Ru doping induced spin frustration and enhancement of the room-temperature anomalous Hall effect in La2/3Sr1/3MnO3 films

In transition-metal-oxide heterostructures, the anomalous Hall effect (AHE) is a powerful tool for detecting the magnetic state and revealing intriguing interfacial magnetic orderings. However, achieving a larger AHE at room temperature in oxide heterostructures is still challenging due to the dilemma of mutually strong spin-orbit coupling and magnetic exchange interactions. Here, we exploit the Ru doping-enhanced AHE in LSMRO epitaxial films. As the B-site Ru doping level increases up to 20 percent, the anomalous Hall resistivity at room temperature can be enhanced from nOhmcm to uOhmcm scale. Ru doping leads to strong competition between ferromagnetic double-exchange interaction and antiferromagnetic super-exchange interaction. The resultant spin frustration and spin-glass state facilitate a strong skew-scattering process, thus significantly enhancing the extrinsic AHE. Our findings could pave a feasible approach for boosting the controllability and reliability of oxide-based spintronic devices

Maternal exercise before and during pregnancy does not impact offspring exercise or body composition in mice

Abstract Background The genome, the environment, and their interactions simultaneously regulate complex traits such as body composition and voluntary exercise levels. One such environmental influence is the maternal milieu (i.e., in utero environment or maternal care). Variability in the maternal environment may directly impact the mother, and simultaneously has the potential to influence the physiology and/or behavior of offspring in utero, post birth, and into adulthood. Here, we utilized a murine model to examine the effects of the maternal environment in regard to voluntary exercise (absence of wheel running, wheel running prior to gestation, and wheel running prior to and throughout gestation) on offspring weight and body composition (% fat tissue and % lean tissue) throughout development (~3 to ~9 weeks of age). Additionally, we examined the effects of ~6 weeks of maternal exercise (prior to and during gestation) on offspring exercise levels at ~9 weeks of age. Results We observed no substantial effects of maternal exercise on subsequent male or female offspring body composition throughout development, or on the propensity of offspring to engage in voluntary wheel running. At the level of the individual, correlational analyses revealed some statistically significant relationships between maternal and offspring exercise levels, likely reflecting previously known heritability estimates for such traits. Conclusions The current results conflict with previous findings in human and mouse models demonstrating that maternal exercise has the potential to alter offspring phenotypes. We discuss our negative findings in the context of the timing of the maternal exercise and the level of biological organization of the examined phenotypes within the offspring

Genetic architecture of voluntary exercise in an advanced intercross line of mice

Exercise is essential for health, yet the amount, duration, and intensity that individuals engage in is strikingly variable, even under prescription. Our focus was to identify the locations and effects of quantitative trait loci (QTL) controlling genetic predisposition for exercise-related traits utilizing a large advanced intercross line (AIL) of mice. This AIL (G4) population originated from a reciprocal cross between mice with genetic propensity for increased voluntary exercise (HR, selectively bred for increased wheel running) and the inbred strain C57BL/6J. After adjusting for family structure, we detected 32 significant and 13 suggestive QTL representing both daily running traits (distance, duration, average speed, and maximum speed) and the mean of these traits on days 5 and 6 (the selection criteria for HR) of a 6-day test conducted at 8 weeks of age, with many colocalizing to similar genomic regions. Additionally, 7 significant and 5 suggestive QTL were observed for the slope and intercept of a linear regression across all 6 days of running, some representing a combination of the daily traits. We also observed 2 significant and 2 suggestive QTL for body mass prior to exercise. These results, using a well-defined animal model, reinforce a genetic basis for the predisposition to engage in voluntary exercise, dissect this predisposition into daily segments across a continuous time period, and present unique QTL that may provide insight into the initiation, continuation, and temporal pattern of voluntary activity in mammals

Identification of quantitative trait loci influencing skeletal architecture in mice: Emergence of Cdh11 as a primary candidate gene regulating femoral morphology

