Pediatric patients diagnosed as overweight and obese have an elevated risk of dyspnea.

We investigated whether pediatric patients with overweight and obesity are more likely to have dyspnea compared with those who are non-overweight. We collected de-identified data from TriNetX, a global federated multicenter research database, using both the UT Southwestern Medical Center and multinational Research Networks. Our analysis focused on patients aged 8-12 years. We identified overweight and obesity using ICD-10-CM codes E66 and dyspnea using code R06.0. Patients with overweight and obesity had a significantly higher risk of dyspnea compared with those who were non-overweight. This association was observed in both the UT Southwestern Network (risk ratio: 1.81, p < 0.001) and the Research Network (risk ratio: 2.70, p < 0.001). Furthermore, within the UT Southwestern Network, the risk was found to be higher in females compared with males (risk ratio: 2.17 vs. 1.67). These results have significant clinical implications, suggesting that clinicians should consider overweight and obesity as independent risk factors for dyspnea in pediatric patients after excluding other possible contributing factors.

Reduced Wheel Running via a High-Fat Diet Is Reversed by a Chow Diet with No Added Benefit from Fecal Microbial Transplants.

PURPOSE: Chronic overfeeding via a high-fat/high-sugar (HFHS) diet decreases wheel running and substantially alters the gut metabolome of C57BL/6J mice. In this study, we tested the hypothesis that fecal microbial transplants can modulate the effect of diet on wheel running. METHODS: Singly housed, 6-wk-old male C57BL/6J mice were fed either a grain-based diet (CHOW) or HFHS diet and provided a running wheel for 13 wk. Low-active, HFHS-exposed mice were then either switched to a CHOW diet and given an oral fecal microbial transplant from mice fed the CHOW diet, switched to a CHOW diet and given a sham transplant, or remained on the HFHS diet and given a fecal microbial transplant from mice fed the CHOW diet. Total wheel running, nutrient intake, body composition, fecal microbial composition, fecal metabolite composition, and liver steatosis were measured at various times throughout the study. RESULTS: We found that an HFHS diet decreases wheel running activity, increases body fat, and decreases microbial alpha diversity compared with a CHOW diet. Improvements in wheel running, body composition, and microbial alpha diversity were accomplished within 2 wk for mice switched from an HFHS diet to a CHOW diet with no clear evidence of an added benefit from fecal transplants. A fecal transplant from mice fed a CHOW diet without altering diet did not improve wheel running or body composition. Wheel running, body composition, fecal microbial composition, fecal metabolite composition, and liver steatosis percentage were primarily determined by diet. CONCLUSIONS: Our results suggest that diet is a primary mediator of wheel running with no clear effect from fecal microbial transplants.

LIFR-α-dependent adipocyte signaling in obesity limits adipose expansion contributing to fatty liver disease.

The role of chronic adipose inflammation in diet-induced obesity (DIO) and its sequelae including fatty liver disease remains unclear. Leukemia inhibitory factor (LIF) induces JAK-dependent adipocyte lipolysis and altered adipo/cytokine expression, suppressing in vivo adipose expansion in normal and obese mouse models. To characterize LIF receptor (LIFR-α)-dependent cytokine signaling in DIO, we created an adipocyte-specific LIFR knockout mouse model (Adipoq-Cre;LIFR fl/fl ). Differentiated adipocytes derived from this model blocked LIF-induced triacylglycerol lipolysis. Adipoq-Cre;LIFR fl/fl mice on a high-fat diet (HFD) displayed reduced adipose STAT3 activation, 50% expansion in adipose, 20% body weight increase, and a 75% reduction in total hepatic triacylglycerides compared with controls. To demonstrate that LIFR-α signals adipocytes through STAT3, we also created an Adipoq-Cre;STAT3 fl/fl model that showed similar findings when fed a HFD as Adipoq-Cre;LIFR fl/fl mice. These findings establish the importance of obesity-associated LIFR-α/JAK/STAT3 inflammatory signaling in adipocytes, blocking further adipose expansion in DIO contributing to ectopic liver triacylglyceride accumulation.

Correction: Protein fractional synthesis rates within tissues of high- and low-active mice.

[This corrects the article DOI: 10.1371/journal.pone.0242926.].

Protein fractional synthesis rates within tissues of high- and low-active mice.

With the rise in physical inactivity and its related diseases, it is necessary to understand the mechanisms involved in physical activity regulation. Biological factors regulating physical activity are studied to establish a possible target for improving the physical activity level. However, little is known about the role metabolism plays in physical activity regulation. Therefore, we studied protein fractional synthesis rate (FSR) of multiple organ tissues of 12-week-old male mice that were previously established as inherently low-active (n = 15, C3H/HeJ strain) and high-active (n = 15, C57L/J strain). Total body water of each mouse was enriched to 5% deuterium oxide (D2O) via intraperitoneal injection and maintained with D2O enriched drinking water for about 24 h. Blood samples from the jugular vein and tissues (kidney, heart, lung, muscle, fat, jejunum, ileum, liver, brain, skin, and bone) were collected for enrichment analysis of alanine by LC-MS/MS. Protein FSR was calculated as -ln(1-enrichment). Data are mean±SE as fraction/day (unpaired t-test). Kidney protein FSR in the low-active mice was 7.82% higher than in high-active mice (low-active: 0.1863±0.0018, high-active: 0.1754±0.0028, p = 0.0030). No differences were found in any of the other measured organ tissues. However, all tissues resulted in a generally higher protein FSR in the low-activity mice compared to the high-activity mice (e.g. lung LA: 0.0711±0.0015, HA: 0.0643±0.0020, heart LA: 0.0649± 0.0013 HA: 0.0712±0.0073). Our observations suggest that high-active mice in most organ tissues are no more inherently equipped for metabolic adaptation than low-active mice, but there may be a connection between protein metabolism of kidney tissue and physical activity level. In addition, low-active mice have higher organ-specific baseline protein FSR possibly contributing to the inability to achieve higher physical activity levels.

A High Fat/High Sugar Diet Alters the Gastrointestinal Metabolome in a Sex Dependent Manner.

The gut metabolome offers insight for identifying the source of diet related pathology. As such, the purpose of this study was to characterize alterations of the gut metabolome in female and male C57BL/6J mice randomly assigned to a standard "chow" diet (CHOW) or a high fat/high sugar diet (HFHS; 45% fat and 20% fructose drinking solution) for nine weeks. Cecal metabolites were extracted and an untargeted analysis via LC-MS/MS was performed. Partial Least Sums Discriminate Analysis (PLS-DA) presented significant differences between the two diet groups in a sex-dependent manner. Mann-Whitney U-tests revealed 2443 and 1669 features to be significantly different between diet groups in the females and males, respectively. The majority of altered metabolites were depleted within the cecum of the HFHS fed mice. Metabolic pathways associated with galactose metabolism, leukotriene metabolism, and androgen and estrogen biosynthesis and metabolism were differentially altered with an HFHS diet between sexes. We concluded the immense metabolite depletion and elevation of adverse metabolites associated with the HFHS diet is suggestive of poor gut health. Further, the differential alterations between female and male mice suggests that sex plays an important role in determining the effect of diet on the metabolome and host health.

Activated whole-body arginine pathway in high-active mice.

Our previous studies suggest that physical activity (PA) levels are potentially regulated by endogenous metabolic mechanisms such as the vasodilatory roles of nitric oxide (NO) production via the precursor arginine (ARG) and ARG-related pathways. We assessed ARG metabolism and its precursors [citrulline (CIT), glutamine (GLN), glutamate (GLU), ornithine (ORN), and phenylalanine (PHE)] by measuring plasma concentration, whole-body production (WBP), de novo ARG and NO production, and clearance rates in previously classified low-active (LA) or high-active (HA) mice. We assessed LA (n = 23) and HA (n = 20) male mice by administering a stable isotope tracer pulse via jugular catheterization. We measured plasma enrichments via liquid chromatography tandem mass spectrometry (LC-MS/MS) and body compostion by echo-MRI. WBP, clearance rates, and de novo ARG and NO were calculated. Compared to LA mice, HA mice had lower plasma concentrations of GLU (71.1%; 36.8 ± 2.9 vs. 17.5 ± 1.7µM; p<0.0001), CIT (21%; 57.3 ± 2.3 vs. 46.4 ± 1.5µM; p = 0.0003), and ORN (40.1%; 55.4 ± 7.3 vs. 36.9 ± 2.6µM; p = 0.0241), but no differences for GLN, PHE, and ARG. However, HA mice had higher estimated NO production ratio (0.64 ± 0.08; p = 0.0197), higher WBP for CIT (21.8%, 8.6 ± 0.2 vs. 10.7 ± 0.3 nmol/g-lbm/min; p<0.0001), ARG (21.4%, 35.0 ± 0.6 vs. 43.4 ± 0.7 nmol/g-lbm/min; p<0.0001), PHE (7.6%, 23.8 ± 0.5 vs. 25.6 ± 0.5 nmol/g-lbm/min; p<0.0100), and lower GLU (78.5%; 9.4 ± 1.1 vs. 4.1 ± 1.6 nmol/g lbm/min; p = 0.0161). We observed no significant differences in WBP for GLN, ORN, PHE, or de novo ARG. We concluded that HA mice have an activated whole-body ARG pathway, which may be associated with regulating PA levels via increased NO production.

Alleles associated with physical activity levels are estimated to be older than anatomically modern humans.

