scholarly journals Pharmacological but not physiological GDF15 suppresses feeding and the motivation to exercise

2020 ◽  
Author(s):  
Anders B. Klein ◽  
Trine S. Nicolaisen ◽  
Niels Ørtenblad ◽  
Kasper D. Gejl ◽  
Rasmus Jensen ◽  
...  
Keyword(s):  
Endurance Exercise ◽  
Energy Homeostasis ◽  
Wheel Running ◽  
Treadmill Running ◽  
Physiological Effects ◽  
Running Activity ◽  
Wheel Running Activity ◽  
Exercise Induced ◽  
And Behavior ◽  
Caloric Excess

AbstractGrowing evidence supports that pharmacological application of growth differentiation factor 15 (GDF15) suppresses appetite but also promotes sickness-like behaviors in rodents via GDNF family receptor α-like (GFRAL)-dependent mechanisms1,2. Conversely, the endogenous regulation and secretion of GDF15 and its physiological effects on energy homeostasis and behavior remain elusive. Here we show, in four independent studies that prolonged, moderate- to high-intensity endurance exercise substantially increases circulating GDF15, in a time-dependent and reversible fashion, to peak levels otherwise only observed in pathophysiological conditions. This exercise-induced increase can be recapitulated in mice following forced treadmill running and is accompanied by increased Gdf15 expression in the liver, skeletal muscle, and heart muscle. Compared to other metabolic stressors, like fasting, acute high-fat diet feeding, severe caloric excess and temperature changes, exercise has a greater impact on circulating GDF15 levels. However, whereas pharmacological GDF15 inhibits appetite and suppresses wheel running activity via GFRAL, in response to exercise, the physiological induction of GDF15 does not. In summary, exercise-induced circulating GDF15 correlates with the duration of endurance exercise. However, higher GDF15 levels after exercise are not sufficient to evoke canonical pharmacological GDF15 effects on appetite or responsible for exercise aversion/fatigue. Thus, the physiological effects of GDF15 as an exerkine remain elusive.

scholarly journals Pharmacological but not physiological GDF15 suppresses feeding and the motivation to exercise

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Anders B. Klein ◽  
Trine S. Nicolaisen ◽  
Niels Ørtenblad ◽  
Kasper D. Gejl ◽  
Rasmus Jensen ◽  
...  
Keyword(s):  
Endurance Exercise ◽  
Energy Homeostasis ◽  
Physiological Effects ◽  
Exercise Motivation ◽  
Growth Differentiation Factor 15 ◽  
Running Activity ◽  
Voluntary Running ◽  
Exercise Induced ◽  
And Behavior ◽  
Pharmacological Application

AbstractGrowing evidence supports that pharmacological application of growth differentiation factor 15 (GDF15) suppresses appetite but also promotes sickness-like behaviors in rodents via GDNF family receptor α-like (GFRAL)-dependent mechanisms. Conversely, the endogenous regulation of GDF15 and its physiological effects on energy homeostasis and behavior remain elusive. Here we show, in four independent human studies that prolonged endurance exercise increases circulating GDF15 to levels otherwise only observed in pathophysiological conditions. This exercise-induced increase can be recapitulated in mice and is accompanied by increased Gdf15 expression in the liver, skeletal muscle, and heart muscle. However, whereas pharmacological GDF15 inhibits appetite and suppresses voluntary running activity via GFRAL, the physiological induction of GDF15 by exercise does not. In summary, exercise-induced circulating GDF15 correlates with the duration of endurance exercise. Yet, higher GDF15 levels after exercise are not sufficient to evoke canonical pharmacological GDF15 effects on appetite or responsible for diminishing exercise motivation.

Role of brain IL-1β on fatigue after exercise-induced muscle damage

2006 ◽  
Vol 291 (5) ◽  
pp. R1344-R1348 ◽  
Author(s):  
Martin D. Carmichael ◽  
J. Mark Davis ◽  
E. Angela Murphy ◽  
Adrienne S. Brown ◽  
James A. Carson ◽  
...  
Keyword(s):  
Muscle Damage ◽  
Wheel Running ◽  
Systematic Evaluation ◽  
Running Performance ◽  
Downhill Running ◽  
Running Activity ◽  
Wheel Running Activity ◽  
Sickness Behaviors ◽  
Exercise Induced

