title: Rapamycin Reverses Metabolic Deficits in Lamin A/C-Deficient Mice.
abstract: 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.
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA 94945, USA.
authors.forename: Chen-Yu
authors.initials: CY
authors.lastname: Liao
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA 94945, USA.
authors.forename: Sydney S
authors.initials: SS
authors.lastname: Anderson
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA 94945, USA.
authors.forename: Nicole H
authors.initials: NH
authors.lastname: Chicoine
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA 94945, USA.
authors.forename: Jarrott R
authors.initials: JR
authors.lastname: Mayfield
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA 94945, USA.
authors.forename: Emmeline C
authors.initials: EC
authors.lastname: Academia
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA 94945, USA.
authors.forename: Joy A
authors.initials: JA
authors.lastname: Wilson
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA 94945, USA.
authors.forename: Chalermkwan
authors.initials: C
authors.lastname: Pongkietisak
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA 94945, USA.
authors.forename: Morgan A
authors.initials: MA
authors.lastname: Thompson
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA 94945, USA.
authors.forename: Earl P
authors.initials: EP
authors.lastname: Lagmay
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA 94945, USA.
authors.forename: Delana M
authors.initials: DM
authors.lastname: Miller
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA 94945, USA.
authors.forename: Yueh-Mei
authors.initials: YM
authors.lastname: Hsu
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA 94945, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: McCormick
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA 94945, USA.
authors.forename: Monique N
authors.initials: MN
authors.lastname: O'Leary
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA 94945, USA. Electronic address: bkennedy@buckinstitute.org.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Kennedy
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D034904:Lamin Type A / Q000235:genetics* / Q000378:metabolism; D008066:Lipolysis / Q000187:drug effects; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000235:genetics; D000076225:Mechanistic Target of Rapamycin Complex 2 / Q000235:genetics; D051379:Mice; D020123:Sirolimus / Q000008:administration & dosage; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D022722:Thermogenesis / Q000235:genetics*; D000071256:Uncoupling Protein 1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D034904:Lamin Type A; C576142:Lmna protein, mouse; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Lmna(−/−) mice; adiposity; lifespan; lipodystrophy; mTOR; progeria; rapamycin; thermoneutrality