title: Rapamycin Blocks Induction of the Thermogenic Program in White Adipose Tissue.
abstract: Rapamycin extends life span in mice, yet paradoxically causes lipid dysregulation and glucose intolerance through mechanisms that remain incompletely understood. Whole-body energy balance can be influenced by beige/brite adipocytes, which are inducible by cold and other stimuli via β-adrenergic signaling in white adipose depots. Induction of beige adipocytes is considered a promising strategy to combat obesity because of their ability to metabolize glucose and lipids, dissipating the resulting energy as heat through uncoupling protein 1. Here, we report that rapamycin blocks the ability of β-adrenergic signaling to induce beige adipocytes and expression of thermogenic genes in white adipose depots. Rapamycin enhanced transcriptional negative feedback on the β3-adrenergic receptor. However, thermogenic gene expression remained impaired even when the receptor was bypassed with a cell-permeable cAMP analog, revealing the existence of a second inhibitory mechanism. Accordingly, rapamycin-treated mice are cold intolerant, failing to maintain body temperature and weight when shifted to 4°C. Adipocyte-specific deletion of the mTORC1 subunit Raptor recapitulated the block in β-adrenergic signaling. Our findings demonstrate a positive role for mTORC1 in the recruitment of beige adipocytes and suggest that inhibition of β-adrenergic signaling by rapamycin may contribute to its physiological effects.
authors: Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors: Cassie M
authors: 0000-0001-7254-2245
authors: CM
authors: Tran
authors: Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors: Sarmistha
authors: S
authors: Mukherjee
authors: State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.
authors: Lan
authors: L
authors: Ye
authors: Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors: David W
authors: DW
authors: Frederick
authors: Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors: Megan
authors: M
authors: Kissig
authors: Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors: James G
authors: JG
authors: Davis
authors: Department of Medicine, University of Wisconsin-Madison, Madison, WI.
authors: Dudley W
authors: DW
authors: Lamming
authors: Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors: Patrick
authors: P
authors: Seale
authors: Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA baur@mail.med.upenn.edu.
authors: Joseph A
authors: JA
authors: Baur
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000502:physiology; D052436:Adipose Tissue, White / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D004149:Dioxoles / Q000494:pharmacology; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020123:Sirolimus / Q000494:pharmacology*; D022722:Thermogenesis / Q000187:drug effects* / Q000235:genetics
chemical_list: D004149:Dioxoles; C076126:disodium (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)-amino)propyl)-1,3-benzodioxole-2,3-dicarboxylate; D020123:Sirolimus