at 60% VO2peak, gradually increasing in duration from 40 to 60 min. Blood was taken before the intervention and 48 h after the last training session, and glucose uptake was measured using [18F]FDG-PET/CT scanning. Cytokines were measured by multiplex and Klotho concentrations by ELISA. RESULTS: Both training protocols similarly increased VO2peak and decreased fat percentage and visceral fat (P < 0.05). MIT and SIT training programs both reduced the concentrations of IL-6, Hepatocyte Growth Factor (HGF) and Leptin. Interestingly, MIT, but not SIT increased monocyte chemoattractant protein-1 (MCP-1) concentrations, an exercise-induced cytokine, as well as Klotho concentrations. CONCLUSION: Short-term exercise training at markedly different intensities similarly improves cardiovascular fitness but results in intensity-specific changes in cytokine responses to exercise.

Early Physical Activity Adoption Predicts Longer-Term Physical Activity Among Individuals Inactive at Baseline.

BACKGROUND: To examine the relationship between early physical activity (PA) adoption (2, 3, and 4 mo) and longer-term PA adherence (1 y) among individuals who were inactive at baseline and received a lifestyle intervention. METHODS: Participants (n = 637) received weekly behavioral weight loss sessions, calorie reduction, and PA goals (50-175 min/wk progression). PA was assessed via self-reported measures at baseline, months 2 to 4, and 1 year. RESULTS: PA at months 2 to 4 was significantly correlated with PA at 1 year (rs = .29-.35, P < .01). At all early time points, those failing to meet the prescribed PA goal (early nonadopters) engaged in significantly less PA at 1 year than those meeting the early PA goal (initial adopters). For example, using 2-month criteria, initial adopters engaged in 108.3 minutes per week more at 1 year compared with early nonadopters (P < .01) and had 2.8 times the odds (95% confidence interval, 1.9-4.2) of meeting the 1-year PA goal (≥175 min/wk, P < .01). CONCLUSIONS: Failure to achieve PA goals at 2, 3, or 4 months results in less overall PA at 1 year. Thus, PA observed as early as month 2 may be a useful indicator for identifying at-risk individuals who may benefit from more intensive PA intervention strategies.

Abnormal Exercise Test or CVD History on Weight Loss or Fitness: the Look AHEAD Trial.

PURPOSE: Obesity and type 2 diabetes are associated with an increased risk of cardiovascular disease (CVD) and the combination of weight loss and increased physical exercise are commonly recommended to reduce CVD. This study examined whether people with obesity and type 2 diabetes with an abnormal graded exercise tolerance test (GXT) or a history of CVD would have less success in achieving weight loss and improved fitness, compared to adults without these conditions. METHODS: The Look AHEAD Study examined whether an intensive lifestyle intervention (ILI) compared with diabetes support and education (DSE) reduced cardiovascular events in adults with overweight/obesity and type 2 diabetes. Participants underwent a baseline maximal GXT and provided medical history data. Weight loss and fitness change were examined in 5011 participants over four years in those with or without an abnormal baseline GXT and/or history of CVD. RESULTS: After four years, weight loss in both ILI and DSE were significantly greater in those without a prior history of CVD than in those with a CVD history (6.69% vs 5.98%, p=0.02, in ILI and 0.73 vs -.07% (weight gain), p=0.01, in DSE). Likewise, those without a prior history of CVD experienced greater improvements in fitness in both ILI and DSE relative to those with a history of CVD. Having an abnormal GXT at baseline did not affect weight loss or fitness. CONCLUSIONS: A history of CVD at baseline modestly lessened weight loss and fitness changes at 4 years, whereas having any abnormality on the baseline GXT did not affect these outcomes. Thus, weight loss and improved fitness are achievable in adults with a history of CVD or ECG abnormalities.

TGF-ß2 is an exercise-induced adipokine that regulates glucose and fatty acid metabolism.

Exercise improves health and well-being across diverse organ systems, and elucidating mechanisms underlying the beneficial effects of exercise can lead to new therapies. Here, we show that transforming growth factor-ß2 (TGF-ß2) is secreted from adipose tissue in response to exercise and improves glucose tolerance in mice. We identify TGF-ß2 as an exercise-induced adipokine in a gene expression analysis of human subcutaneous adipose tissue biopsies after exercise training. In mice, exercise training increases TGF-ß2 in scWAT, serum, and its secretion from fat explants. Transplanting scWAT from exercise-trained wild type mice, but not from adipose tissue-specific Tgfb2-/- mice, into sedentary mice improves glucose tolerance. TGF-ß2 treatment reverses the detrimental metabolic effects of high fat feeding in mice. Lactate, a metabolite released from muscle during exercise, stimulates TGF-ß2 expression in human adipocytes. Administration of the lactate-lowering agent dichloroacetate during exercise training in mice decreases circulating TGF-ß2 levels and reduces exercise-stimulated improvements in glucose tolerance. Thus, exercise training improves systemic metabolism through inter-organ communication with fat via a lactate-TGF-ß2-signaling cycle.

12,13-diHOME: An Exercise-Induced Lipokine that Increases Skeletal Muscle Fatty Acid Uptake.

Circulating factors released from tissues during exercise have been hypothesized to mediate some of the health benefits of regular physical activity. Lipokines are circulating lipid species that have recently been reported to affect metabolism in response to cold. Here, lipidomics analysis revealed that a bout of moderate-intensity exercise causes a pronounced increase in the circulating lipid 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) in male, female, young, old, sedentary, and active human subjects. In mice, both a single bout of exercise and exercise training increased circulating 12,13-diHOME and surgical removal of brown adipose tissue (BAT) negated the increase in 12,13-diHOME, suggesting that BAT is the tissue source for exercise-stimulated 12,13-diHOME. Acute 12,13-diHOME treatment of mice in vivo increased skeletal muscle fatty acid uptake and oxidation, but not glucose uptake. These data reveal that lipokines are novel exercise-stimulated circulating factors that may contribute to the metabolic changes that occur with physical exercise.