Effects Of Exercise In Mice Research Articles

Moderate-intensity interval exercise exacerbates cardiac lipotoxicity in high-fat, high-calories diet-fed mice

Physical exercise is a cornerstone for preventing diet-induced obesity, while it is unclear whether physical exercise could offset high-fat, high-calories diet (HFCD)-induced cardiac dysfunction. Here, mice were fed with HFCD and simultaneously subjected to physical exercise. As expected, physical exercise prevented HFCD-induced whole-body fat deposition. However, physical exercise exacerbated HFCD-induced cardiac damage. Further metabolomic analysis results showed that physical exercise induced circulating lipid redistribution, leading to excessive cardiac lipid uptake and lipotoxicity. Our study provides valuable insights into the cardiac effects of exercise in mice fed with HFCD, suggesting that counteracting the negative effect of HFCD by simultaneous physical exercise might be detrimental. Moreover, inappropriate physical exercise may damage certain organs even though it leads to weight loss and overall metabolic benefits. Of note, the current findings are based on animal experiments, the generalizability of these findings beyond this specific diet and mouse strain remains to be further explored.

Exercise-induced benefits on glucose handling in a model of diet-induced obesity are reduced by concurrent nicotinamide mononucleotide.

Almost 40% of adults worldwide are classified as overweight or obese. Exercise is a beneficial intervention in obesity, partly due to increases in mitochondrial activity and subsequent increases in nicotinamide adenine dinucleotide (NAD+), an important metabolic cofactor. Recent studies have shown that increasing NAD+ levels through pharmacological supplementation with precursors such as nicotinamide mononucleotide (NMN) improved metabolic health in high-fat-diet (HFD)-fed mice. However, the effects of combined exercise and NMN supplementation are unknown. Thus, here we examined the combined effects of NMN and treadmill exercise in female mice with established obesity after 10 wk of diet. Five-week-old female C57BL/6J mice were exposed to a control diet (n = 16) or HFD. Mice fed a HFD were either untreated (HFD; n = 16), received NMN in drinking water (400 mg/kg; HNMN; n = 16), were exposed to treadmill exercise 6 days/wk (HEx; n = 16), or were exposed to exercise combined with NMN (HNEx; n = 16). Although some metabolic benefits of NMN have been described, at this dose, NMN administration impaired several aspects of exercise-induced benefits in obese mice, including glucose tolerance, glucose-stimulated insulin secretion from islets, and hepatic triglyceride accumulation. HNEx mice also exhibited increased antioxidant and reduced prooxidant gene expression in both islets and muscle, suggesting that altered redox status is associated with the loss of exercise-induced health benefits with NMN cotreatment. Our data show that NMN treatment impedes the beneficial metabolic effects of exercise in a mouse model of diet-induced obesity in association with disturbances in redox metabolism.NEW & NOTEWORTHY NMN dampened exercise-induced benefits on glucose handling in diet-induced obesity. NMN administration alongside treadmill exercise enhanced the ratio of antioxidants to prooxidants. We suggest that NMN administration may not be beneficial when NAD+ levels are replete.

Voluntary wheel running: patterns and physiological effects in mice.

Exercise can prevent and improve the pathophysiology of diseases and promote healthy aging. Thus, understanding the mechanisms that regulate the beneficial effects of exercise may lead to the development of new strategies to enhance quality of life and to counteract chronic diseases. Voluntary wheel running is an interesting model to study the effects of exercise in mice. Compared to forced treadmill exercise, voluntary wheel running presents several advantages such as: 1) running pattern is similar to natural running behavior of mice; 2) it is performed under non-stressed conditions, according to the rhythmicity of the animal; 3) it does not require direct interference from the researcher, and can be easily applied in long-term studies. Mice run spontaneously when given access to running wheels, for a total distance of ∼4 to 20 km per day and a total activity time of ∼3 to 7 hours a day. Hence, voluntary wheel running can result in robust endurance-like adaptation in skeletal and cardiac muscles and protect from sarcopenia. However, due to the lack of control over exercise parameters in voluntary exercise models, it is important for the researcher to understand the patterns and variability of wheel running in mice, as well as the factors that can affect voluntary running activity. Overall, voluntary wheel running in mice is a very interesting approach to study the chronic adaptation to exercise, analyze the effects of exercise, and test exercise capacity in different experimental models.

