Breaking prolonged sitting increases 24-h physical activity and self-perceived energy levels but does not acutely affect cognition in healthy adults.

INTRODUCTION: It is unknown whether predetermined (un)interrupted sitting within a laboratory setting will induce compensatory changes in human behaviours (energy intake and physical activity) once people return to a free-living environment. The effects of breaking up prolonged sitting on cognition are also unclear. METHODS: Twenty-four (male = 13) healthy participants [age 31 ± 8 y, BMI 22.7 ± 2.3 kg/m2 (mean ± SD)] completed 320 min mixed-feeding trials under prolonged sitting (SIT) or with 2 min walking at 6.4 km/h every 20 min (ACTIVE), in a randomised crossover design. Human behaviours were recorded post-trial under free-living conditions until midnight. Cognitive performance was evaluated before and immediately after SIT and ACTIVE trials. Self-perceived sensations (appetite, energy and mood) and finger prick blood glucose levels were collected at regular intervals throughout the trials. RESULTS: There were no differences between trials in eating behaviour and spontaneous physical activity (both, p > 0.05) in free-living conditions, resulting in greater overall total step counts [11,680 (10740,12620) versus 6049 (4845,7253) steps] and physical activity energy expenditure (PAEE) over 24-h period in ACTIVE compared to SIT (all, p < 0.05). Greater self-perceived levels of energy and lower blood glucose iAUC were found in ACTIVE trial compared to SIT trial (both, p < 0.05). No differences were found in cognitive performance between trials (all, p > 0.05). CONCLUSION: Breaking up sitting does not elicit subsequent behavioural compensation, resulting in greater 24-h step counts and PAEE in healthy adults. Breaking up sitting reduces postprandial glucose concentrations and elicits greater self-perceived energy levels, but these positive effects do not acutely translate into improved cognitive function.

Long-Term High-Fat Diet Limits the Protective Effect of Spontaneous Physical Activity on Mammary Carcinogenesis.

Breast cancer is influenced by factors such as diet, a sedentary lifestyle, obesity, and postmenopausal status, which are all linked to prolonged hormonal and inflammatory exposure. Physical activity offers protection against breast cancer by modulating hormones, immune responses, and oxidative defenses. This study aimed to assess how a prolonged high-fat diet (HFD) affects the effectiveness of physical activity in preventing and managing mammary tumorigenesis. Ovariectomised C57BL/6 mice were provided with an enriched environment to induce spontaneous physical activity while being fed HFD. After 44 days (short-term, ST HFD) or 88 days (long-term, LT HFD), syngenic EO771 cells were implanted into mammary glands, and tumour growth was monitored until sacrifice. Despite similar physical activity and food intake, the LT HFD group exhibited higher visceral adipose tissue mass and reduced skeletal muscle mass. In the tumour microenvironment, the LT HFD group showed decreased NK cells and TCD8+ cells, with a trend toward increased T regulatory cells, leading to a collapse of the T8/Treg ratio. Additionally, the LT HFD group displayed decreased tumour triglyceride content and altered enzyme activities indicative of oxidative stress. Prolonged exposure to HFD was associated with tumour growth despite elevated physical activity, promoting a tolerogenic tumour microenvironment. Future studies should explore inter-organ exchanges between tumour and tissues.

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.

Association between physical function and various patterns of physical activity in older adults: a cross-sectional analysis.

