Glucose tolerance status associates with improvements in cognitive function following high-intensity exercise in adults with obesity.

PURPOSE: Obesity, insulin resistance (IR), and proinflammatory cytokines associate with cognitive decline. Numerous studies document cognitive benefits of acute exercise bouts in lean individuals. However, how co-morbidities such as obesity and IR influence cognitive changes induced by acute exercise is unclear. We examined the effects of acute high-intensity aerobic exercise on cognitive function in age-matched and BMI-matched obese adults with normal glucose tolerance (NGT) or impaired glucose tolerance (IGT) and in lean, NGT adults. METHODS: 49 adults (15 Lean, 18 Obese-NGT, 16 Obese-IGT) performed one session of high-intensity interval exercise (four cycles of 4-min at 75% Wmax with 3-min rest). Cognitive function testing and blood sampling were performed pre- and post-exercise. RESULTS: Following exercise, measurements of executive function and working memory were improved in Lean and Obese-NGT (p < 0.05), but not Obese-IGT. Changes in cognitive function following exercise negatively correlated with 2-hr glucose during an OGTT after controlling for body weight and body composition (rp = -0.40, p = 0.007). Serum levels of inflammatory cytokines IL-6 and CRP remained increased 60-minutes post-exercise in Obese-IGT, but not in Lean or Obese-NGT, which positively associated with 2-hr glucose during an OGTT (p < 0.01) and negatively with changes in cognitive function following exercise (p < 0.01). Greater insulin levels in Obese-IGT post-exercise also negatively correlated with changes in cognitive function following exercise (p < 0.01). CONCLUSION: Improvements in cognition following acute high-intensity exercise positively associate with glucose tolerance, independent of body weight and body composition. Further, poorer changes in cognitive performance following exercise associate with persistent peripheral inflammation.

High-intensity aerobic, but not resistance or combined, exercise training improves both cardiometabolic health and skeletal muscle mitochondrial dynamics.

This study investigated how different exercise training modalities influence skeletal muscle mitochondrial dynamics. Healthy [average body mass index (BMI): 25.8 kg/m2], sedentary younger and older participants underwent 12 wk of supervised high-intensity aerobic interval training (HIIT; n = 13), resistance training (RT; n = 14), or combined training (CT; n = 11). Mitochondrial structure was assessed using transmission electron microscopy (TEM). Regulators of mitochondrial fission and fusion, cardiorespiratory fitness (V̇o2peak), insulin sensitivity via a hyperinsulinemic-euglycemic clamp, and muscle mitochondrial respiration were assessed. TEM showed increased mitochondrial volume, number, and perimeter following HIIT (P < 0.01), increased mitochondrial number following CT (P < 0.05), and no change in mitochondrial abundance after RT. Increased mitochondrial volume associated with increased mitochondrial respiration and insulin sensitivity following HIIT (P < 0.05). Increased mitochondrial perimeter associated with increased mitochondrial respiration, insulin sensitivity, and V̇o2peak following HIIT (P < 0.05). No such relationships were observed following CT or RT. OPA1, a regulator of fusion, was increased following HIIT (P < 0.05), whereas FIS1, a regulator of fission, was decreased following HIIT and CT (P < 0.05). HIIT also increased the ratio of OPA1/FIS1 (P < 0.01), indicative of the balance between fission and fusion, which positively correlated with improvements in respiration, insulin sensitivity, and V̇o2peak (P < 0.05). In conclusion, HIIT induces a larger, more fused mitochondrial tubular network. Changes indicative of increased fusion following HIIT associate with improvements in mitochondrial respiration, insulin sensitivity, and V̇o2peak supporting the idea that enhanced mitochondrial fusion accompanies notable health benefits of HIIT.NEW & NOTEWORTHY We assessed the effects of 12 wk of supervised high-intensity interval training (HIIT), resistance training, and combined training (CT) on skeletal muscle mitochondrial abundance and markers of fission and fusion. HIIT increased mitochondrial area and size and promoted protein changes indicative of increased mitochondrial fusion, whereas lessor effects were observed after CT and no changes were observed after RT. Furthermore, increased mitochondrial area and size after HIIT associated with improved mitochondrial respiration, cardiorespiratory fitness, and insulin sensitivity.

