title: Rapamycin Modulates Markers of Mitochondrial Biogenesis and Fatty Acid Oxidation in the Adipose Tissue of db/db Mice.
abstract: Excess nutrient uptake leads to obesity, insulin resistance, and type 2 diabetes. Mammalian target of the rapamycin (mTOR), a major component of the nutrient-sensing pathway also regulates mitochondrial oxidative function. Rapamycin, a pharmacological inhibitor of mTOR, causes glucose intolerance and inhibits mitochondrial oxidative function. While a number of studies have focused on the effect of rapamycin on control wild-type mice, ours is the first to study the effect of rapamycin on mitochondrial gene expression and insulin sensitivity in the db/db mouse, a model of diabetic dyslipidemia. Female db/+ and db/db mice were fedad libituma rapamycin-containing diet or a control diet for 6 months, starting at two months of age. Body weight, fat mass, lean mass and food intake were measured monthly. Effect of rapamycin or control diet on markers of adipogenesis, fatty acid oxidation and mitochondrial biogenesis in the gonadal white adipose tissue (WAT) as well as different serum parameters were assessed. Whole body insulin sensitivity was measured by insulin tolerance test. Rapamycin feeding to db/db mice decreased body weight (58%) and fat mass (33%), elevated markers of fatty acid oxidation and mitochondrial biogenesis in WAT, reduced circulating non-esterified free fatty acids (NEFA), elevated circulating adiponectin and improved insulin sensitivity, compared to control diet fed db/db mice. These data demonstrate that rapamycin exhibits an anti-obesity effect and improves whole body insulin sensitivity in db/db mice and suggest an unexpected effect of simultaneous inhibition mTOR and leptin signaling in mice.
authors.affiliation: Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78245, USA ; Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
authors.forename: Sathyaseelan S
authors.initials: SS
authors.lastname: Deepa
authors.affiliation: Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78245, USA ; Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Walsh
authors.affiliation: Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78245, USA.
authors.forename: Ryan T
authors.initials: RT
authors.lastname: Hamilton
authors.affiliation: Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78245, USA ; Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Pulliam
authors.affiliation: Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78245, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78245, USA.
authors.forename: Shauna
authors.initials: S
authors.lastname: Hill
authors.affiliation: Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78245, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78245, USA ; Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA ; Geriatric Research, Education, and Clinical Center, South Texas Veterans Health Care System, San Antonio, Texas 78229, USA.
authors.forename: Holly
authors.initials: H
authors.lastname: Van Remmen
keywords: db/db mouse; fat oxidation; insulin sensitivity; mitochondria; obesity