Dataset Information

Compound D159687, a phosphodiesterase 4D inhibitor, induces weight and fat mass loss in aged mice without changing lean mass, physical and cognitive function.

ABSTRACT:

Aims

Therapies that recapitulate the health benefits of caloric restriction in older adults are needed. Phosphodiesterase 4 inhibitors demonstrate such promise. We examined their effects on body weight and composition, physical and cognitive function in aged mice using Compound D159687 (D159687).

Methods

Nineteen 18-months old mice were randomized to receive either control (DMSO) or D159687 for seven weeks. We assessed food intake, body weight and body composition over time and performed once the following tests: treadmill, inverted grip strength, rotarod, spontaneous Y maze tests and skeletal muscle mitochondrial biogenesis.

Results

Four of the D159687 treated mice died in the first week. Necropsy suggests acute lung injury. D159687 treated mice weighed more than control mice at baseline. After controlling for baseline weight, D159687 treated mice lost 4.2 grams(g) more weight than control mice, mainly from fat mass loss (p value < 0.001). Muscle mass was unchanged between the two mice groups. D159587 mice ate significantly more food than the control mice. We found no difference between the two groups in the results of treadmill, rotarod and spontaneous Y maze tests and in mitochondrial biogenesis.

Conclusion

Compound D159687 induced weight loss, predominantly fat mass loss and increased food intake in aged mice. The caloric restriction and lean mass preservation potential of PDE4D inhibitors deserve further verification. Findings may have major therapeutic implications when translated to the older adult population. Although physical and cognitive parameters were unchanged in this study, further studies would be needed to verify these results. The high death rate in the D159687 treated mice may have been due to the technical aspects of oral gavage.

SUBMITTER: Muo IM

PROVIDER: S-EPMC8367197 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Weight gain in pregnancy is an essential physiologic adaptation that supports growth and development of a fetus and is distributed among lean mass that includes total body water and fat mass gains. Although gestational weight gain provides a source of energy for the mother and fetus, excess gestational weight gain may underlie reported associations between parity and future metabolic disorders and is linked to postpartum weight retention and insulin resistance. Although weight gain often is proposed as a modifiable variable to mitigate adverse maternal and offspring health outcomes, our knowledge of specific maternal body composition changes with weight gain and the potential metabolic consequences is limited. Furthermore, although gestational weight gain alters maternal body composition, the impact of excess weight gain on fat and lean mass is not well-studied. Understanding the accrual of fat and lean body mass may improve our understanding of the role of excessive gestational weight gain and metabolic dysfunction.The purpose of our study was to quantify the relationship between gestational weight gain and maternal fat and lean body mass accrual and to compare fat and lean body mass accrual according to the 2009 Institute of Medicine Guidelines for Gestational Weight Gain in Pregnancy adherence. We hypothesized that exceeding current weight gain guidelines would be associated with greater fat, compared with lean body, mass accrual.This is a secondary analysis of a randomized controlled trial of 49 overweight/obese women; all 49 are included in this secondary analysis. Maternal weight and body composition were collected in early (13 0/6 to 16 6/7 weeks gestation) and late (34 0/7 to 36 6/7 weeks gestation) pregnancy with the use of air densitometry. Correlations were drawn between gestational weight gain and change in fat and lean body mass. We compared change in fat and lean body mass by adherence to the 2009 Institute of Medicine Guidelines for Gestational Weight Gain in Pregnancy. Nonparametric tests and chi-square analyses were performed; a probability value of <.05 was significant.Early pregnancy body mass index was 30.3 kg/m(2) (interquartile range [IQR], 28.5-35.2 kg/m(2)); women gained 9.0 kg (IQR, 5.3-13.2 kg). Overweight and obese women were equally likely to gain excess weight (48% vs 35%; P = .6). Weight gain correlated strongly with fat mass change (r = 0.87; P < .001); women with excess vs adequate vs inadequate weight gain had greater fat mass change overall (5.2 [IQR, 4.2-8.1] vs 0.2 [IQR, -0.4-2.2] vs -2.7 [IQR, -5.2- -0.7] kg, respectively; P < .001) and in all pairwise comparisons. Weight gain also correlated with lean body mass change (r = 0.52; P = .001), but women with excess vs adequate weight gain had similar lean body mass change (8.4 [IQR, 7.2-10.1] vs 7.8 [IQR, 6.0-8.7] kg; P = .1).Excess gestational weight gain is associated primarily with maternal fat, but not with lean body mass accrual. Our results may help explain the reason that excess gestational weight gain or fat mass accrual is associated with long-term obesity, metabolic dysfunction, and cardiovascular disease risk.

Project description:BackgroundWeight loss reduces body fat and lean mass, but whether these changes are influenced by macronutrient composition of the diet is unclear.ObjectiveWe determined whether energy-reduced diets that emphasize fat, protein, or carbohydrate differentially reduce total, visceral, or hepatic fat or preserve lean mass.DesignIn a subset of participants in a randomized trial of 4 weight-loss diets, body fat and lean mass (n = 424; by using dual-energy X-ray absorptiometry) and abdominal and hepatic fat (n = 165; by using computed tomography) were measured after 6 mo and 2 y. Changes from baseline were compared between assigned amounts of protein (25% compared with 15%) and fat (40% compared with 20%) and across 4 carbohydrate amounts (35% through 65%).ResultsAt 6 mo, participants lost a mean (±SEM) of 4.2 ± 0.3 kg (12.4%) fat and 2.1 ± 0.3 kg (3.5%) lean mass (both P < 0.0001 compared with baseline values), with no differences between 25% and 15% protein (P ≥ 0.10), 40% and 20% fat (P ≥ 0.34), or 65% and 35% carbohydrate (P ≥ 0.27). Participants lost 2.3 ± 0.2 kg (13.8%) abdominal fat: 1.5 ± 0.2 kg (13.6%) subcutaneous fat and 0.9 ± 0.1 kg (16.1%) visceral fat (all P < 0.0001 compared with baseline values), with no differences between the diets (P ≥ 0.29). Women lost more visceral fat than did men relative to total-body fat loss. Participants regained ~40% of these losses by 2 y, with no differences between diets (P ≥ 0.23). Weight loss reduced hepatic fat, but there were no differences between groups (P ≥ 0.28). Dietary goals were not fully met; self-reported contrasts were closer to 2% protein, 8% fat, and 14% carbohydrate at 6 mo and 1%, 7%, and 10%, respectively, at 2 y.ConclusionParticipants lost more fat than lean mass after consumption of all diets, with no differences in changes in body composition, abdominal fat, or hepatic fat between assigned macronutrient amounts. This trial was registered at clinicaltrials.gov as NCT00072995.

Project description:BackgroundLittle is known about the association of changes in two body components, muscle and fat mass, with the risk of cardiovascular disease (CVD) among young adults. We investigated the association of changes in predicted lean body mass index (LBMI), appendicular skeletal muscle mass index (ASMI), and body fat mass index (BFMI) with the development of CVD among young adults.MethodsThis nationwide, population-based cohort study included 3 727 738 young adults [2 406 046 (64.5%) men and 1 321 692 (35.5%) women] aged 20-39 years without a previous history of CVD who underwent two health screening examinations during 2009-2010 and 2011-2012. Using validated and robust prediction equations, we calculated the changes in predicted LBMI, ASMI, and BFMI from the first to the second examinations.ResultsThe mean (SD) age was 32.2 (4.9) years, and 2 406 046 (64.5%) of the participants were men. A total of 23 344 CVD events were detected during 22 257 632 person-years of follow-up. Each 1 kg/m2 increase in predicted LBMI and ASMI change was associated with a reduced risk of CVD among men [adjusted hazard ratio (aHR): 0.86, 95% confidence interval (CI) 0.82-0.91; aHR: 0.76, 95% CI 0.69-0.82, respectively] and women (aHR: 0.77, 95% CI 0.63-0.95; aHR: 0.75, 95% CI 0.59-0.96). Each 1 kg/m2 increase in predicted BFMI change was associated with an increased risk of CVD among men (aHR: 1.16, 95% CI 1.10-1.22) and women (aHR: 1.32, 95% CI 1.06-1.65). In both sexes, decreases in predicted LBMI and ASMI were associated with greater CVD risk, and decreased predicted BFMI was associated with a reduced CVD risk. Those who maintained their BMI between -1 and +1 kg/m2 also had a decreased risk of CVD per 1 kg/m2 increase in predicted LBMI and ASMI change among men (aHR: 0.86, 95% CI 0.80-0.92; aHR: 0.85, 95% CI 0.76-0.95) and women (aHR: 0.62, 95% CI 0.47-0.83; aHR: 0.59, 95% CI 0.44-0.80) and had a greater risk of CVD per 1 kg/m2 increase in predicted BFMI change among men (aHR: 1.17, 95% CI 1.10-1.25) and women (aHR: 1.64, 95% CI 1.20-2.23). Regardless of changes in weight, such as from normal to obese or vice versa, these results were consistent.ConclusionsAmong young adults, increased predicted muscle mass or decreased predicted fat mass were associated with a reduced risk of development of CVD. Decreased predicted muscle mass or increased predicted fat mass were associated with an elevated risk of development of CVD.

Project description:BackgroundRecent studies suggest that adjustment of measures of lean mass for adiposity improves associations with physical function. Our objective was to develop and test a method to adjust appendicular lean mass for adiposity.MethodsWhole-body DXA data in 14,850 adults in the National Health and Nutrition Examination Survey were used to generate sex-, and race-specific standard deviation scores (Z-Scores relative to age and T-scores relative to 25 year-olds) for appendicular lean mass index (ALMI, kg/m2) and fat mass index (FMI, kg/m2). Correlations between ALMI and FMI Z- and T-Scores were assessed within demographic categories. Fat-adjusted ALMI (ALMIFMI) scores were determined using residual methods. Sarcopenia was defined as a T-Score <-2.0 and low lean for age as a Z-Score <-1.0. Correlations with physical function were assessed in an at-risk population.ResultsPositive associations between ALMI and FMI Z- and T-Scores were significant (R >0.50; p<0.001) within all demographic categories. The impact of a unit greater FMI Z-score on ALMI Z-score was less in the elderly, men, white subjects, and among individuals with lower FMI (all tests for interaction p<0.001). There was fair agreement between ALMI and ALMIFMI estimates of sarcopenia and low lean for age [Kappa: 0.46, 0.52, respectively (p<0.0001)]. Elderly subjects were likely to be re-classified as sarcopenic while young subjects were likely to be re-classified as normal using ALMIFMI. ALMIFMI T-scores resulted in approximately twice the number of subjects defined as sarcopenic, compared with ALMI T-Scores. (1299 v. 534). Among rheumatoid arthritis patients, ALMIFMI Z-scores correlated with physical function (Health Assessment Questionnaire: rho = -0.22, p = 0.04; Short Physical Performance Battery: rho = 0.27, p = 0.01); however, the ALMI Z-Score did not.ConclusionsAdjustment of ALMI for the confounding association with FMI impacts the definition of lean mass deficits. These methods provide a practical tool for investigators and clinicians based on population-based reference data.