Induction of adipocyte complement-related protein of 30 kilodaltons by PPARgamma agonists: a potential mechanism of insulin sensitization.
Adipocyte complement-related protein of 30 kDa (Acrp30, adiponectin, or AdipoQ) is a fat-derived secreted protein that circulates in plasma. Adipose tissue expression of Acrp30 is lower in insulin-resistant states and it is implicated in the regulation of in vivo insulin sensitivity. Here we have characterized the ability of PPARgamma agonists to modulate Acrp30 expression. After chronic treatment of obese-diabetic (db/db) mice with PPARgamma agonists (11 d), mean plasma Acrp30 protein levels increased (>3x). Similar effects were noted in a nongenetic type 2 diabetes model (fat-fed and low-dose streptozotocin-treated mice). In contrast, treatment of mice (db/db or fat-fed) with metformin or a PPARalpha agonist did not affect plasma Acrp30 protein levels. In a cohort of normal human subjects, 14-d treatment with rosiglitazone also produced a 130% increase in circulating Acrp30 levels vs. placebo. In addition, circulating Acrp30 levels were suppressed 5-fold in patients with severe insulin resistance in association with dominant-negative PPARgamma mutations. Thus, induction of adipose tissue Acrp30 expression and consequent increases in circulating Acrp30 levels represents a novel potential mechanism for PPARgamma-mediated enhancement of whole-body insulin sensitivity. Furthermore, Acrp30 is likely to be a biomarker of in vivo PPARgamma activation.
Combs
Terry P
TP
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Wagner
John A
JA
Berger
Joel
J
Doebber
Tom
T
Wang
Wen-Jun
WJ
Zhang
Bei B
BB
Tanen
Michael
M
Berg
Anders H
AH
O'Rahilly
Stephen
S
Savage
David B
DB
Chatterjee
Krishna
K
Weiss
Stuart
S
Larson
Patrick J
PJ
Gottesdiener
Keith M
KM
Gertz
Barry J
BJ
Charron
Maureen J
MJ
Scherer
Philipp E
PE
Moller
David E
DE
D016475:3T3 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D052242:Adiponectin; D000818:Animals; D001798:Blood Proteins / Q000096:biosynthesis*; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D008687:Metformin / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D010865:Pilot Projects; D011506:Proteins; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics; D000077154:Rosiglitazone; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists* / Q000235:genetics
D052242:Adiponectin; D001798:Blood Proteins; D007004:Hypoglycemic Agents; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone; D008687:Metformin