Bone strength is influenced by many properties intrinsic to bone, including its mass, geometry, and mineralization. To further advance our understanding of the genetic basis of bone strength-related traits, we utilized a large (N=815), moderately (G4) advanced intercross line (AIL) of mice derived from a high-runner selection line (HR) and the C57BL/6J inbred strain. In total, 16 quantitative trait loci (QTL) were identified that affected areal bone mineral density (aBMD) and femoral length and width. Four significant (P<0.05) and one suggestive (P<0.10) QTL were identified for three aBMD measurements: total body, vertebral and femoral. A QTL on Chromosome (Chr.) 3 influenced all three aBMD measures, while the other four QTL were unique to a single measure. A total of 10 significant and one suggestive QTL were identified for femoral length (FL) and two measures of femoral width, anterior-posterior (AP) and medial-lateral (ML). FL QTL were distinct from loci affecting AP and ML width, and of the seven AP QTL, only three affected ML. A QTL on Chr. 8 that explained 7.1% and 4.0% of the variance in AP and ML, respectively, was mapped to a six megabase (Mb) region harboring 12 protein-coding genes. The pattern of haplotype diversity across the QTL region and expression profiles of QTL genes, suggested that of the 12, cadherin 11 (Cdh11) was most likely the causal gene. These findings, when combined with existing data from gene knockouts, identify Cdh11 as a strong candidate gene within which genetic variation may affect bone morphology

CC002/Unc females are mouse models of exercise-induced paradoxical fat response

Exercise results in beneficial health outcomes and protects against a variety of chronic diseases. However, U.S. exercise guidelines recommend identical exercise programs for everyone, despite individual variation in responses to these programs, including paradoxical fat gain. Experimental models of exercise-induced paradoxical outcomes may enable the dissection of underlying physiological mechanisms as well as the evaluation of potential interventions. Whereas several studies have identified individual mice exhibiting paradoxical fat gain following exercise, no systematic effort has been conducted to identify and characterize models of paradoxical response. Strains from the Collaborative Cross (CC) genetic reference population were used due to its high levels of genetic variation, its reproducible nature, and the observation that the CC is a rich source of novel disease models, to assess the impact genetic background has on exercise responses. We identified the strain CC002/Unc as an exercise-induced paradoxical fat response model in a controlled voluntary exercise study across multiple ages in female mice. We also found sex and genetic differences were consistent with this pattern in a study of forced exercise programs. These results provide a novel model for studies to determine the mechanisms behind paradoxical metabolic responses to exercise, and enable development of more rational personalized exercise recommendations based on factors such as age, sex, and genetic background

Improving Metabolic Health Through Precision Dietetics in Mice

The incidence of diet-induced metabolic disease has soared over the last half-century, despite national efforts to improve health through universal dietary recommendations. Studies comparing dietary patterns of populations with health outcomes have historically provided the basis for healthy diet recommendations. However, evidence that population-level diet responses are reliable indicators of responses across individuals is lacking. This study investigated how genetic differences influence health responses to several popular diets in mice, which are similar to humans in genetic composition and the propensity to develop metabolic disease, but enable precise genetic and environmental control. We designed four human-comparable mouse diets that are representative of those eaten by historical human populations. Across four genetically distinct inbred mouse strains, we compared the American diet’s impact on metabolic health to three alternative diets (Mediterranean, Japanese, and Maasai/ketogenic). Furthermore, we investigated metabolomic and epigenetic alterations associated with diet response. Health effects of the diets were highly dependent on genetic background, demonstrating that individualized diet strategies improve health outcomes in mice. If similar genetic-dependent diet responses exist in humans, then a personalized, or “precision dietetics,” approach to dietary recommendations may yield better health outcomes than the traditional one-size-fits-all approach

Functional characterization of cytochrome P450-derived epoxyeicosatrienoic acids in adipogenesis and obesity

