Macrophage PPAR gamma is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones.
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.
Hevener
Andrea L
AL
Department of Medicine, Division of Endocrinology and Metabolism, UCSD, La Jolla, California, USA. ahevener@mednet.ucla.edu
Olefsky
Jerrold M
JM
Reichart
Donna
D
Nguyen
M T Audrey
MT
Bandyopadyhay
Gautam
G
Leung
Ho-Yin
HY
Watt
Matthew J
MJ
Benner
Chris
C
Febbraio
Mark A
MA
Nguyen
Anh-Khoi
AK
Folian
Brian
B
Subramaniam
Shankar
S
Gonzalez
Frank J
FJ
Glass
Christopher K
CK
Ricote
Mercedes
M
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*
D017931:DNA Primers; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones