title: Macrophage PPAR gamma is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones.
abstract: PPAR gamma is required for fat cell development and is the molecular target of antidiabetic thiazolidinediones (TZDs), which exert insulin-sensitizing effects in adipose tissue, skeletal muscle, and liver. Unexpectedly, we found that inactivation of PPAR gamma in macrophages results in the development of significant glucose intolerance plus skeletal muscle and hepatic insulin resistance in lean mice fed a normal diet. This phenotype was associated with increased expression of inflammatory markers and impaired insulin signaling in adipose tissue, muscle, and liver. PPAR gamma-deficient macrophages secreted elevated levels of factors that impair insulin responsiveness in muscle cells in a manner that was enhanced by exposure to FFAs. Consistent with this, the relative degree of insulin resistance became more severe in mice lacking macrophage PPAR gamma following high-fat feeding, and these mice were only partially responsive to TZD treatment. These findings reveal an essential role of PPAR gamma in macrophages for the maintenance of whole-body insulin action and in mediating the antidiabetic actions of TZDs.
authors.affiliation: Department of Medicine, Division of Endocrinology and Metabolism, UCSD, La Jolla, California, USA. ahevener@mednet.ucla.edu
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Hevener
authors.forename: Jerrold M
authors.initials: JM
authors.lastname: Olefsky
authors.forename: Donna
authors.initials: D
authors.lastname: Reichart
authors.forename: M T Audrey
authors.initials: MT
authors.lastname: Nguyen
authors.forename: Gautam
authors.initials: G
authors.lastname: Bandyopadyhay
authors.forename: Ho-Yin
authors.initials: HY
authors.lastname: Leung
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Watt
authors.forename: Chris
authors.initials: C
authors.lastname: Benner
authors.forename: Mark A
authors.initials: MA
authors.lastname: Febbraio
authors.forename: Anh-Khoi
authors.initials: AK
authors.lastname: Nguyen
authors.forename: Brian
authors.initials: B
authors.lastname: Folian
authors.forename: Shankar
authors.initials: S
authors.lastname: Subramaniam
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Glass
authors.forename: Mercedes
authors.initials: M
authors.lastname: Ricote
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D020869:Gene Expression Profiling; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D047495:PPAR gamma / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D017931:DNA Primers; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones