PPAR gamma mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance.
Agonist-induced activation of peroxisome proliferator-activated receptor gamma (PPAR gamma) is known to cause adipocyte differentiation and insulin sensitivity. The biological role of PPAR gamma was investigated by gene targeting. Homozygous PPAR gamma-deficient embryos died at 10.5-11.5 dpc due to placental dysfunction. Quite unexpectedly, heterozygous PPAR gamma-deficient mice were protected from the development of insulin resistance due to adipocyte hypertrophy under a high-fat diet. These phenotypes were abrogated by PPAR gamma agonist treatment. Heterozygous PPAR gamma-deficient mice showed overexpression and hypersecretion of leptin despite the smaller size of adipocytes and decreased fat mass, which may explain these phenotypes at least in part. This study reveals a hitherto unpredicted role for PPAR gamma in high-fat diet-induced obesity due to adipocyte hypertrophy and insulin resistance, which requires both alleles of PPAR gamma.
Kubota
N
N
Department of Metabolic Diseases, University of Tokyo, Japan.
Terauchi
Y
Y
Miki
H
H
Tamemoto
H
H
Yamauchi
T
T
Komeda
K
K
Satoh
S
S
Nakano
R
R
Ishii
C
C
Sugiyama
T
T
Eto
K
K
Tsubamoto
Y
Y
Okuno
A
A
Murakami
K
K
Sekihara
H
H
Hasegawa
G
G
Naito
M
M
Toyoshima
Y
Y
Tanaka
S
S
Shiota
K
K
Kitamura
T
T
Fujita
T
T
Ezaki
O
O
Aizawa
S
S
Kadowaki
T
T
D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D048429:Cell Size / Q000235:genetics*; D004032:Diet; D004435:Eating; D004734:Energy Metabolism; D005223:Fats / Q000494:pharmacology*; D005328:Fetal Viability / Q000235:genetics; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007333:Insulin Resistance / Q000235:genetics*; D020738:Leptin / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000473:pathology; D000077205:Pioglitazone; D010920:Placenta / Q000473:pathology; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists / Q000235:genetics* / Q000378:metabolism
D001786:Blood Glucose; D005223:Fats; D007004:Hypoglycemic Agents; D020738:Leptin; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077205:Pioglitazone