BACKGROUND: To improve physical function, physical activity (PA) guidelines for older adults recommend completing PA in bouts of 10 min or more. Spontaneous PA (< 10 min) can also benefit older adults. However, a paucity of research exists examining if shorter bouts of PA are associated with greater physical function. AIM: To determine the association between various patterns of PA and the likelihood of greater physical function in older adults. METHODS: Older adults from the 2003-2004 and 2005-2006 cycles of the National Health and Nutrition Examination Survey were included for analysis. PA lasting 1, 5, 10, 30, and 60 min was quantified using accelerometers. Physical function was assessed using a Likert scale reflecting the self-reported capability to complete 11 tasks. A single function score was then computed using factor analysis. Logistic regression analyses calculated the association between PA bout length and the likelihood of above average function. RESULTS: PA performed in 1-min (odds ratio [OR] 1.02; 95% confidence interval [CI] 1.01-1.03), 5-min (OR 1.02; CI 1.01-1.03), or 10-min bouts (OR 1.02; CI 1.01-1.03) was associated with greater physical function following adjustment for confounders. When scaled to represent an accumulation of 10 min of MVPA, likelihoods increased for both 1-min ([OR] 1.25; 95% [CI] 1.11-1.39) and 5-min (OR 1.22; 95% CI 1.08-1.37) bouts. DISCUSSION/CONCLUSIONS: Our findings suggest bouts of PA lasting 10 min or shorter in duration are associated with greater physical function in older adults.

Chemogenetic activation of orexin/hypocretin neurons ameliorates aging-induced changes in behavior and energy expenditure.

Aging affects numerous physiological processes, as well as behavior. A large number of these processes are regulated, at least partially, by hypothalamic orexin neurons, and orexin tone may decrease with normal aging. In this study, we hypothesized that designer receptors exclusively activated by designer drugs (DREADD) stimulation of orexin neuronal activity will ameliorate the effect of aging on behavioral and metabolic alterations in young and middle-aged mice. DREADD targeting was achieved by stereotaxic injection of AAV vectors (AAV2-hSyn-DIO-hM3D(Gq)-mCherry) into the lateral hypothalamus of 5- and 12-mo old orexin-cre female mice and was confirmed by immunohistochemistry (IHC) analysis of orexin A and mCherry expression. After recovery, animals were subjected to a behavioral test battery consisting of the elevated plus maze (EPM), open field (OFT), and novel object recognition tests (NORT) to assess effects of aging on anxiety-like behavior, general locomotion, and working memory. A comprehensive laboratory animal monitoring system (CLAMS) was used to measure spontaneous physical activity (SPA) and energy expenditure (EE). The results indicate that activation of orexin neurons mitigates aging-induced reductions in anxiety-like behavior in middle-aged mice (P < 0.005) and increases locomotion in both young and middle-aged mice (P < 0.05). Activation of orexin neurons increases SPA (P < 0.01) and EE (P < 0.005) in middle-aged mice, restoring the levels to that observed in young animals. Results from this study identify orexin neurons as potential therapeutic targets for age-related impairments in cognitive and anxiety-related behavior, and energy balance.

Housing conditions modulate spontaneous physical activity, feeding behavior, aerobic running capacity and adiposity in C57BL/6J mice.

