Rapamycin Reverses Metabolic Deficits in Lamin A/C-Deficient Mice

The role of the mTOR inhibitor, rapamycin, in regulation of adiposity remains controversial. Here, we evaluate mTOR signaling in lipid metabolism in adipose tissues of Lmna−/− mice, a mouse model for dilated cardiomyopathy and muscular dystrophy. Lifespan extension by rapamycin is associated with in...

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Bibliographic Details
Published in:Cell reports (Cambridge) 2016-12, Vol.17 (10), p.2542-2552
Main Authors: Liao, Chen-Yu, Anderson, Sydney S., Chicoine, Nicole H., Mayfield, Jarrott R., Academia, Emmeline C., Wilson, Joy A., Pongkietisak, Chalermkwan, Thompson, Morgan A., Lagmay, Earl P., Miller, Delana M., Hsu, Yueh-Mei, McCormick, Mark A., O'Leary, Monique N., Kennedy, Brian K.
Format: Article
Language:English
Subjects:
Adipose Tissue - metabolism
adiposity
Animals
Lamin Type A - genetics
Lamin Type A - metabolism
lifespan
lipodystrophy
Lipolysis - drug effects
Lmna−/− mice
Mechanistic Target of Rapamycin Complex 1 - genetics
Mechanistic Target of Rapamycin Complex 2 - genetics
Mice
mTOR
progeria
rapamycin
Sirolimus - administration & dosage
Thermogenesis - genetics
thermoneutrality
TOR Serine-Threonine Kinases - genetics
TOR Serine-Threonine Kinases - metabolism
Uncoupling Protein 1 - genetics
Uncoupling Protein 1 - metabolism
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Summary:The role of the mTOR inhibitor, rapamycin, in regulation of adiposity remains controversial. Here, we evaluate mTOR signaling in lipid metabolism in adipose tissues of Lmna−/− mice, a mouse model for dilated cardiomyopathy and muscular dystrophy. Lifespan extension by rapamycin is associated with increased body weight and fat content, two phenotypes we link to suppression of elevated energy expenditure. In both white and brown adipose tissue of Lmna−/− mice, we find that rapamycin inhibits mTORC1 but not mTORC2, leading to suppression of elevated lipolysis and restoration of thermogenic protein UCP1 levels, respectively. The short lifespan and metabolic phenotypes of Lmna−/− mice can be partially rescued by maintaining mice at thermoneutrality. Together, our findings indicate that altered mTOR signaling in Lmna−/− mice leads to a lipodystrophic phenotype that can be rescued with rapamycin, highlighting the effect of loss of adipose tissue in Lmna−/− mice and the consequences of altered mTOR signaling. [Display omitted] •Rapamycin suppresses the elevated energy expenditure in Lmna−/− mice•Rapamycin suppresses elevated lipolysis of white adipose tissue in Lmna−/− mice•Rapamycin restores the thermogenic protein UCP1 levels in Lmna−/− mice•Thermoneutrality partially rescues the metabolic phenotypes of Lmna−/− mice Liao et al. find that lifespan extension by rapamycin is associated with suppression of elevated energy expenditure in Lmna−/− mice, a model for lipodystrophy. Molecularly, rapamycin suppresses elevated lipolysis and restores the levels of the thermogenic protein, UCP1. The metabolic phenotypes of Lmna−/− mice can also be partially rescued by maintaining mice at thermoneutrality.
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2016.10.040