Brain cytokines, induced by various inflammatory challenges, have been linked to sickness behaviors, including fatigue. However, the relationship between brain cytokines and fatigue after exercise is not well understood. Delayed recovery of running performance after muscle-damaging downhill running is associated with increased brain IL-1β concentration compared with uphill running. However, there has been no systematic evaluation of the direct effect of brain IL-1β on running performance after exercise-induced muscle damage. This study examined the specific role of brain IL-1β on running performance (either treadmill or wheel running) after uphill and downhill running by manipulating brain IL-1β activity via intracerebroventricular injection of either IL-1 receptor antagonist (ra; downhill runners) or IL-1β (uphill runners). Male C57BL/6 mice were assigned to the following groups: uphill-saline, uphill-IL-1β, downhill-saline, or downhill-IL-1ra. Mice initially ran on a motor-driven treadmill at 22 m/min and −14% or +14% grade for 150 min. After the run, at 8 h (wheel cage) or 22 h (treadmill), uphill mice received intracerebroventricular injections of IL-1β (900 pg in 2 μl saline) or saline (2 μl), whereas downhill runners received IL-1ra (1.8 μg in 2 μl saline) or saline (2 μl). Later (2 h), running performance was measured (wheel running activity and treadmill run to fatigue). Injection of IL-1β significantly decreased wheel running activity in uphill runners ( P < 0.01), whereas IL-1ra improved wheel running in downhill runners ( P < 0.05). Similarly, IL-1β decreased and Il-1ra increased run time to fatigue in the uphill and downhill runners, respectively ( P < 0.01). These results support the hypothesis that increased brain IL-1β plays an important role in fatigue after muscle-damaging exercise.

Increased mitochondrial glycerol-3-phosphate acyltransferase protein and enzyme activity in rat epididymal fat upon cessation of wheel running

2006 ◽  
Vol 290 (3) ◽  
pp. E480-E489 ◽  
Author(s):  
David S. Kump ◽  
Matthew J. Laye ◽  
Frank W. Booth
Keyword(s):  
Physical Activity ◽  
Protein Level ◽  
Wheel Running ◽  
Binding Protein ◽  
Treadmill Running ◽  
Triacylglycerol Synthesis ◽  
Epididymal Fat ◽  
Running Activity ◽  
Wheel Running Activity ◽  
Reduced Physical Activity

Triacylglycerol synthesis in rat epididymal fat overshoots sedentary levels at 10, 29, and 53 h of physical inactivity after 21 days of wheel running. The purposes of the present study were to determine 1) whether this effect is also observed after an acute bout of physical activity and 2) what enzymatic changes might contribute to this effect. We show that more than one bout of physical activity, such as that which occurs with 21 days of wheel running, is necessary for palmitic acid incorporation into triacylglyceride (triglyceride synthesis) to overshoot sedentary values, which suggests that pretranslational mechanisms may be responsible for this overshoot effect. Ten hours after 21 days of wheel running, activity of the mitochondrial glycerol-3-phosphate acyltransferase-1 (mtGPAT1) isoform, a key regulator of triacylglycerol synthesis, overshot sedentary values by 48% and remained higher than sedentary values at 29 and 53 h of reduced physical activity. The overshoot in mtGPAT1 activity was accompanied by an increase in mtGPAT protein level. Cyclic AMP response element-binding protein-binding protein level was higher in sedentary 29 h after 21 days of wheel running. AMP kinase-α Thr172 phosphorylation was increased immediately after treadmill running, but decreased to sedentary values by 5 h after activity. Casein kinase-2α protein level and activity were unchanged. We conclude that an increase in mtGPAT protein might contribute to the overshoot in triacylglycerol synthesis.

Differential effects of food restriction on pituitary-testicular function in mice

1985 ◽  
Vol 248 (2) ◽  
pp. R181-R189 ◽  
Author(s):  
J. L. Blank ◽  
C. Desjardins
Keyword(s):  
Food Intake ◽  
Animal Models ◽  
Food Restriction ◽  
Wheel Running ◽  
Temporal Organization ◽  
Deer Mice ◽  
House Mice ◽  
Testicular Function ◽  
Running Activity ◽  
Wheel Running Activity

The reproductive responses of two species of wild rodents, house mice and deer mice, were evaluated following a 30% reduction in food intake for 5 wk. These animal models were chosen as prototypes of other rodent species because each employs unique functional adjustments when confronted with reduced resources in their natural habitats. Modest inanition failed to alter pituitary-testicular function in house mice; neither spermatogenesis nor plasma concentrations of luteinizing hormone (LH) and testosterone were modified. In sharp distinction, deer mice exposed to restricted food intake showed significant reductions in plasma LH and testosterone and an accompanying loss in spermatogenesis. Reduced food intake also caused pronounced shifts in the temporal organization and amount of wheel-running activity in both animal models, albeit in a dichotomous fashion. House mice exhibited the same amount of wheel-running activity throughout inanition, but the diel periodicity of locomotor behavior was shifted from the dark to the light period. Deer mice, in comparison, significantly curtailed wheel-running activity during the dark hours but ran in precise phase relationship with the light-dark cycle. Taken together, our results establish that the male reproductive system and its supporting neuroendocrine and behavioral correlates can be disrupted by modest levels of food restriction in certain animal models.