There is evidence of reduced adiposity in rodents living in a large cages (LC) as compared to animals housed in small cages (SC). Because spontaneous physical activity (SPA) provides an important portion of the total daily energy expenditure, an increase of SPA in rodents kept in LC could explain their reduced body fat accumulation. The relationship between SPA and components of physical fitness (i.e. aerobic and anaerobic fitness and body leanness) has not been previously determined. We examined the effects of eight weeks of LC exposure on SPA, body composition, feeding behavior, as well as aerobic and anaerobic running capacity in adult C57BL/6J mice. Male mice were housed in cages of two different sizes for 8 weeks: a small (SC, n = 10) and large (LC n = 10) cages with 1320 cm2 and 4800 cm2 floor space, respectively. SPA was measured gravimetrically, and food and water intake were recorded daily. Mice had critical velocity (CV) and anaerobic running capacity (ARC) evaluated at the beginning, middle course (4th week) and at the end of study (8th week). Despite non-significant differences in each week LC-mice were more active than SC-mice by considering all SPA values obtained in the entire period of 8 weeks. The difference in SPA over the whole day was mainly due to light phase activity, but also due to activity at dark period (from 6 pm to 9 pm and from 5 am to 6 am). LC-mice also exhibited higher food and water intake over the entire 8-wk period. LC-mice had lower content of fat mass (% of the eviscerated carcass) than SC-mice (SC: 8.4 ±â€¯0.4 vs LC: 6.3 ±â€¯0.3, p < 0.05). LC-mice also exhibited reduced epididymal fat pads (% of body mass) compared to SC-mice (SC: 1.3 ±â€¯0.1 vs LC: 0.9 ±â€¯0.1, p < 0.05) and retroperitoneal fat pads (SC: 0.4 ±â€¯0.05 vs LC: 0.2 ±â€¯0.02, p < 0.05). The LC-group showed significantly higher critical velocity than SC-group at the fourth week (SC: 14.9 ±â€¯0.6 m·min-1 vs LC: 18.0 ±â€¯0.3 m·min-1, p < 0.05) and eighth week (SC: 17.1 ±â€¯0.5 m·min-1 vs LC: 18.8 ±â€¯0.6 m·min-1, p < 0.05). Our findings demonstrate that eight weeks of LC housing increases SPA of C57BL/6J mice, and this may lead to reduced fat accumulation as well as higher aerobic fitness. Importantly, our study implies that SC limits SPA, possibly generating experimental artifacts in long-term rodent studies.

Impact of dietary macronutrient profile on feline body weight is not consistent with the protein leverage hypothesis.

The protein leverage hypothesis proposes that the need to prioritise protein intake drives excess energy intake (EI) when the dietary ratio of protein to fat and carbohydrate is reduced. We hypothesised that cats may become prone to overconsuming energy content when moderate protein diets were offered, and considered the potential influence of fat and carbohydrate on intake. To determine the effect of dietary protein and macronutrient profile (MNP) on EI, weight and body composition, cats (1-4 years) were offered food in excess of energy requirements (ER). A total of six diets were formulated, containing moderate (approximately 7 % w/w; approximately 22 % metabolisable energy (ME)) or high (approximately 10 % w/w; approximately 46 % ME) protein and varying levels of carbohydrate and fat. For 4 weeks, 120 cats were offered 100 % of their individual ER of a diet at the MNP selected by adult cats (50:40:10 protein energy ratio:fat energy ratio:carbohydrate energy ratio). EI, body weight (BW), body composition, activity and palatability were measured. Subsequently, cats were offered one of the six diets at 200 % of their individual ER for 4 weeks when measurements were repeated. Cats offered excess high protein diets had higher EI (kJ/kg) throughout, but at 4 weeks BW was not significantly different to baseline. Cats offered excess moderate protein diets reduced EI and gradually lost weight (average loss of 0·358 (99 % CI 0·388, 0·328) kg), irrespective of fat:carbohydrate and initial palatability. The data do not support the protein leverage hypothesis. Furthermore, cats were able to adapt intake of a wet diet with high protein in an overfeeding environment within 28 d.

Orexin signaling in rostral lateral hypothalamus and nucleus accumbens shell in the control of spontaneous physical activity in high- and low-activity rats.

Spontaneous physical activity (SPA) describes activity outside of formal exercise and shows large interindividual variability. The hypothalamic orexin/hypocretin peptides are key regulators of SPA. Orexins drive SPA within multiple brain sites, including rostral lateral hypothalamus (LH) and nucleus accumbens shell (NAcSh). Rats with high basal SPA (high activity, HA) show higher orexin mRNA expression and SPA after injection of orexin-A in rostral LH compared with low-activity (LA) rats. Here, we explored the contribution of orexin signaling in rostral LH and NAcSh to the HA/LA phenotype. We found that HA rats have higher sensitivity to SPA after injection of orexin-A in rostral LH, but not in NAcSh. HA and LA rats showed similar levels of orexin receptor expression in rostral LH, and activation of orexin-producing neurons after orexin-A injection in rostral LH. Also, in HA and LA rats, the coinjection of orexin-A in rostral LH and NAcSh failed to further increase SPA beyond the effects of orexin-A in rostral LH. Pretreatment with muscimol, a GABAA receptor agonist, in NAcSh potentiated SPA produced by orexin-A injection in rostral LH in HA but not in LA rats. Our results suggest that a feedback loop from orexin-responsive neurons in rostral LH to orexin neurons and a the NAcSh-orexin neuron-rostral LH circuit regulate SPA. Overall, our data suggest that differences in orexin sensitivity in rostral LH and its modulation by GABA afferents from NAcSh contribute to individual SPA differences.