Enhancement of anaerobic glycolysis - a role of PGC-1α4 in resistance exercise.

Resistance exercise training (RET) is an effective countermeasure to sarcopenia, related frailty and metabolic disorders. Here, we show that an RET-induced increase in PGC-1α4 (an isoform of the transcriptional co-activator PGC-1α) expression not only promotes muscle hypertrophy but also enhances glycolysis, providing a rapid supply of ATP for muscle contractions. In human skeletal muscle, PGC-1α4 binds to the nuclear receptor PPARß following RET, resulting in downstream effects on the expressions of key glycolytic genes. In myotubes, we show that PGC-1α4 overexpression increases anaerobic glycolysis in a PPARß-dependent manner and promotes muscle glucose uptake and fat oxidation. In contrast, we found that an acute resistance exercise bout activates glycolysis in an AMPK-dependent manner. These results provide a mechanistic link between RET and improved glucose metabolism, offering an important therapeutic target to counteract aging and inactivity-induced metabolic diseases benefitting those who cannot exercise due to many reasons.

A meal enriched in saturated fat acutely impairs cognitive performance in obese men.

BACKGROUND: Diets chronically high in saturated fat (SFA) associate with obesity and insulin resistance (IR), which in turn associate with cognitive decline and dementia. However, understanding how acute SFA consumption influences cognition is less clear despite short-term SFA-enriched diets inducing whole-body IR. We examined how consuming meals enriched with SFA or monounsaturated fat (MUFA) acutely influence cognitive function in lean and obese men. We hypothesized that greater diet-induced IR following a SFA-enriched meal would associate with decreased cognitive performance. METHODS: Twelve lean and 12 obese males ingested meals containing no fat (CTL), enriched with SFA, or enriched with MUFA in a single-blind, randomized fashion. Cognitive testing and blood sampling were performed pre- and 2 h post-meal. Oral glucose tolerance (OGTT) and body composition were also assessed. RESULTS: At baseline, fasting glucose, insulin, HOMA-IR, triglyceride, IL-6, and 2-hr glucose during an OGTT were higher in obese men (p < 0.001), while executive function (Stroop Test and Trail Making Test B-A) and working memory (Digit Span Test) were lower in obese men (p < 0.05). In response to the CTL and MUFA-enriched, no differences in cognitive measures were observed in lean or obese subjects. Following a SFA-enriched meal, obese subjects scored worse during cognitive testing (Stroop Test, Trail Making Test B-A, and Digit Span Test) compared to pre-meal scores (p < 0.05). These impairments in cognitive testing scores following the SFA-enriched meal associated with increased HOMA-IR (p < 0.01) and decreased plasma IL-6 (p < 0.05). No changes in cognitive function were observed in lean subjects following a SFA-enriched meal. CONCLUSIONS: These data demonstrate that cognitive performance of obese men acutely worsens following a high-SFA meal. Reductions in cognitive performance associated with increased IR, suggesting that diet-induced IR may acutely decrease cognitive function.

Resistance-exercise training attenuates LPS-induced astrocyte remodeling and neuroinflammatory cytokine expression in female Wistar rats.

Neuroinflammation is an early detectable marker of mild cognitive impairment, the transition state between normal cognition and dementia. Resistance-exercise training can attenuate the cognitive decline observed in patients with mild cognitive impairment. However, the underlying mechanisms of resistance training effects are largely unknown. To further elucidate mechanisms of the known cognitive health benefits from resistance-exercise training, we tested if resistance-exercise training could ameliorate lipopolysaccharide-induced neuroinflammation. Five-week-old female Wistar rats received intracerebroventricular injections of lipopolysaccharides to induce neuroinflammation and cognitive impairment. Rats then underwent 3 wk of progressive ladder climbing to recapitulate resistance-exercise training in humans. Cognition was assessed toward the end of the training period by novelty object recognition testing. Neuroinflammation was measured one and 24 h after the last resistance-exercise training workout. Resistance-exercise training ameliorated cognitive impairment, diminished lipopolysaccharide-induced neuroinflammatory cytokine expression, and attenuated astrocyte remodeling in the dentate gyrus 24 h post exercise. Here, we provide evidence that the ladder-climbing model of resistance-exercise training in rats can improve cognition as early as 3 wk. In addition, these data support the hypothesis that resistance exercise can reduce lipopolysaccharide-induced neuroinflammation in the dentate gyrus.NEW & NOTEWORTHY To further elucidate the known cognitive health benefits from resistance-exercise training, we tested if resistance-exercise training in rats would attenuate lipopolysaccharide-induced neuroinflammation. Our data demonstrated that resistance training had an anti-inflammatory effect in the brain as LPS-induced neuroinflammatory cytokine expression and reactive astrocytic remodeling were reduced in the dentate gyrus after 3 wk of progressive ladder climbing.

