Increased weight loading reduces body weight and body fat in obese subjects - A proof of concept randomized clinical trial.

BACKGROUND: Recently we provided evidence for a leptin-independent homeostatic regulation, the gravitostat, of body weight in rodents. The aim of the present translational proof of concept study was to test the gravitostat hypothesis in humans. METHODS: We conducted a randomized controlled single center trial (ClinicalTrial.gov number, NCT03672903), to evaluate the efficacy of artificially increased weight loading on body weight in subjects with mild obesity (BMI 30-35 kg/m2). Subjects were either treated with a heavy (=high load; 11% of body weight) or light (=low load; 1% of body weight) weight vest for eight hours per day for three weeks. The primary outcome was change in body weight. Secondary outcomes included change in body fat mass and fat-free mass as measured using bioelectrical impedance analysis. FINDINGS: In total 72 participants underwent randomization and 69 (36 high load and 33 low load) completed the study for the primary outcome. High load treatment resulted in a more pronounced relative body weight loss compared to low load treatment (mean difference -1.37%, 95% confidence interval (CI), -1.96 to -0.79; p = 1.5 × 10-5). High load treatment reduced fat mass (-4.04%, 95% CI, -6,53 to -1.55; p = 1.9 × 10-3) but not fat free mass (0.43%, 95% CI, -1.47 to 2.34; p = 0.65) compared to low load treatment. INTERPRETATION: Increased weight loading reduces body weight and fat mass in obese subjects in a similar way as previously shown in obese rodents. These findings demonstrate that there is weight loading dependent homeostatic regulation of body weight, the gravitostat, also in humans. FUNDING: Funded by Jane and Dan Olsson (JADO) Foundation, the Torsten Söderberg Foundation, The Knut and Alice Wallenberg's Foundation and the Novo Nordisk Foundation.

Development of age-dependent dose modification factors for acute radiation lethality.

Purpose: The aim of our work was to develop an approach to account for the impact of age at exposure on acute radiation lethality risk for the purpose of improving casualty estimation tools when applied to a diverse population.Materials and Methods: Age-dependent radiation lethality data were collected from published animal studies. The 50% lethal dose responses (LD50) were extracted, grouped according to developmental stages in humans and average LD50 values calculated for select age categories. Dose modification factors (DMFs) were developed by dividing LD50 values of non-young, adult groups to the reference adult category within each study. DMFs were combined across each age group to provide a DMF for each age category.Results: Data from 12 studies with age-dependent LD50 values from 5 species (>21,000 animals) demonstrate increased sensitivity to acute radiation in elderly and young animals compared to young adults. DMFs were developed for infant (0.80), juvenile (0.86), late adult (0.86), and elderly (0.71) populations.Conclusions: Animal and human data support increased radiosensitivity in infants, juveniles, and aging adults. DMFs provide a mechanism to account for age-dependent variability in health effects models and to determine the impact of age on casualty estimates.

Impact analysis of age on radiation casualty estimations for nuclear detonation scenarios.

Purpose: The purpose of this research was to demonstrate the impact of accounting for age-based radiation response when estimating radiation casualties in a nuclear detonation scenario.Materials and methods: Three nuclear device detonation scenarios were simulated using densely populated regions to compare traditional casualty estimates with age-dependent casualty estimates. Fatalities were estimated using age-based dose-response curves. The surviving population was assumed injured (requiring medical care) if their dose exceeded a lower bound, represented by the minimum dose required to cause deterministic effects, for each age group.Results: In each of the three scenarios, the affected area increased significantly for radiosensitive age groups. In two of the three scenarios, accounting for age-dependent radiosensitivity resulted in up to a 10% increase in fatalities and up to a 12% increase in radiation injuries compared to traditional estimates. This study demonstrates that the differences in casualty estimates are dependent on the relative density and location of radiosensitive populations.Conclusions: These results demonstrate that the inclusion of age-based demographic data and associated dose responses may result in significantly higher estimates of casualties depending on the location and age of the affected population. This information could be useful for the emergency management planning community.

Modeling Reveals a Key Mechanism for Light-Dependent Phase Shifts of Neurospora Circadian Rhythms.

Light shifts and synchronizes the phase of the circadian clock to daily environments, which is critical for maintaining the daily activities of an organism. It has been proposed that such light-dependent phase shifts are triggered by light-induced upregulation of a negative element of the core circadian clock (i.e., frq, Per1/2) in many organisms, including fungi. However, we find, using systematic mathematical modeling of the Neurospora crassa circadian clock, that the upregulation of the frq gene expression alone is unable to reproduce the observed light-dependent phase responses. Indeed, we find that the depression of the transcriptional activator white-collar-1, previously shown to be promoted by FRQ and VVD, is a key molecular mechanism for accurately simulating light-induced phase response curves for wild-type and mutant strains of Neurospora. Our findings elucidate specific molecular pathways that can be utilized to control phase resetting of circadian rhythms.