Altered regulation of energy homeostasis in older rats in response to thyroid hormone administration.

Hyperthyroidism causes increased energy intake and expenditure, although anorexia and higher weight loss have been reported in elderly individuals with hyperthyroidism. To determine the effect of age on energy homeostasis in response to experimental hyperthyroidism, we administered 200 µg tri-iodothyronine (T3) in 7- and 27-mo-old rats for 14 d. T3 increased energy expenditure (EE) in both the young and the old rats, although the old rats lost more weight (147 g) than the young rats (58 g) because of the discordant effect of T3 on food intake, with a 40% increase in the young rats, but a 40% decrease in the old ones. The increased food intake in the young rats corresponded with a T3-mediated increase in the appetite-regulating proteins agouti-related peptide, neuropeptide Y, and uncoupling protein 2 in the hypothalamus, but no increase occurred in the old rats. Evidence of mitochondrial biogenesis in response to T3 was similar in the soleus muscle and heart of the young and old animals, but less consistent in old plantaris muscle and liver. Despite the comparable increase in EE, T3's effect on mitochondrial function was modulated by age in a tissue-specific manner. We conclude that older rats lack compensatory mechanisms to increase caloric intake in response to a T3-induced increase in EE, demonstrating a detrimental effect of age on energy homeostasis.

Effects of weight gain induced by controlled overfeeding on physical activity.

It is unclear whether physical activity changes following long-term overfeeding and in response to different dietary protein intakes. Twenty-five (16 males, 9 females) healthy adults (18-35 yr) with BMI ranging from 19 to 30 kg/m(2) enrolled in this inpatient study. In a parallel group design, participants were fed 140% of energy needs, with 5, 15, or 25% of energy from protein, for 56 days. Participants wore an RT3 accelerometer for at least 59 days throughout baseline and during overfeeding and completed 24-h whole room metabolic chamber assessments at baseline and on days 1, 14, and 56 of overfeeding and on day 57, when the baseline energy intake was consumed, to measure percent of time active and spontaneous physical activity (SPA; kcal/day). Changes in activity were also assessed by doubly labeled water (DLW). From accelerometry, vector magnitude (VM), a weight-independent measure of activity, and activity energy expenditure (AEE) increased with weight gain during overfeeding. AEE remained increased after adjusting for changes in body composition. Activity-related energy expenditure (AREE) from DLW and percent activity and SPA in the metabolic chamber increased with overfeeding, but SPA was no longer significant after adjusting for change in body composition. Change in VM and AEE were positively correlated with weight gain; however, change in activity was not affected by protein intake. Overfeeding produces an increase in physical activity and in energy expended in physical activity after adjusting for changes in body composition, suggesting that increased activity in response to weight gain might be one mechanism to support adaptive thermogenesis.

Interactions between Lateral Hypothalamic Orexin and Dorsal Raphe Circuitry in Energy Balance.

