Microbiota influences host exercise capacity via modulation of skeletal muscle glucose metabolism in mice.

The microbiota enhances exercise performance and regulates host physiology and energy metabolism by producing beneficial metabolites via bacterial fermentation. In this study, we discovered that germ-free (GF) mice had a reduced capacity for aerobic exercise as well as low oxygen consumption rates and glucose availability. Surprisingly, GF mice showed lower body weight gain and lower fat mass than specific pathogen-free (SPF) mice. Therefore, we hypothesized that these paradoxical phenotypes could be mediated by a compensatory increase in lipolysis in adipose tissues owing to impaired glucose utilization in skeletal muscle. Our data revealed that gut microbiota depletion impairs host aerobic exercise capacity via the deterioration of glucose storage and utilization. The improved browning ability of GF mice may have contributed to the lean phenotype and negatively affected energy generation. These adaptations limit obesity in GF mice but impede their immediate fuel supply during exercise, resulting in decreased exercise performance.

Resistance exercise training-induced skeletal muscle strength provides protective effects on high-fat-diet-induced metabolic stress in mice.

BACKGROUND: Resistance exercise training is known to improve metabolic disorders, such as obesity and type2 diabetes. In this study, we investigated whether the beneficial effects of resistance exercise training persisted even after the discontinuation of training with high-fat diet (HFD)-induced metabolic stress. We further evaluated whether the improvement in skeletal muscle strength and endurance by training were correlated with improved metabolism. Eight-week-old male C57BL/6N mice were divided into groups that remained sedentary or had access to daily resistance exercise via ladder climbing for 8 weeks. Trained and untrained mice were fed an HFD for 1 week after the exercise training intervention (n = 5-8 per group). RESULTS: Resistance exercise-trained mice had a lean phenotype and counteracted diet-induced obesity and glucose tolerance, even after exercise cessation. Grip strength was significantly inversely correlated with the body weight, fat mass, and glucose tolerance. However, hanging time was significantly inversely correlated with body weight only. CONCLUSIONS: These results have strong implications for the preventive effect of resistance exercise-induced metabolic improvement by enhancing skeletal muscle strength rather than endurance.

YAP-dependent Wnt5a induction in hypertrophic adipocytes restrains adiposity.

Wnt5a, a prototypic non-canonical Wnt, is an inflammatory factor elevated in the sera of obese humans and mice. In the present study, fat-specific knockout of Wnt5a (Wnt5a-FKO) prevented HFD-induced increases in serum Wnt5a levels in male C57BL/6 J mice, which suggested adipocytes are primarily responsible for obesity-induced increases in Wnt5a levels. Mouse subcutaneous white adipose tissues (WATs) more sensitively responded to HFD, in terms of cell size increases and Wnt5a levels than epididymal WATs. Furthermore, adipocyte sizes were positively correlated with Wnt5a levels in vitro and in vivo. In hypertrophic adipocytes, enlarged lipid droplets increased cell stiffness and rearranged the f-actin stress fibers from the cytoplasm to the cortical region. The activities of YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif) increased in response to these mechanical changes in hypertrophic adipocytes, and inhibition or knock-down of YAP and TAZ reduced Wnt5a expression. ChIP (chromatin immunoprecipitation) analyses revealed that YAP was recruited by Wnt5a-1 gene promoter and increased Wnt5a expression. These results suggested that YAP responds to mechanical stress in hypertrophic adipocytes to induce the expression Wnt5a. When 8-week-old Wnt5a-FKO mice were fed an HFD for 20 weeks, the fat mass increased, especially in subcutaneous WATs, as compared with that observed in floxed mice, without significant changes in food intake or activity. Furthermore, Wnt5a-FKO mice showed impaired glucose tolerance regardless of diet type. Our findings show that hypertrophy/YAP/Wnt5a signaling constitutes a negative-feedback loop that retrains adipose tissue hypertrophy.

Aerobic exercise for eight weeks provides protective effects towards liver and cardiometabolic health and adipose tissue remodeling under metabolic stress for one week: A study in mice.

BACKGROUND: The relationship between exercise training and health benefits is under thorough investigation. However, the effects of exercise training on the maintenance of metabolic health are unclear. METHODS: Our experimental design involved initial exercise training followed by a high-fat diet (HFD) challenge. Eight-week-old male was trained under voluntary wheel running aerobic exercise for eight weeks to determine the systemic metabolic changes induced by exercise training and whether such changes persisted even after discontinuing exercise. The mice were given either a normal chow diet (NCD) or HFD ad libitum for one week after discontinuation of exercise (CON-NCD, n = 29; EX-NCD, n = 29; CON-HFD, n = 30; EX-HFD, n = 31). RESULTS: Our study revealed that metabolic stress following the transition to an HFD in mice that discontinued training failed to reverse the aerobic exercise training-induced improvement in metabolism. We report that the mice subjected to exercise training could better counteract weight gain, adipose tissue hypertrophy, insulin resistance, fatty liver, and mitochondrial dysfunction in response to an HFD compared with untrained mice. This observation could be attributed to the fact that exercise enhances the browning of white fat, whole-body oxygen uptake, and heat generation. Furthermore, we suggest that the effects of exercise persist due to PPARα-FGF21-FGFR1 mechanisms, although additional pathways cannot be excluded and require further research. Although our study suggests the preventive potential of exercise, appropriate human trials are needed to demonstrate the efficacy in subjects who cannot perform sustained exercise; this may provide an important basis regarding human health.

AMP-activated protein kinase activation in skeletal muscle modulates exercise-induced uncoupled protein 1 expression in brown adipocyte in mouse model.

Aerobic exercise is an effective intervention in preventing obesity and is also an important factor associated with thermogenesis. There is an increasing interest in the factors and mechanisms induced by aerobic exercise that can influence the metabolism and thermogenic activity in an individual. Recent studies suggest that exercise induced circulating factors (known as 'exerkines'), which are able to modulate activation of brown adipose tissue (BAT) and browning of white adipose tissue. However, the underlying molecular mechanisms associated with the effect of exercise-induced peripheral factors on BAT activation remain poorly understood. Furthermore, the role of exercise training in BAT activation is still debatable. Hence, the purpose of our study is to assess whether exercise training affects the expression of uncoupled protein 1 (UCP1) in brown adipocytes via release of different blood factors. Four weeks of exercise training significantly decreased the body weight gain and fat mass gain. Furthermore, trained mice exhibit higher levels of energy expenditure and UCP1 expression than untrained mice. Surprisingly, treatment with serum from exercise-trained mice increased the expression of UCP1 in differentiated brown adipocytes. To gain a better understanding of these mechanisms, we analysed the conditioned media obtained after treating the C2C12 myotubes with an AMP-activated protein kinase (AMPK) activator (AICAR; 5-aminoimidazole-4-carboxamide ribonucleotide), which leads to an increased expression of UCP1 when added to brown adipocytes. Our observations suggest the possibility of aerobic exercise-induced BAT activation via activation of AMPK in skeletal muscles. KEY POINTS: Exercise promotes thermogenesis by activating uncoupling protein 1 (UCP1), which leads to a decrease in the body weight gain and body fat content. However, little is known about the role of exerkines in modulating UCP1 expression and subsequent brown adipose tissue (BAT) activation. Four weeks of voluntary wheel-running exercise reduces body weight and fat content. Exercise induces the increase in AMP-activated protein kinase (AMPK) and slow-type muscle fibre marker genes in skeletal muscles and promotes UCP1 expression in white and brown adipose tissues. Incubation of brown adipocytes with serum isolated from exercise-trained mice significantly increased their UCP1 gene and protein levels; moreover, conditioned media of AMPK-activator-treated C2C12 myotubes induces increased UCP1 expression in brown adipocytes. These results show that aerobic exercise-induced skeletal muscle AMPK has a significant effect on UCP1 expression in BAT.

A comparison of the metabolic effects of treadmill and wheel running exercise in mouse model.