The purpose of this study was to determine the estimated mutation age and conservation of single-nucleotide polymorphisms (SNPs) associated with physical activity (PA) in humans. All human SNPs found to be significantly associated with PA levels in the literature were cross-referenced with the National Heart, Lung, and Blood Institute's Grand Opportunity Exome Sequencing Project to find estimated African-American (AA) and European-American (EA) mutation age. As a secondary measure of mutation age, SNPs were searched for in Hawk's mutation age prediction database which utilizes linkage equilibrium. To determine conservation among hominids, all SNPs were searched in the University of California, Santa Cruz Genome Browser, which contains Neanderthal and chimpanzee reference genomes. Six of the 104 SNPs associated with PA regulation were exon-located missense variants found in IFNAR2, PPARGC1A, PML, CTBP2, IL5RA, and APOE genes. The remaining 98 SNPs were located in non-protein coding regions. Average AA and EA estimated mutation age of the exon-located SNPs were 478.4 ± 327.5 kya and 542.1 ± 369.4 kya, respectively. There were four selective sweeps (suggestive of strong positive selection) of SNPs in humans when compared to Neanderthal or chimpanzee genomes. Exon-located PA candidate SNPs are older than the hypothesized emergence of anatomically modern humans. However, 95% of PA associated SNPs are found in intron and intergenic location. Across all SNPs, there seems to be a high level of conservation of alleles between humans, Neanderthals, and chimpanzees. However, the presence of four selective sweeps suggests there were selection pressures or drift unique to Homo sapiens that influenced the development of mutations associated with PA regulation.

An Acute Bout of Aquatic Treadmill Exercise Induces Greater Improvements in Endothelial Function and Postexercise Hypotension Than Land Treadmill Exercise: A Crossover Study.

OBJECTIVE: The purpose of the study was to compare acute bouts of aquatic treadmill (ATM) and land treadmill (LTM) exercise on flow-mediated dilation, postexercise blood pressure, plasma nitrate/nitrite, and atrial natriuretic peptide in untrained, prehypertensive men. DESIGN: In a counterbalanced, crossover design, 19 untrained, prehypertensive men completed bouts of ATM and LTM on separate days. Flow-mediated dilation was measured pre-exercise and 1-hr postexercise. Blood samples were obtained pre-exercise and immediately postexercise and analyzed for plasma nitrate/nitrite and atrial natriuretic peptide. A magnitude-based inference approach to inference was used for statistical analysis. RESULTS: A possible clinically beneficial increase in flow-mediated dilation (1.2%, 90% confidence interval = -0.07% to 2.5%) was observed 1 hr after ATM. In contrast, a possible clinically harmful decrease in flow-mediated dilation (-1.3%, 90% confidence interval = -2.7% to 0.2%) was observed 1 hr after LTM. The magnitude of the postexercise systolic blood pressure reduction was greater after ATM (-4.9, SD = 2.9 mm Hg) than LTM (-2.6, SD = 2.5 mm Hg). Atrial natriuretic peptide increased 34.3 (SD = 47.0%) after ATM and decreased -9.0 (SD = 40.0%) after LTM. CONCLUSIONS: An acute bout of ATM induced a more favorable endothelial response and greater postexercise hypotensive response than LTM. These changes were associated with increased atrial natriuretic peptide levels after ATM.

High Fat High Sugar Diet Reduces Voluntary Wheel Running in Mice Independent of Sex Hormone Involvement.

Introduction: Indirect results in humans suggest that chronic overfeeding decreases physical activity with few suggestions regarding what mechanism(s) may link overfeeding and decreased activity. The primary sex hormones are known regulators of activity and there are reports that chronic overfeeding alters sex hormone levels. Thepurpose of this study was to determine if chronic overfeeding altered wheel running through altered sex hormone levels. Materials and Methods: C57BL/6J mice were bred and the pups were weaned at 3-weeks of age and randomly assigned to either a control (CFD) or high fat/high sugar (HFHS) diet for 9-11 weeks depending on activity analysis. Nutritional intake, body composition, sex hormone levels, and 3-day and 2-week wheel-running activity were measured. Additionally, groups of HFHS animals were supplemented with testosterone (males) and 17ß-estradiol (females) to determine if sex hormone augmentation altered diet-induced changes in activity. Results: 117 mice (56♂, 61♀) were analyzed. The HFHS mice consumed significantly more calories per day than CFD mice (male: p < 0.0001; female: p < 0.0001) and had significantly higher body fat (male: p < 0.0001; female: p < 0.0001). The HFHS diet did not reduce sex hormone levels, but did significantly reduce acute running-wheel distance in male (p = 0.05, 70 ± 28%) and female mice (p = 0.02, 57 ± 26%). In animals that received hormone supplementation, there was no significant effect on activity levels. Two-weeks of wheel access was not sufficient to alter HFHS-induced reductions in activity or increases in body fat. Conclusion: Chronic overfeeding reduces wheel running, but is independent of the primary sex hormones.