Orexin/hypocretin terminals innervate the dorsal raphe nucleus (DRN), which projects to motor control areas important for spontaneous physical activity (SPA) and energy expenditure (EE). Orexin receptors are expressed in the DRN, and obesity-resistant (OR) rats show higher expression of these receptors in the DRN and elevated SPA/EE. We hypothesized that orexin-A in the DRN enhances SPA/EE and that DRN-GABA modulates the effect of orexin-A on SPA/EE. We manipulated orexin tone in the DRN either through direct injection of orexin-A or through the chemogenetic activation of lateral-hypothalamic (LH) orexin neurons. In the orexin neuron activation experiment, fifteen minutes prior to the chemogenetic activation of orexin neurons, the mice received either the GABA-agonist muscimol or antagonist bicuculline injected into the DRN, and SPA/EE was monitored for 24 h. In a separate experiment, orexin-A was injected into the DRN to study the direct effect of DRN orexin on SPA/EE. We found that the activation of orexin neurons elevates SPA/EE, and manipulation of GABA in the DRN does not alter the SPA response to orexin neuron activation. Similarly, intra-DRN orexin-A enhanced SPA and EE in the mice. These results suggest that orexin-A in the DRN facilitates negative energy balance by increasing physical activity-induced EE, and that modulation of DRN orexin-A is a potential strategy to promote SPA and EE.

Secular trends and determinants of ad libitum energy intake measured in a research setting from 1999-2020.

Introduction: Historically, secular and seasonal trend analyses have been examined using self-report measures of intake. Rarely are objective measures and known determinants of dietary intake used in these analyses. Our objective was to quantify the seasonal and secular differences in an objective ad libitum intake paradigm while considering the contribution of determinants, such as fat-free mass (FFM) index and spontaneous physical activity (SPA) limited to the restricted space of a whole-room calorimeter. Methods: For this study, recruitment of N = 292 healthy, diabetes free, adults occurred from 1999 to 2020. Assessment during their 10-day stay included body composition (by DXA), SPA (by an approximately 24-h stay in whole-room calorimetry), and ad libitum intake (by a vending machine for 3 days). This secondary analysis used general linear models (GLM) to investigate secular and seasonal differences while adjusting for sex, age, FFM index, FM (fat mass) index, SPA, and race/ethnicity. Results: FFM index and SPA were positively associated with all intake measures (p < 0.05). In all adjusted seasonal models, season did not affect intake. Adjusted secular trends models (kcals/year) demonstrated a decrease in total kcals (ß = -55), intake as percent weight maintaining energy needs (ß = -2), protein kcals (ß = -10), fat kcals (ß = -27), and carbohydrates kcals (ß = -22) (all p < 0.05). After further adjustment for SPA, significance remained in all intake measures (p < 0.05). Secular trends in body composition revealed no changes in weight, BMI, and percent body fat (all p > 0.20). Discussion: Our results indicate that over time, ad libitum intake decreased in this controlled research setting and remained significant even after accounting for positive determinants of intake. A significant ad libitum decrease, coupled with no change in body composition, may highlight a participant bias toward calorie restriction in a controlled setting over time and deserves further investigation.

Effects of food restriction on voluntary wheel-running behavior and body mass in selectively bred High Runner lines of mice.

Food restriction can have profound effects on various aspects of behavior, physiology, and morphology. Such effects might be amplified in animals that are highly active, given that physical activity can represent a substantial fraction of the total daily energy budget. More specifically, some effects of food restriction could be associated with intrinsic, genetically based differences in the propensity or ability to perform physical activity. To address this possibility, we studied the effects of food restriction in four replicate lines of High Runner (HR) mice that have been selectively bred for high levels of voluntary wheel running. We hypothesized that HR mice would respond differently than mice from four non-selected Control (C) lines. Healthy adult females from generation 65 were housed individually with wheels and provided access to food and water ad libitum for experimental days 1-19 (Phase 1), which allowed mice to attain a plateau in daily running distances. Ad libitum food intake of each mouse was measured on days 20-22 (Phase 2). After this, each mouse experienced a 20 % food restriction for 7 days (days 24-30; Phase 3), and then a 40 % food restriction for 7 additional days (days 31-37; Phase 4). Mice were weighed on experimental days 1, 8, 9, 15, 20, and 23-37 and wheel-running activity was recorded continuously, in 1-minute bins, during the entire experiment. Repeated-measures ANOVA of daily wheel-running distance during Phases 2-4 indicated that HR mice always ran much more than C, with values being 3.29-fold higher during the ad libitum feeding trial, 3.58-fold higher with -20 % food, and 3.06-fold higher with -40 % food. Seven days of food restriction at -20 % did not significantly reduce wheel-running distance of either HR (-5.8 %, P = 0.0773) or C mice (-13.3 %, P = 0.2122). With 40 % restriction, HR mice showed a further decrease in daily wheel-running distance (P = 0.0797 vs. values at 20 % restriction), whereas C mice did not (P = 0.4068 vs. values at 20 % restriction) and recovered to levels similar to those on ad libitum food (P = 0.3634). For HR mice, daily running distances averaged 11.4 % lower at -40 % food versus baseline values (P = 0.0086), whereas for C mice no statistical difference existed (-4.8 %, P = 0.7004). Repeated-measures ANOVA of body mass during Phases 2-4 indicated a highly significant effect of food restriction (P = 0.0001), but no significant effect of linetype (P = 0.1764) and no interaction (P = 0.8524). Both HR and C mice had a significant reduction in body mass only when food rations were reduced by 40 % relative to ad libitum feeding, and even then the reductions averaged only -0.60 g for HR mice (-2.6 %) and -0.49 g (-2.0 %) for C mice. Overall, our results indicate a surprising insensitivity of body mass to food restriction in both high-activity (HR) and ordinary (C) mice, and also insensitivity of wheel running in the C lines of mice, thus calling for studies of compensatory mechanisms that allow this insensitivity.

Significance of variation in basal metabolic rate in laboratory mice for translational experiments.

The basal metabolic rate (BMR) accounts for 60-70% of the daily energy expenditure (DEE) in sedentary humans and at least 50% of the DEE in laboratory mice in the thermoneutral zone. Surprisingly, however, the significance of the variation in the BMR is largely overlooked in translational research using such indices as physical activity level (PAL), i.e., the ratio of DEE/BMR. In particular, it is unclear whether emulation of human PAL in mouse models should be carried out within or below the thermoneutral zone. It is also unclear whether physical activity within the thermoneutral zone is limited by the capacity to dissipate heat generated by exercise and obligatory metabolic processes contributing to BMR. We measured PAL and spontaneous physical activity (SPA) in laboratory mice from two lines, divergently selected towards either high or low level of BMR, and acclimated to 30 °C (i.e., the thermoneutral zone), 23 or 4 °C. The mean PAL did not differ between both lines in the mice acclimated to 30 °C but became significantly higher in the low BMR mouse line at the lower ambient temperatures. Acclimation to 30 °C reduced the mean locomotor activity but did not affect the significant difference observed between the selected lines. We conclude that carrying out experiments within the thermoneutral zone can increase the consistency of translational studies aimed at the emulation of human energetics, without affecting the variation in physical activity correlated with BMR.

Early-life mice housed in standard stocking density reduce the spontaneous physical activity and increase visceral fat deposition before reaching adulthood.

Laboratory rodents spend the entire day housed in standard cages that provide a restricted area for movements and might, therefore, limit physical activity. However, it has not been tested in immature rodents of ages ranging from weaning to adulthood (adolescence period) whether the restricted area per animal does actually reduce physical activity and impact the body composition. We analyzed the spontaneous physical activity and feeding behavior during the adolescence of mice kept in two different housing conditions (standard stocking density (SSD) versus low stocking density (LSD)). We aimed to compare the body composition between SSD and LSD groups before they reached adulthood. Differential housing began at four weeks of age and was maintained for four weeks until euthanasia at eight weeks of age. The SSD group had a floor space of 88 cm2 available per animal, while LSD mice were housed with a floor space of 320 cm2 per animal, increasing the individual radius for movement more than three-fold compared with standard requirements. Mice kept in SSD exhibit lower spontaneous physical activity than mice kept in LSD. Early-life exposure to reduced physical activity in mice housed in SSD resulted in greater visceral fat accumulation before adulthood. An environment enabling/stimulating physical activity should be established for rodents as early as possible. This study will be helpful in showing that mice kept in SSD are early exposed to a reduced physical activity already in the adolescence period. Our findings could raise reflections about the translatability of rodents kept in SSD to healthy active humans.

Physical Activity and Inhibition of ACE Additively Modulate ACE/ACE-2 Balance in Heart Failure in Mice.

Angiotensin-converting enzyme inhibition (ACE-I) and physical activity favorably modulate the ACE/ACE-2 balance. However, it is not clear whether physical activity and ACE-I could synergistically modulate ACE/ACE-2 balance in the course of heart failure (HF). Here, we studied the effects of combined spontaneous physical activity and ACE-I-based treatment on angiotensin (Ang) pattern and cardiac function in a mouse model of HF (Tgαq*44). Tgαq*44 mice with advanced HF (at the age of 12 months) were running spontaneously in a running wheel (exercise training group, ExT) and/or were treated with ACE inhibitor (ACE-I, perindopril, 10 mg/kg) for 2 months. Angiotensin profile was characterized by an LC-MS/MS-based method. The cardiac performance was assessed in vivo by MRI. Ang-(1-7)/Ang II ratio in both plasma and the aorta was significantly higher in the combined treatment group than the ACE-I group or ExT alone, suggesting the additive favorable effects on ACE-2/Ang-(1-7) and ACE/Ang II axes' balance induced by a combination of ACE-I with ExT. The basal cardiac performance did not differ among the experimental groups of Tgαq*44 mice. We demonstrated additive changes in ACE/ACE-2 balance in both plasma and the aorta by spontaneous physical activity and ACE-I treatment in Tgαq*44 mice. However, these changes did not result in an improvement of failing heart function most likely because the disease was at the end-stage. Ang-(1-7)/Ang II balance represents a valuable biochemical end point for monitoring therapeutic intervention outcome in heart failure.

The Central Role of Hypothermia and Hyperactivity in Anorexia Nervosa: A Hypothesis.

Typically, the development of anorexia nervosa (AN) is attributed to psycho-social causes. Several researchers have recently challenged this view and suggested that hypothermia and hyperactivity (HyAc) are central to AN. The following hypothesis will attempt to clarify their role in AN. Anorexia nervosa patients (ANs) have significantly lower core temperatures (Tcore) compared to healthy controls (HCs). This reduced temperature represents a reset Tcore that needs to be maintained. However, ANs cannot maintain this Tcore due primarily to a reduced basal metabolic rate (BMR); BMR usually supplies heat to sustain Tcore. Therefore, to generate the requisite heat, ANs revert to the behavioral-thermoregulatory strategy of HyAc. The majority of ANs (~89%) are reportedly HyAc. Surprisingly, engagement in HyAc is not motivated by a conscious awareness of low Tcore, but rather by the innocuous sensation of "cold- hands" frequently reported by ANs. That is, local hand-thermoreceptors signal the brain to initiate HyAc, which boosts perfusion of the hands and alters the sensation of "cold-discomfort" to one of "comfort." This "rewarding" consequence encourages repetition/habit formation. Simultaneously, hyperactivity increases the availability of heat to assist with the preservation of Tcore. Additionally, HyAc induces the synthesis of specific brain neuromodulators that suppress food intake and further promote HyAc; this outcome helps preserve low weight and perpetuates this vicious cycle. Based on this hypothesis and supported by rodent research, external heat availability should reduce the compulsion to be HyAc to thermoregulate. A reduction in HyAc should decrease the production of brain neuromodulators that suppress appetite. If verified, hopefully, this hypothesis will assist with the development of novel treatments to aid in the resolution of this intractable condition.