Aerobic exercise is well known to have a positive impact on body composition, muscle strength, and oxidative capacity. In animal model, both treadmill and wheel running exercise modalities have become more popular, in order to study physiological adaptation associated with aerobic exercise. However, few studies have compared physiological adaptations in response to either treadmill exercise (TE), or voluntary wheel running exercise (WE). We therefore compared each exercise intervention on body composition and oxidative markers in male C57BL/6 N mice. The total distance run was remarkably higher in the WE group than in the TE group. Both forms of exercise resulted in the reduction of body weight, fat mass, and adipocyte size. However, the average for grip strength of WE was higher than for control and TE. Interestingly, PGC-1α expression was increased in the gastrocnemius (glycolytic-oxidative) and soleus (oxidative) muscle of TE group, whereas WE showed a significant effect on PGC-1α expression only in the soleus muscle. However, muscle fiber type composition was not shifted remarkably in either type of exercise. These results suggest that TE and WE may exert beneficial effects in suppressing metabolic risks in mouse model through attenuating body weight, fat mass, size, and increase in mitochondria biogenesis marker, PGC-1α.

Metabolic dysfunction following weight regain compared to initial weight gain in a high-fat diet-induced obese mouse model.

Diet-induced weight loss and regain leads to physiological and metabolic changes, some of which are potentially harmful. However, the specific metabolic processes and dysfunctions associated with weight regain, and how they differ from initial weight gain, remain unclear. Thus, we examined the metabolic profiles of mice following weight regain compared to initial weight gain. Mice were fed a normal diet or a high-fat diet or were cycled between the two diets to alternate between obese and lean states. Liver samples were collected and hepatic metabolites were profiled using nuclear magnetic resonance (NMR). The identified metabolites associated with weight regain were quantified using gas chromatography/mass spectrometry (GC/MS) and lipid profiles were assessed using ultra-high-performance liquid chromatography-quadrupole time-of-flight MS (UPLC-QTOF-MS). In addition, changes in expression of pro-inflammatory cytokines and gluconeogenic enzymes were investigated using polymerase chain reaction (PCR) and western blotting, respectively. Hepatic levels of several amino acids were reduced in mice during weight regain compared with initial weight gain. In addition, gluconeogenic enzyme levels were increased following weight regain, indicating an up-regulation of gluconeogenesis. Lipidomic profiling revealed that levels of ceramide and sphingomyelin, which are related to obesity-induced inflammation, were significantly increased during weight regain compared to initial weight gain. Moreover, tumor necrosis factor-α (TNF-α) and transforming growth factor-ß1 (TGF-ß1) levels were significantly up-regulated during weight regain. In this study, weight regains lead to an up-regulation of gluconeogenesis and aggravated inflammation. Additionally, weight regain can worsen the metabolic dysfunction associated with obesity.

AHNAK deficiency promotes browning and lipolysis in mice via increased responsiveness to ß-adrenergic signalling.

In adipose tissue, agonists of the ß3-adrenergic receptor (ADRB3) regulate lipolysis, lipid oxidation, and thermogenesis. The deficiency in the thermogenesis induced by neuroblast differentiation-associated protein AHNAK in white adipose tissue (WAT) of mice fed a high-fat diet suggests that AHNAK may stimulate energy expenditure via development of beige fat. Here, we report that AHNAK deficiency promoted browning and thermogenic gene expression in WAT but not in brown adipose tissue of mice stimulated with the ADRB3 agonist CL-316243. Consistent with the increased thermogenesis, Ahnak(-/-) mice exhibited an increase in energy expenditure, accompanied by elevated mitochondrial biogenesis in WAT depots in response to CL-316243. Additionally, AHNAK-deficient WAT contained more eosinophils and higher levels of type 2 cytokines (IL-4/IL-13) to promote browning of WAT in response to CL-316243. This was associated with enhanced sympathetic tone in the WAT via upregulation of adrb3 and tyrosine hydroxylase (TH) in response to ß-adrenergic activation. CL-316243 activated PKA signalling and enhanced lipolysis, as evidenced by increased phosphorylation of hormone-sensitive lipase and release of free glycerol in Ahnak(-/-) mice compared to wild-type mice. Overall, these findings suggest an important role of AHNAK in the regulation of thermogenesis and lipolysis in WAT via ß-adrenergic signalling.

