title: Large increases in adipose triacylglycerol flux in Cushingoid CRH-Tg mice are explained by futile cycling.
abstract: Glucocorticoids are extremely effective anti-inflammatory therapies, but their clinical use is limited due to severe side effects, including osteoporosis, muscle wasting, fat redistribution, and skin thinning. Here we use heavy water labeling and mass spectrometry to measure fluxes through metabolic pathways impacted by glucocorticoids. We combine these methods with measurements of body composition in corticotropin-releasing hormone (CRH)-transgenic (Tg)(+) mice that have chronically elevated, endogenously produced corticosterone and a phenotype that closely mimics Cushing's disease in humans. CRH-Tg(+) mice had increased adipose mass, adipose triglyceride synthesis, and greatly increased triglyceride/fatty acid cycling in subcutaneous and abdominal fat depots and increased de novo lipogenesis in the abdominal depot. In bone, CRH-Tg(+) mice had decreased bone mass, absolute collagen synthesis rates, and collagen breakdown rate. In skin, CRH-Tg(+) mice had decreased skin thickness and absolute collagen synthesis rates but no decrease in the collagen breakdown rate. In muscle, CRH-Tg(+) mice had decreased muscle mass and absolute protein synthesis but no decrease in the protein breakdown rate. We conclude that chronic exposure to endogenous glucocorticoid excess in mice is associated with ongoing decreases in bone collagen, skin collagen, and muscle protein synthesis without compensatory reduction (coupling) of breakdown rates in skin and muscle. Both of these actions contribute to reduced protein pool sizes. We also conclude that increased cycling between triglycerides and free fatty acids occurs in both abdominal and subcutaneous fat depots in CRH-Tg(+) mice. CRH-Tg mice have both increased lipolysis and increased triglyceride synthesis in adipose tissue.
authors.affiliation: Gladstone Institute for Cardiovascular Disease, San Francisco, CA, USA. charris@gladstone.ucsf.edu
authors.forename: Charles
authors.initials: C
authors.lastname: Harris
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Roohk
authors.forename: Mark
authors.initials: M
authors.lastname: Fitch
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Boudignon
authors.forename: Bernard P
authors.initials: BP
authors.lastname: Halloran
authors.forename: Marc K
authors.initials: MK
authors.lastname: Hellerstein
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D050154:Adiposity; D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D047748:Pituitary ACTH Hypersecretion / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism*
chemical_list: D014280:Triglycerides; D003346:Corticotropin-Releasing Hormone