Genetic analysis of daily physical activity using a mouse chromosome substitution strain

2009 ◽  
Vol 39 (1) ◽  
pp. 47-55 ◽  
Author(s):  
He S. Yang ◽  
Martha H. Vitaterna ◽  
Aaron D. Laposky ◽  
Kazuhiro Shimomura ◽  
Fred W. Turek
Keyword(s):  
Physical Activity ◽  
Physical Activity Level ◽  
Wheel Running ◽  
Daily Physical Activity ◽  
Activity Level ◽  
Constant Darkness ◽  
Circadian Period ◽  
Chromosome 13 ◽  
Running Activity ◽  
Wheel Running Activity

There is considerable evidence for a genetic basis underlying individual differences in spontaneous physical activity in humans and animals. Previous publications indicate that the physical activity level and pattern vary among inbred strains of mice and identified a genomic region on chromosome 13 as quantitative trait loci (QTL) for physical activity. To confirm and further characterize the role of chromosome 13 in regulating daily physical activity level and pattern, we conducted a comprehensive phenotypic study in the chromosome 13 substitution strain (CSS-13) in which the individual chromosome 13 from the A/J strain was substituted into an otherwise complete C57BL/6J (B6) genome. The B6 and A/J parental strains exhibited pronounced differences in daily physical activity, sleep-wake structure, circadian period and body weight. Here we report that a single A/J chromosome 13 in the context of a B6 genetic background conferred a profound reduction in both total cage activity and wheel-running activity under a 14:10-h light-dark cycle, as well as in constant darkness, compared with B6 controls. Additionally, CSS-13 mice differed from B6 controls in the diurnal distribution of activity and the day-to-day variability in activity onset. We further performed a linkage analysis and mapped a significant QTL on chromosome 13 regulating the daily wheel running activity level in mice. Taken together, our findings indicate a QTL on chromosome 13 with dramatic and specific effects on daily voluntary physical activity, but not on circadian period, sleep, or other aspects of activity that are different between B6 and A/J strains.

scholarly journals Strain screen and haplotype association mapping of wheel running in inbred mouse strains

2010 ◽  
Vol 109 (3) ◽  
pp. 623-634 ◽  
Author(s):  
J. Timothy Lightfoot ◽  
Larry Leamy ◽  
Daniel Pomp ◽  
Michael J. Turner ◽  
Anthony A. Fodor ◽  
...  
Keyword(s):  
Physical Activity ◽  
Association Mapping ◽  
Wheel Running ◽  
Association Studies ◽  
Mouse Strains ◽  
Haplotype Association ◽  
Male And Female ◽  
Female Mice ◽  
Running Activity ◽  
Wheel Running Activity

Previous genetic association studies of physical activity, in both animal and human models, have been limited in number of subjects and genetically homozygous strains used as well as number of genomic markers available for analysis. Expansion of the available mouse physical activity strain screens and the recently published dense single-nucleotide polymorphism (SNP) map of the mouse genome (≈8.3 million SNPs) and associated statistical methods allowed us to construct a more generalizable map of the quantitative trait loci (QTL) associated with physical activity. Specifically, we measured wheel running activity in male and female mice (average age 9 wk) in 41 inbred strains and used activity data from 38 of these strains in a haplotype association mapping analysis to determine QTL associated with activity. As seen previously, there was a large range of activity patterns among the strains, with the highest and lowest strains differing significantly in daily distance run (27.4-fold), duration of activity (23.6-fold), and speed (2.9-fold). On a daily basis, female mice ran further (24%), longer (13%), and faster (11%). Twelve QTL were identified, with three (on Chr. 12, 18, and 19) in both male and female mice, five specific to males, and four specific to females. Eight of the 12 QTL, including the 3 general QTL found for both sexes, fell into intergenic areas. The results of this study further support the findings of a moderate to high heritability of physical activity and add general genomic areas applicable to a large number of mouse strains that can be further mined for candidate genes associated with regulation of physical activity. Additionally, results suggest that potential genetic mechanisms arising from traditional noncoding regions of the genome may be involved in regulation of physical activity.

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