Adipogenesis plays a critical role in the initiation and progression of obesity. Although cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) have emerged as a potential therapeutic target for cardiometabolic disease, the functional contribution of EETs to adipogenesis and the pathogenesis of obesity remain poorly understood. Our studies demonstrated that induction of adipogenesis in differentiated 3T3-L1 cells (in vitro) and obesity-associated adipose expansion in high-fat diet (HFD)-fed mice (in vivo) significantly dysregulate the CYP epoxygenase pathway and evoke a marked suppression of adipose-derived EET levels. Subsequent in vitro experiments demonstrated that exogenous EET analog administration elicits potent anti-adipogenic effects via inhibition of the early phase of adipogenesis. Furthermore, EET analog administration to mice significantly mitigated HFD-induced weight gain, adipose tissue expansion, pro-adipogenic gene expression, and glucose intolerance. Collectively, these findings suggest that suppression of EET bioavailability in adipose tissue is a key pathological consequence of obesity, and strategies that promote the protective effects of EETs in adipose tissue offer enormous therapeutic potential for obesity and its downstream pathological consequences

Exercise and Diet Affect Quantitative Trait Loci for Body Weight and Composition Traits in an Advanced Intercross Population of Mice

Driven by the recent obesity epidemic, interest in understanding the complex genetic and environmental basis of body weight and composition is great. We investigated this by searching for quantitative trait loci (QTLs) affecting a number of weight and adiposity traits in a G10 advanced intercross population produced from crosses of mice in inbred strain C57BL/6J with those in a strain selected for high voluntary wheel running. The mice in this population were fed either a high-fat or a control diet throughout the study and also measured for four exercise traits prior to death, allowing us to test for pre- and postexercise QTLs as well as QTL-by-diet and QTL-by-exercise interactions. Our genome scan uncovered a number of QTLs, of which 40% replicated QTLs previously found for similar traits in an earlier (G4) generation. For those replicated QTLs, the confidence intervals were reduced from an average of 19 Mb in the G4 to 8 Mb in the G10. Four QTLs on chromosomes 3, 8, 13, and 18 were especially prominent in affecting the percentage of fat in the mice. About of all QTLs showed interactions with diet, exercise, or both, their genotypic effects on the traits showing a variety of patterns depending on the diet or level of exercise. It was concluded that the indirect effects of these QTLs provide an underlying genetic basis for the considerable variability in weight or fat loss typically found among individuals on the same diet and/or exercise regimen

Quantitative Genomics of Voluntary Exercise in Mice: Transcriptional Analysis and Mapping of Expression QTL in Muscle

Motivation and ability both underlie voluntary exercise, each with a potentially unique genetic architecture. Muscle structure and function are one of many morphological and physiological systems acting to simultaneously determine exercise ability. We generated a large (n = 815) advanced intercross line of mice (G4) derived from a line selectively bred for increased wheel running (high runner) and the C57BL/6J inbred strain. We previously mapped quantitative trait loci (QTL) contributing to voluntary exercise, body composition, and changes in body composition as a result of exercise. Using brain tissue in a subset of the G4 (n = 244), we have also previously reported expression QTL (eQTL) colocalizing with the QTL for the higher-level phenotypes. Here, we examined the transcriptional landscape of hind limb muscle tissue via global mRNA expression profiles. Correlations revealed an ∼1,168% increase in significant relationships between muscle transcript expression levels and the same exercise and body composition phenotypes examined previously in the brain. The exercise trait most often significantly correlated with gene expression in the brain was running duration while in the muscle it was maximum running speed. This difference may indicate that time spent engaging in exercise behavior may be more influenced by central (neurobiological) mechanisms, while intensity of exercise may be largely controlled by peripheral mechanisms. Additionally, we used subsets of cis-acting eQTL, colocalizing with QTL, to identify candidate genes based on both positional and functional evidence. We discuss three plausible candidate genes (Insig2, Prcp, Sparc) and their potential regulatory role