PPARgamma activation in adipocytes is sufficient for systemic insulin sensitization.
Although peroxisome proliferator-activated receptor gamma (PPARgamma) agonists such as thiazolidinediones (TZDs) are widely used to treat type 2 diabetes, how its activation in individual tissues contributes to TZD's therapeutic action remains controversial. As TZDs are known to have receptor-independent effects, we sought to establish gain-of-function animal models to delineate the receptor's insulin-sensitizing actions. Unexpectedly, we find that selective activation of PPARgamma in adipocytes, but not in macrophages, is sufficient for whole-body insulin sensitization equivalent to systemic TZD treatment. In addition to improved adipokine, inflammatory, and lipid profiles, PPARgamma activation in mature adipocytes normalizes serum insulin without increased adipogenesis. Co-culture studies indicated that PPARgamma-activated adipocytes broadly suppress induction of inflammatory cytokines and C-X-C family chemokines in macrophages. Collectively, these data describe an "adipocentric" model in which adipose activation of PPARgamma is sufficient for complete insulin sensitization and suggest a specific application for fat selective PPARgamma modulators in diabetic therapy.
Sugii
Shigeki
S
Gene Expression Laboratory, Howard Hughes Medical Institute and The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Olson
Peter
P
Sears
Dorothy D
DD
Saberi
Maziyar
M
Atkins
Annette R
AR
Barish
Grant D
GD
Hong
Suk-Hyun
SH
Castro
Glenda L
GL
Yin
Yun-Qiang
YQ
Nelson
Michael C
MC
Hsiao
Gene
G
Greaves
David R
DR
Downes
Michael
M
Yu
Ruth T
RT
Olefsky
Jerrold M
JM
Evans
Ronald M
RM
D041721:3T3-L1 Cells; D052438:Adipocytes, White / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D000077205:Pioglitazone; D051381:Rats; D011924:Rats, Zucker; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000494:pharmacology
D018925:Chemokines; D007004:Hypoglycemic Agents; D018836:Inflammation Mediators; D007328:Insulin; D047495:PPAR gamma; D011993:Recombinant Fusion Proteins; D045162:Thiazolidinediones; D000077205:Pioglitazone