Aerobic training associated with an active lifestyle exerts a protective effect against oxidative damage in hypothalamus and liver: The involvement of energy metabolism.

BACKGROUND: Oxidation resistance protein 1 (OXR1) is of scientific interest due its role in protecting tissues against oxidative stress, DNA mutations and tumorigenesis, but little is known regarding strategies to increase OXR1 in different tissues. As an improved antioxidant defense may result from a high total amount of physical activity, the present study was designed to determine whether an active lifestyle including aerobic training exercise and spontaneous physical activity (SPA) can increase OXR1. We have built a large cage (LC) that allows animals to move freely, promoting an increase in SPA in comparison to a small cage (SC). METHODS: We examined the effects of aerobic training applied for 8 weeks on SPA and OXR1 of C57BL/6 J mice living in two types of housing (SC and LC). OXR1 protein was studied in hypothalamus, muscle and liver, which were chosen due to their important role in energy and metabolic homeostasis. RESULTS: LC-mice were more active than SC-mice as determined by SPA values. Despite both trained groups exhibiting similar gains in aerobic capacity, only trained mice kept in a large cage (but not for trained mice housed in SC) exhibited high OXR1 in the hypothalamus and liver. Trained mice housed in LC that exhibited an up-regulation of OXR1 also were those who exhibited an energy-expensive metabolism (based on metabolic parameters). CONCLUSIONS: These results suggest that aerobic training associated with a more active lifestyle exerts a protective effect against oxidative damage and may be induced by changes in energy metabolism.

Mice selectively bred for high voluntary wheel-running behavior conserve more fat despite increased exercise.

Physical activity is an important component of energy expenditure, and acute changes in activity can lead to energy imbalances that affect body composition, even under ad libitum food availability. One example of acute increases in physical activity is four replicate, selectively-bred High Runner (HR) lines of mice that voluntarily run ~3-fold more wheel revolutions per day over 6-day trials and are leaner, as compared with four non-selected control (C) lines. We expected that voluntary exercise would increase food consumption, build lean mass, and reduce fat mass, but that these effects would likely differ between HR and C lines or between the sexes. We compared wheel running, cage activity, food consumption, and body composition between HR and C lines for young adults of both sexes, and examined interrelationships of those traits across 6 days of wheel access. Before wheel testing, HR mice weighed less than C, primarily due to reduced lean mass, and females were lighter than males, entirely due to lower lean mass. Over 6 days of wheel access, all groups tended to gain small amounts of lean mass, but lose fat mass. HR mice lost less fat than C mice, in spite of much higher activity levels, resulting in convergence to a fat mass of ~1.7 g for all 4 groups. HR mice consumed more food than C mice (with body mass as a covariate), even accounting for their higher activity levels. No significant sex-by-linetype interactions were observed for any of the foregoing traits. Structural equation models showed that the four sex-by-linetype groups differed considerably in the complex phenotypic architecture of these traits. Interrelationships among traits differed by genetic background and sex, lending support to the idea that recommendations regarding weight management, diet, and exercise may need to be tailored to the individual level.

Data on COA-Cl administration to the APP/PS2 double-transgenic mouse model of Alzheimer׳s disease: Improved hippocampus-dependent learning and unchanged spontaneous physical activity.

We herein present behavioral data regarding whether COA-Cl, a novel adenosine-like nucleic acid analog that promotes angiogenesis and features neuroprotective roles, improves cognitive and behavioral deficits in a murine model for Alzheimer׳s disease (AD). COA-Cl induced significant spatial memory improvement in the amyloid precursor protein/presenilin 2 double-transgenic mouse model of AD (PS2Tg2576 mice). Correspondingly, non-spatial novel object cognition test performance also significantly improved in COA-Cl-treated PS2Tg2576 mice; however, these mice demonstrated no significant changes in physical activity or motor performance. COA-Cl did not change the spontaneous activities and cognitive ability in the wild-type mice.