FGF-21 as a Potential Mediator for the Antidepressant Effects of Physical Exercise

Major depressive disorder (MDD), a common psychiatric disease co-morbid with obesity and diabetes, has been one of the most important causes of disability worldwide. Physical exercise by far, is the most effective strategy for the prevention and treatment of MDD. Fibroblast growth factor 21 (FGF-21) is critically involved in energy metabolism and a potential therapeutic agent for treating obesity and its related medical complications. Although the brain is known to be a target of FGF-21 actions, its role in neuropsychological disorders remain unclear. Here, we showed that serum FGF-21 increased progressively with physical exercise and peaked at 3 hours after running, which was 1-2 hours later than that of free fatty acids, suggesting that increased free fatty acids might be the natural agonist of PPARα that induces FGF-21 production during exercise. Real-time PCR analysis further demonstrated that exercise-induced elevation of circulating FGF-21 was predominately from the liver. Furthermore, a series of behavior studies, including tail suspension test, forced swimming test and saccharin preference test uniformly showed that exercise training significantly alleviated depressive symptoms in wild type (WT) mice, which were largely diminished in FGF-21 knockout (KO) mice. Likewise, levels of inflammation markers in the hippocampus were significantly decreased, while synaptic plasticity were notably increased in exercised WT, but not in FGF-21 KO mice, suggesting that inhibition of neuroinflammation and neurogenesis might contribute to the antidepressant effects of FGF-21 during exercise. In conclusion, FGF-21 is a liver-derived exercise responsive factor mediating the anti-depressant effect of exercise in mice. Disclosure Y. Liu: None. S. Yau: None. Y. Wang: None. A. Xu: None.

0311 : Physical exercise regulates angiogenesis in adipose tissue of dietinduced obese mice thru ECSCR/Akt pathways

Reduced capillary density in adipose tissue is associated with obesity and results in decrease perfusion, decreased oxygen consumption and insulin resistance. Pro- (VEGF-A) and anti-angiogenic (TSP-1) factors expression is central determinant of angiogenesis, with greater VEGF-A/TSP-1 ratio promoting angiogenesis. Since endothelial cells are involved in the pathogenesis of insulin resistance through their role in insulin delivery and adipose tissue angiogenesis, we investigated the role of ECSCR (endothelial cell surface expressed chemotaxis and apoptosis regulator) – Akt axis. In this context, we studied effects of voluntary exercise in mice fed with a high fat diet (HFD) on the AT vascularization. We have demonstrated that 7 weeks-exercise training reduced epididymal and subcutaneous white adipose tissue (eWAT) and (sWAT) mass by 33% and 45% respectively compared to sedentary HFD mice and stimulated capillary growth in AT with a significant increased of capillaries/ adipocyte ratio on eWAT and sWAT (+16% and 28% respectively), associated with a significant VEGF-A/TSP-1 expression ratio increase. Furthermore, while ECSCR protein expression was decreased and associated to a lower ratio of PhosphoAkt/Akt in eWAT and sWAT of HFD mice in comparison to control mice, 7 weeks-exercise training led to a significant increase of ECSCR protein expression associated to the raise of PhosphoAkt/Akt ratio in both eWAT and sWAT. In addition, eWAT and sWAT thermogenic and metabolic activities were stimulated by 7 weeks-exercise training, with increased PGC-1α, Sirt-3 and PPARα in comparison to eWAT and sWAT from sedentary HFD mice. In conclusion, our results indicate that physical exercise acts as a pro-angiogenic stimulus in AT in favor of capillary growth, and that ECSCR – Akt axis as well as VEGF-A/TSP-1 play central role in angioadaptation of AT. The author hereby declares no conflict of interest

0230 : Physical exercise angio-adaptation ameliorates metabolic dysfunction and inflammation in visceral adipose tissue of diet-induced obese mice