Estimation of the Infection Window for the 2010/2011 Korean Foot-and-Mouth Disease Outbreak.

OBJECTIVES: This study aims to develop a method for calculating infection time lines for disease outbreaks on farms was developed using the 2010/2011 foot-and-mouth disease (FMD) epidemic in the Republic of Korea. METHODS: Data on farm demography, the detection date of FMD, the clinical history for the manifestation of lesions, the presence of antibodies against FMD virus (including antibodies against the structural and nonstructural proteins of serotype O), vaccination status (O1 Manisa strain), the number of reactors and information on the slaughter of infected animals were utilized in this method. RESULTS: Based on estimates of the most likely infection date, a cumulative detection probability that an infected farm would be identified on a specific day was determined. Peak infection was observed between late December and early January, but peak detection occurred in mid-January. The early detection probability was highest for pigs, followed by cattle (dairy, then beef) and small ruminants. Nearly 90% of the infected pig farms were detected by Day 11 post-infection while 13 days were required for detection for both dairy and beef cattle farms, and 21 days were necessary for small ruminant (goat and deer) farms. On average, 8.1 ± 3.1 days passed prior to detecting the presence of FMD virus on a farm. The interval between infection and detection of FMD was inversely associated with the intensity of farming. CONCLUSION: The results of our study emphasize the importance of intensive clinical inspection, which is the quickest method of detecting FMD infection and minimizing the damage caused by an epidemic.

Korean red ginseng ameliorates acute 3-nitropropionic acid-induced cochlear damage in mice.

3-Nitropropionic acid (3-NP), a mitochondrial toxin, has been reported to induce an acute cochlear damage. Korean red ginseng (KRG) is known to have protective effects from some types of hearing loss. This study aimed to observe the protective effect of KRG in an ototoxic animal model using 3-NP intratympanic injection. BALB/c mice were classified into 5 groups (n=15) and dose-dependent toxic effects after intratympanic injection with 3-NP (300-5000 mM) on the left ear were investigated to determine the appropriate toxicity level of 3-NP. For observation of the protective effects of KRG, 23 mice were grouped into 3-NP (500 mM, n=12) and KRG+3-NP groups (300 mg/kg KRG for 7 days before 500 mM 3-NP administration, n=11). Auditory brain response (ABR) and cochlear morphological evaluations were performed before and after drug administration. The ABR thresholds in the 800-5000 mM groups exceeded the maximum recording limit at 16 and 32 kHz 1 day after 3-NP administration. The ABR threshold in the 500 mM 3-NP+KRG group was significantly lower than that in the 500 mM 3-NP group from post 1 week to 1 month. The mean type II fibrocyte counts significantly differed between the control and 3-NP groups and between the 3-NP and 3-NP+KRG groups. Spiral ganglion cell degeneration in the 3-NP group was more severe than that in the 3-NP+KRG group. This animal model exhibited a dose-dependent hearing loss with histological changes. KRG administration ameliorated the deterioration of hearing by 3-NP.

Impact of bovine brucellosis eradication programs in the Republic of Korea.

This study concerns a quantitative analysis of the bovine brucellosis eradication program in the Republic of Korea to provide insight into how to plan better future control strategies. In 2004, an active bovine brucellosis eradication program, based principally on intensive test-and-slaughter, was implemented in Korea. With more intensive testing on cattle, the reported incidence rate at herd level increased significantly, becoming 61 times higher in 2006 (225.1 per 10,000 farms) than in 2003 (3.7 per 10,000 farms). Since 2006, when the greatest numbers of infected farms and animals were detected, the incidence rate has been decreasing. All control measures applied in the brucellosis eradication program contributed significantly to the reduction in the incidence of brucellosis. The continuation of the current control strategies, combined with new, innovative measures, may facilitate the eradication of bovine brucellosis in Korea in the near future.