A size-exclusion-based approach for purifying extracellular vesicles from human plasma.

Extracellular vesicles (EVs) are released into blood from multiple organs and carry molecular cargo that facilitates inter-organ communication and an integrated response to physiological and pathological stimuli. Interrogation of the protein cargo of EVs is currently limited by the absence of optimal and reproducible approaches for purifying plasma EVs that are suitable for downstream proteomic analyses. We describe a size-exclusion chromatography (SEC)-based method to purify EVs from platelet-poor plasma (PPP) for proteomics profiling via high-resolution mass spectrometry (SEC-MS). The SEC-MS method identifies more proteins with higher precision than several conventional EV isolation approaches. We apply the SEC-MS method to identify the unique proteomic signatures of EVs released from platelets, adipocytes, muscle cells, and hepatocytes, with the goal of identifying tissue-specific EV markers. Furthermore, we apply the SEC-MS approach to evaluate the effects of a single bout of exercise on EV proteomic cargo in human plasma.

Brain functions and cognition on transient insulin deprivation in type 1 diabetes.

BACKGROUNDType 1 diabetes (T1D) is a risk factor for dementia and structural brain changes. It remains to be determined whether transient insulin deprivation that frequently occurs in insulin-treated individuals with T1D alters brain function.METHODSWe therefore performed functional and structural magnetic resonance imaging, magnetic resonance spectroscopy, and neuropsychological testing at baseline and following 5.4 ± 0.6 hours of insulin deprivation in 14 individuals with T1D and compared results with those from 14 age-, sex-, and BMI-matched nondiabetic (ND) participants with no interventions.RESULTSInsulin deprivation in T1D increased blood glucose, and ß-hydroxybutyrate, while reducing bicarbonate levels. Participants with T1D showed lower baseline brain N-acetyl aspartate and myo-inositol levels but higher cortical fractional anisotropy, suggesting unhealthy neurons and brain microstructure. Although cognitive functions did not differ between participants with T1D and ND participants at baseline, significant changes in fine motor speed as well as attention and short-term memory occurred following insulin deprivation in participants with T1D. Insulin deprivation also reduced brain adenosine triphosphate levels and altered the phosphocreatine/adenosine triphosphate ratio. Baseline differences in functional connectivity in brain regions between participants with T1D and ND participants were noted, and on insulin deprivation further alterations in functional connectivity between regions, especially cortical and hippocampus-caudate regions, were observed. These alterations in functional connectivity correlated to brain metabolites and to changes in cognition.CONCLUSIONTransient insulin deprivation therefore caused alterations in executive aspects of cognitive function concurrent with functional connectivity between memory regions and the sensory cortex. These findings have important clinical implications, as many patients with T1D inadvertently have periods of transient insulin deprivation.TRIAL REGISTRATIONClinicalTrials.gov NCT03392441.FUNDINGClinical and Translational Science Award (UL1 TR002377) from the National Center for Advancing Translational Science; NIH grants (R21 AG60139 and R01 AG62859); the Mayo Foundation.

Exercise and metformin counteract altered mitochondrial function in the insulin-resistant brain.

Insulin resistance associates with increased risk for cognitive decline and dementia; however, the underpinning mechanisms for this increased risk remain to be fully defined. As insulin resistance impairs mitochondrial oxidative metabolism and increases ROS in skeletal muscle, we considered whether similar events occur in the brain, which - like muscle - is rich in insulin receptors and mitochondria. We show that high-fat diet-induced (HFD-induced) brain insulin resistance in mice decreased mitochondrial ATP production rate and oxidative enzyme activities in brain regions rich in insulin receptors. HFD increased ROS emission and reduced antioxidant enzyme activities, with the concurrent accumulation of oxidatively damaged mitochondrial proteins and increased mitochondrial fission. Improvement of insulin sensitivity by both aerobic exercise and metformin ameliorated HFD-induced abnormalities. Moreover, insulin-induced enhancement of ATP production in primary cortical neurons and astrocytes was counteracted by the insulin receptor antagonist S961, demonstrating a direct effect of insulin resistance on brain mitochondria. Further, intranasal S961 administration prevented exercise-induced improvements in ATP production and ROS emission during HFD, supporting that exercise enhances brain mitochondrial function by improving insulin action. These results support that insulin sensitizing by exercise and metformin restores brain mitochondrial function in insulin-resistant states.

TFAM Enhances Fat Oxidation and Attenuates High-Fat Diet-Induced Insulin Resistance in Skeletal Muscle.

Diet-induced insulin resistance (IR) adversely affects human health and life span. We show that muscle-specific overexpression of human mitochondrial transcription factor A (TFAM) attenuates high-fat diet (HFD)-induced fat gain and IR in mice in conjunction with increased energy expenditure and reduced oxidative stress. These TFAM effects on muscle are shown to be exerted by molecular changes that are beyond its direct effect on mitochondrial DNA replication and transcription. TFAM augmented the muscle tricarboxylic acid cycle and citrate synthase facilitating energy expenditure. TFAM enhanced muscle glucose uptake despite increased fatty acid (FA) oxidation in concert with higher ß-oxidation capacity to reduce the accumulation of IR-related carnitines and ceramides. TFAM also increased pAMPK expression, explaining enhanced PGC1α and PPARß, and reversing HFD-induced GLUT4 and pAKT reductions. TFAM-induced mild uncoupling is shown to protect mitochondrial membrane potential against FA-induced uncontrolled depolarization. These coordinated changes conferred protection to TFAM mice against HFD-induced obesity and IR while reducing oxidative stress with potential translational opportunities.

Rats Selectively Bred for High Voluntary Physical Activity Behavior are Not Protected from the Deleterious Metabolic Effects of a Western Diet When Sedentary.

BACKGROUND: Physical activity and diet are well-established modifiable factors that influence chronic disease risk. We developed a selectively bred, polygenic model for high and low voluntary running (HVR and LVR, respectively) distances. After 8 generations, large differences in running distance were noted. Despite these inherent behavioral differences in physical activity levels, it is unknown whether HVR rats would be inherently protected from diet-induced metabolic dysfunction. OBJECTIVES: The aim of this study was to determine whether HVR rats without voluntary running wheels would be inherently protected from diet-induced metabolic dysfunction. METHODS: Young HVR, LVR, and a wild-type (WT) control group were housed with no running wheel access and fed either a normal diet (ND) or a high-sugar/fat Western diet (WD) for 8 wk. Body weight, percentage body fat (by dual-energy X-ray absorptiometry scan), blood lipids [total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides (TGs), nonesterified fatty acids], and hepatic TG content were measured, and indices of insulin sensitivity were determined via an intravenous glucose tolerance test. Additionally, weekly energy intake and feed efficiency were calculated. RESULTS: After 8 wk, significant differences in body weight and body fat percentage were noted in all WD animals compared with ND animals, with the LVR-WD exhibiting the greatest increase due, in part, to their enhanced feed efficiency. Lipid dysregulation was present in all WD rat lines compared with ND counterparts. Furthermore, LVR-WD rats had higher total cholesterol, HDL cholesterol, and TG concentrations, and higher areas under the curve (AUC) for insulin than HVR-WD and WT-WD, although HVR-WD animals had higher AUCglucose than both LVR-WD and WT-WD and higher LDL than WT-WD. CONCLUSIONS: In the absence of high voluntary running behavior, the genetic predisposition for high running in HVR did not largely protect them from the deleterious effects of a WD compared with LVR, suggesting genetic factors influencing physical activity levels may, in part, be independent from genes influencing metabolism.