Adipose tissue (AT) homeostasis and growth are dependent on microvasculature. Adipose capillary bed displays a remarkable plasticity, a process called tissue angio-adaptation. In response to metabolic alterations linked to obesity, signaling pathways involved in vascular and microenvironment homeostasis maintenance of AT appear to be affected. We demonstrated that Mdm-2/FoxO1 axis had a key role in muscle angio-adaptive response to exercise affecting pro- (VEGF-A) and anti-angiogenic (TSP-1) factors expression. However, regulation of this process in AT occurring during obesity and/or physical exercise remains unknown. In this context, we studied effects of voluntary exercise in mice fed with a high fat diet (HFD) on the AT vascularization and microenvironment. Trained HFD mice after 7 week-exercise showed a 30% lower body fat mass and 33% reduced epididymal white adipose tissue (eWAT) mass compared to sedentary HFD mice. Histological analysis of eWAT revealed a decreased adipocyte size (-26%) combined with reduced fibrotic area per adipocyte (-45%) in trained HFD vs. sedentary HFD mice. Furthermore, 7 weeks of exercise training of HFD mice stimulated the angiogenesis process in AT with significant increased of capillaries/adipocyte ratio on eWAT (+16%) associated to VEGF-A/TSP-1 expression ratio and Mdm 2 protein expression while FoxO1 protein was decreased. In addition, eWAT inflammatory status evaluated by mRNA analysis indicated that CD11c (M1 macrophage marker), TNFα, IL-6 and leptin (pro-inflammatory cytokines) levels were decreased by 65%, 45% and 55% respectively in comparison to eWAT from sedentary HFD mice. A concomitant increase in Chil3 (M2 macrophage marker) (+84%) and IL-10 (anti-inflammatory cytokine) (+29%) were also observed. In conclusion, our results show that physical exercise acts as a pro-angiogenic stimulus in AT in favor of capillary growth, thru activation of Mdm 2 – FoxO1 and rise of VEGF-A/TSP-1 ratio ultimately promoting an improvement of AT microenvironment by reducing fibrosis, adipocyte hypertrophy and inflammation. The author hereby declares no conflict of interest

(362) The effects of voluntary wheel running on pain

Chronic pain is a major public health problem, afflicting more of the general population than cardiovascular disease, diabetes, and cancer combined. Despite the prevalence of chronic pain, clinically prescribed analgesics with high efficacy often have undesirable off-target effects. Exercise is commonly prescribed to chronic pain patients and gives rise to analgesia in some cases. Preclinical animal models support a conserved mechanism for exercise-induced analgesia as exercise attenuates hypersensitivity in rodent inflammatory and neuropathic pain models. The cellular mechanisms that mediate the therapeutic effects of exercise are not well characterized, though a role for neurotrophic factors has been suggested. Exercise significantly increases neurotrophic factor levels in the central nervous system, and in turn, is associated with enhanced functional plasticity. We hypothesize that analogous changes in the peripheral nervous system underlie exercise-induced analgesia. Understanding these mechanisms may aid development of novel analgesics. To investigate the behavioral effects of exercise in mice, we are testing the effects of voluntary wheel running on thermal and mechanical sensitivity and in acute pain models, as compared to sedentary control animals. To elucidate the cellular mechanisms underlying the effects of exercise, neurotrophic factor levels in dorsal root ganglia and spinal cord are being quantified biochemically as candidate signaling molecules involved in exercise-induced analgesia. These studies will enhance our understanding of both the molecular effects exercise, and more broadly, our comprehension of pain modulation. Supported by NINDS grant R01NS042595. Chronic pain is a major public health problem, afflicting more of the general population than cardiovascular disease, diabetes, and cancer combined. Despite the prevalence of chronic pain, clinically prescribed analgesics with high efficacy often have undesirable off-target effects. Exercise is commonly prescribed to chronic pain patients and gives rise to analgesia in some cases. Preclinical animal models support a conserved mechanism for exercise-induced analgesia as exercise attenuates hypersensitivity in rodent inflammatory and neuropathic pain models. The cellular mechanisms that mediate the therapeutic effects of exercise are not well characterized, though a role for neurotrophic factors has been suggested. Exercise significantly increases neurotrophic factor levels in the central nervous system, and in turn, is associated with enhanced functional plasticity. We hypothesize that analogous changes in the peripheral nervous system underlie exercise-induced analgesia. Understanding these mechanisms may aid development of novel analgesics. To investigate the behavioral effects of exercise in mice, we are testing the effects of voluntary wheel running on thermal and mechanical sensitivity and in acute pain models, as compared to sedentary control animals. To elucidate the cellular mechanisms underlying the effects of exercise, neurotrophic factor levels in dorsal root ganglia and spinal cord are being quantified biochemically as candidate signaling molecules involved in exercise-induced analgesia. These studies will enhance our understanding of both the molecular effects exercise, and more broadly, our comprehension of pain modulation. Supported by NINDS grant R01NS042595.

EXERCISE TRAINING REVERSES THE DELETERIOUS EFFECT OF SUCROSE INTAKE ON INSULIN RESISTANCE AND VISCERAL FAT MASS DEPOSITION ON MICE

Abnormal fat deposition has been identified as an i mportant mechanism of obesity-associated with insulin resistance. Literature data also indicate that exer cise can improve insulin action. The heme pathway enzyme δAminolevulinate Dehydratase (δ-ALA-D) is a good marker for oxidative stress and t his sulfhydryl enzyme is inhibited in such oxidative pathologies diabetes. T he aim of this study was to evaluate the effects of physical exercise in mice fed high sucrose (20% in drinking water), on aspects of insulin resistance, profile o f oxidative status in different tissues and influence on δ-ALA-D activity. Glucose (p<0.003), insulin (p<0.01) plasma levels and abdominal fat index (p<0.001) were signi ficantly higher in mice fed the sucrose in the wate r when compared to control group. Not have difference on t hese parameters between exercised mice fed the sucrose and control group. Hepatic, ALA-D activity and TBARS from liver, kidney and brain, of sucrose fed animals with and without exercise were not different than t hat of control group. The results of the present st udy possibly indicate that the sucrose administration i n the water, cause marked insulin resistance and th at the physical exercise showed efficient in increase insu lin sensibility in mice with insulin resistance.

Reply

Nonalcoholic fatty liver disease (NAFLD) is a potentially progressive liver disease associated with hepatic insulin resistance. Although a cause-effect relationship between NAFLD and insulin resistance has not yet been confirmed, it is generally accepted that NAFLD is a hepatic component of the metabolic syndrome and an independent risk factor for the development of type 2 diabetes.1, 2 Several therapeutic approaches such as antioxidants, insulin sensitizers, and lipid-lowering agents have been tested for the treatment of NAFLD. Although a weight-reducing diet in overweight patients has proved effective, no therapeutic regime has proven effective to date.3 In our recent article “Peroxisome Proliferator-Activated Receptor-delta Induces Insulin-Induced Gene-1 and Suppresses Hepatic Lipogenesis in Obese Diabetic Mice,” we demonstrated that peroxisome proliferator-activated receptor-δ (PPAR-δ) suppressed the activation of sterol regulatory element-binding protein-1 via transactivation of insulin-induced gene-1 and consequently reduced lipogenesis in cultured human hepatocytes as well as in the liver of obese diabetic mice.4 These results revealed a novel mechanism by which PPAR-δ regulates lipid metabolism. Following the publication of our article, Sharma et al. expressed their interest and concern about transforming the results from basic research into clinical practice. We generally agree with the comment from Sharma et al. that the results from basic research have to be translated into clinical practice with caution. They note that targeting a single PPAR-δ gene has a limitation, because the metabolic syndrome is an outcome of complex interaction between numerous hereditary and environmental factors and thus needs to be treated holistically. This is in line with the concept of polypill. In fact, emerging evidence shows that PPAR-δ agonists have plural effects on multiple components of the metabolic syndrome. For example, PPAR-δ agonists have been reported to increase plasma levels of high-density lipoprotein, boost fatty acid oxidation in skeletal muscle, and improve insulin sensitivity. Furthermore, PPAR-δ agonists have a suppressive effect on inflammation, which is also an important feature of hepatic steatosis. Most recently, PPAR-δ agonist has been reported to mimic and potentiate the effects of exercise in mice.5 Taken together, these results point to a potential of PPAR-δ in treating the metabolic syndrome and NAFLD. We also agree with Sharma et al. in that discrepancies may exist between the results from rodents and humans. In addition, as they suggested, using human hepatic cell lines from patients with fatty liver will be a more ideal system to further stringently examine the relevance of the mechanism to NAFLD. Notably, consistent with our results in obese diabetic mice, a recent clinical trial demonstrated that the PPAR-δ agonist significantly improved liver fat in obese men, indicating a potential benefit of PPAR-δ for NAFLD.6 We thank Sharma et al. for their comments and fully agree that clinical efficacy and safety can only be thoroughly assessed through strictly controlled clinical trials. Nanping Wang MD, PhD*, Yi Zhu MD , * Institute of Cardiovascular Science and Diabetes Center, Peking University Health Science Center, Beijing, China, Department of Physiology and Pathophysiology and Diabetes Center, Peking University Health Science Center, Beijing, China.