Compound D159687, a phosphodiesterase 4D inhibitor, induces weight and fat mass loss in aged mice without changing
Ijeoma M Muo1, Sung-Jun Park1, Antoine Smith1
1Laboratory of Obesity and Aging Research, NHLBI, National Institute of Health, Bethesda, MD 20892, USA.
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.
Insights
Phosphodiesterase 4 inhibitors show promise for replicating caloric restriction benefits. Compound D159687 induced significant fat loss and increased food intake in aged mice, warranting further investigation for therapeutic potential in older adults.
Area of Science:
- Gerontology and Metabolic Research
- Pharmacology and Drug Discovery
Background:
- Caloric restriction (CR) offers health benefits for aging populations, but adherence is challenging.
- Therapies mimicking CR are needed to improve healthspan in older adults.
- Phosphodiesterase 4 (PDE4) inhibitors are potential candidates for recapitulating CR's effects.
Purpose of the Study:
- To investigate the effects of a novel PDE4 inhibitor, Compound D159687, on body composition, physical, and cognitive function in aged mice.
- To assess the potential of D159687 to mimic the health benefits of caloric restriction.
Main Methods:
- Aged mice (18 months old) were randomized to receive either control (DMSO) or D159687 for seven weeks.
- Body weight, food intake, and body composition were monitored.
- Physical function (treadmill, grip strength, rotarod) and cognitive function (Y maze) were assessed.
- Skeletal muscle mitochondrial biogenesis was analyzed.
Main Results:
- D159687 treatment led to significant weight loss, primarily from fat mass reduction (p < 0.001), with no change in muscle mass.
- Treated mice exhibited increased food intake compared to controls.
- No significant differences were observed in physical or cognitive function tests between groups.
- A high mortality rate (4/19) was noted in the D159687 group, with necropsy suggesting acute lung injury.
Conclusions:
- Compound D159687 effectively reduced fat mass and increased food intake in aged mice, suggesting potential for mimicking CR.
- The therapeutic implications for older adults require further study, particularly regarding lean mass preservation and safety.
- The high death rate necessitates investigation into the drug's toxicity and administration method (oral gavage).
- Further research is needed to confirm the efficacy and safety of PDE4 inhibitors for CR-mimicking therapies.
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