Intrinsic High Aerobic Capacity in Male Rats Protects Against Diet-Induced Insulin Resistance.

Low aerobic capacity increases the risk for insulin resistance but the mechanisms are unknown. In this study, we tested susceptibility to acute (3-day) high-fat, high-sucrose diet (HFD)-induced insulin resistance in male rats selectively bred for divergent intrinsic aerobic capacity, that is, high-capacity running (HCR) and low-capacity running (LCR) rats. We employed hyperinsulinemic-euglycemic clamps, tracers, and transcriptome sequencing of skeletal muscle to test whether divergence in aerobic capacity impacted insulin resistance through systemic and tissue-specific metabolic adaptations. An HFD evoked decreased insulin sensitivity and insulin signaling in muscle and liver in LCR rats, whereas HCR rats were protected. An HFD led to increased glucose transport in skeletal muscle (twofold) of HCR rats while increasing glucose transport into adipose depots of the LCR rats (twofold). Skeletal muscle transcriptome revealed robust differences in the gene profile of HCR vs LCR on low-fat diet and HFD conditions, including robust differences in specific genes involved in lipid metabolism, adipogenesis, and differentiation. HCR transcriptional adaptations to an acute HFD were more robust than for LCR and included genes driving mitochondrial energy metabolism. In conclusion, intrinsic aerobic capacity robustly impacts systemic and skeletal muscle adaptations to HFD-induced alterations in insulin resistance, an effect that is likely driven by baseline differences in oxidative capacity, gene expression profile, and transcriptional adaptations to an HFD.

Insulin deficiency and intranasal insulin alter brain mitochondrial function: a potential factor for dementia in diabetes.

Despite the strong association between diabetes and dementia, it remains to be fully elucidated how insulin deficiency adversely affects brain functions. We show that insulin deficiency in streptozotocin-induced diabetic mice decreased mitochondrial ATP production and/or citrate synthase and cytochrome oxidase activities in the cerebrum, hypothalamus, and hippocampus. Concomitant decrease in mitochondrial fusion proteins and increased fission proteins in these brain regions likely contributed to altered mitochondrial function. Although insulin deficiency did not cause any detectable increase in reactive oxygen species (ROS) emission, inhibition of monocarboxylate transporters increased ROS emission and further reduced ATP production, indicating the causative roles of elevated ketones and lactate in counteracting oxidative stress and as a fuel source for ATP production during insulin deficiency. Moreover, in healthy mice, intranasal insulin administration increased mitochondrial ATP production, demonstrating a direct regulatory role of insulin on brain mitochondrial function. Proteomics analysis of the cerebrum showed that although insulin deficiency led to oxidative post-translational modification of several proteins that cause tau phosphorylation and neurofibrillary degeneration, insulin administration enhanced neuronal development and neurotransmission pathways. Together these results render support for the critical role of insulin to maintain brain mitochondrial homeostasis and provide mechanistic insight into the potential therapeutic benefits of intranasal insulin.-Ruegsegger, G. N., Manjunatha, S., Summer, P., Gopala, S., Zabeilski, P., Dasari, S., Vanderboom, P. M., Lanza, I. R., Klaus, K. A., Nair, K. S. Insulin deficiency and intranasal insulin alter brain mitochondrial function: a potential factor for dementia in diabetes.

Overexpression of Protein Kinase Inhibitor Alpha Reverses Rat Low Voluntary Running Behavior.

A gene was sought that could reverse low voluntary running distances in a model of low voluntary wheel-running behavior. In order to confirm the low motivation to wheel-run in our model does not result from defects in reward valuation, we employed sucrose preference and conditioned place preference for voluntary wheel-access. We observed no differences between our model and wild-type rats regarding the aforementioned behavioral testing. Instead, low voluntary runners seemed to require less running to obtain similar rewards for low voluntary running levels compared to wild-type rats. Previous work in our lab identified protein kinase inhibitor alpha as being lower in low voluntary running than wild-type rats. Next, nucleus accumbens injections of an adenoviral-associated virus that overexpressed the protein kinase inhibitor alpha gene increased running distance in low voluntary running, but not wild-type rats. Endogenous mRNA levels for protein kinase inhibitor alpha, dopamine receptor D1, dopamine receptor D2, and Fos were all only lower in wild-type rats following overexpression compared to low voluntary runners, suggesting a potential molecular and behavioral resistance in wild-type rats. Utilizing a nucleus accumbens preparation, three intermediate early gene mRNAs increased in low voluntary running slices after dopamine receptor agonist SKF-38393 exposure, while wild-type had no response. In summary, the results suggest that protein kinase inhibitor alpha is a promising gene candidate to partially rescue physical activity in the polygenic model of low voluntary running. Importantly, there were divergent molecular responses to protein kinase inhibitor alpha overexpression in low voluntary runners compared to wild-type rats.

Correction to: Overexpression of Protein Kinase Inhibitor Alpha Reverses Rat Low Voluntary Running Behavior.

The original version of this article unfortunately contained mistake in Table 2 to where two directionality arrows were inverted.

Altered mitochondrial function in insulin-deficient and insulin-resistant states.

Diabetes profoundly alters fuel metabolism; both insulin deficiency and insulin resistance are characterized by inefficient mitochondrial coupling and excessive production of reactive oxygen species (ROS) despite their association with normal to high oxygen consumption. Altered mitochondrial function in diabetes can be traced to insulin's pivotal role in maintaining mitochondrial proteome abundance and quality by enhancing mitochondrial biogenesis and preventing proteome damage and degradation, respectively. Although insulin enhances gene transcription, it also induces decreases in amino acids. Thus, if amino acid depletion is not corrected, increased transcription will not result in enhanced translation of transcripts to proteins. Mitochondrial biology varies among tissues, and although most studies in humans are performed in skeletal muscle, abnormalities have been reported in multiple organs in preclinical models of diabetes. Nutrient excess, especially fat excess, alters mitochondrial physiology by driving excess ROS emission that impairs insulin action. Excessive ROS irreversibly damages DNA and proteome with adverse effects on cellular functions. In insulin-resistant people, aerobic exercise stimulates both mitochondrial biogenesis and efficiency concurrent with enhancement of insulin action. This Review discusses the association between both insulin-deficient and insulin-resistant diabetes and alterations in mitochondrial proteome homeostasis and function that adversely affect cellular functions, likely contributing to many diabetic complications.

Maternal Physical Activity and Sex Impact Markers of Hepatic Mitochondrial Health.

INTRODUCTION: Maternal exercise and physical activity during the gestational period can be protective against maternal high-fat diet-induced hepatic steatosis in older offspring. However, it is unknown whether these protective effects are seen in younger offspring. In this study, we investigated whether maternal physical activity would attenuate maternal western diet (WD)-induced steatosis in young adult rats. METHODS: Female Wistar rats (7-8 wk of age) were randomized into WD (42% fat, 27% sucrose) or normal chow diet (ND), and further randomized into physical activity (RUN) or sedentary (SED) conditions for a total of four groups. Dams returned to ND/SED conditions after parturition. Postweaning, offspring were maintained in ND/SED conditions for 18 wk. RESULTS: Maternal WD-induced increases in male offspring body mass was attenuated in the WD/RUN offspring (P < 0.05). Maternal WD feeding significantly increased hepatic steatosis in male (but not female offspring), which was not attenuated by maternal RUN. However, maternal RUN increased (P < 0.05) hepatic markers of mitochondrial biogenesis and mitophagy (mitochondrial transcription factor A, peroxisome proliferator activator receptor γ, and nuclear factor E2-related factor 2) in all offspring and the mitophagy marker BCL2-interacting protein 3 in WD/RUN offspring. Interestingly, hepatic markers of de novo lipogenesis (fatty acid synthase and acetyl coenzyme A carboxylase), mitophagy (autophagy-related gene 12:5, BCL2-interacting protein 3, P62, and LC3 II/I), and mitochondria biogenesis/content (mitochondrial transcription factor A and OXPHOS-Complex II) were significantly increased in female versus male offspring. CONCLUSION: Although maternal physical activity did not attenuate maternal WD-induced hepatic steatosis as has been previously reported in older adult offspring, it did significantly increase hepatic markers of mitochondrial biogenesis and mitophagy. Furthermore, female offspring had elevated hepatic markers of mitochondrial health, possibly explaining why female rats are protected against maternal WD-induced hepatic steatosis. Future studies are warranted to shed light on the time line of hepatic steatosis development under the influence of maternal physical activity.

Health Benefits of Exercise.

Overwhelming evidence exists that lifelong exercise is associated with a longer health span, delaying the onset of 40 chronic conditions/diseases. What is beginning to be learned is the molecular mechanisms by which exercise sustains and improves quality of life. The current review begins with two short considerations. The first short presentation concerns the effects of endurance exercise training on cardiovascular fitness, and how it relates to improved health outcomes. The second short section contemplates emerging molecular connections from endurance training to mental health. Finally, approximately half of the remaining review concentrates on the relationships between type 2 diabetes, mitochondria, and endurance training. It is now clear that physical training is complex biology, invoking polygenic interactions within cells, tissues/organs, systems, with remarkable cross talk occurring among the former list.

Maternal Western diet age-specifically alters female offspring voluntary physical activity and dopamine- and leptin-related gene expression.

Prenatal overnutrition affects development into adulthood and influences risk of obesity. We assessed the transgenerational effect of maternal Western diet (WD) consumption on offspring physical activity. Voluntary wheel running was increased in juvenile (4-7 wk of age), but decreased in adult (16-19 wk of age), F1 female WD offspring In contrast, no wheel-running differences in F1 male offspring were observed. Increased wheel running in juvenile female WD offspring was associated with up-regulated dopamine receptor (DRD)-1 and -2 in the nucleus accumbens (NAc) and with down-regulated Lepr in the ventral tegmental area (VTA). Conversely, decreased wheel running by adult female WD offspring was associated with down-regulated DRD1 in the NAc and with up-regulated Lepr in the VTA. Body fat, leptin, and insulin were increased in male, but not in female, F1 WD offspring. Recombinant virus (rAAV) leptin antagonism in the VTA decreased wheel running in standard diet but not in WD F1 female offspring. Analysis of F2 offspring found no differences in wheel running or adiposity in male or female offspring, suggesting that changes in the F1 generation were related to in utero somatic reprogramming. Our findings indicate prenatal WD exposure leads to age-specific changes in voluntary physical activity in female offspring that are differentially influenced by VTA leptin antagonism.-Ruegsegger, G. N., Grigsby, K. B., Kelty, T. J., Zidon, T. M., Childs, T. E., Vieira-Potter, V. J., Klinkebiel, D. L., Matheny, M., Scarpace, P. J., Booth, F. W. Maternal Western diet age-specifically alters female offspring voluntary physical activity and dopamine- and leptin-related gene expression.

Role of Inactivity in Chronic Diseases: Evolutionary Insight and Pathophysiological Mechanisms.

This review proposes that physical inactivity could be considered a behavior selected by evolution for resting, and also selected to be reinforcing in life-threatening situations in which exercise would be dangerous. Underlying the notion are human twin studies and animal selective breeding studies, both of which provide indirect evidence for the existence of genes for physical inactivity. Approximately 86% of the 325 million in the United States (U.S.) population achieve less than the U.S. Government and World Health Organization guidelines for daily physical activity for health. Although underappreciated, physical inactivity is an actual contributing cause to at least 35 unhealthy conditions, including the majority of the 10 leading causes of death in the U.S. First, we introduce nine physical inactivity-related themes. Next, characteristics and models of physical inactivity are presented. Following next are individual examples of phenotypes, organ systems, and diseases that are impacted by physical inactivity, including behavior, central nervous system, cardiorespiratory fitness, metabolism, adipose tissue, skeletal muscle, bone, immunity, digestion, and cancer. Importantly, physical inactivity, itself, often plays an independent role as a direct cause of speeding the losses of cardiovascular and strength fitness, shortening of healthspan, and lowering of the age for the onset of the first chronic disease, which in turn decreases quality of life, increases health care costs, and accelerates mortality risk.