Genetic modulation of PPARgamma phosphorylation regulates insulin sensitivity.
Obesity-associated diabetes is epidemic in industrialized societies. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is highly expressed in adipose tissue and the presumed molecular target for antidiabetic thiazolidinedione drugs that reverse insulin resistance but also promote weight gain. Phosphorylation reduces the activity of PPARgamma in vitro, but physiological relevance has not been demonstrated. We have studied mice homozygous for a mutation (S112A) that prevents PPARgamma phosphorylation. Surprisingly, the weights and adipose mass of PPARgamma-S112A mice are not greater than wild-type. Remarkably, however, genetic prevention of PPARgamma phosphorylation preserves insulin sensitivity in the setting of diet-induced obesity. Underlying this protection are smaller fat cells, elevated serum adiponectin, and reduced free fatty acid levels. Thus, the phosphorylation state of PPARgamma modulates insulin sensitivity. Compounds that prevent PPARgamma phosphorylation or ligands that induce the conformation of nonphosphorylated PPARgamma may selectively enhance insulin sensitivity without increasing body weight.
Rangwala
Shamina M
SM
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Rhoades
Ben
B
Shapiro
Jennifer S
JS
Rich
A Sophie
AS
Kim
Jason K
JK
Shulman
Gerald I
GI
Kaestner
Klaus H
KH
Lazar
Mitchell A
MA
D052242:Adiponectin; D000273:Adipose Tissue / Q000378:metabolism; D002001:Adipose Tissue, Brown; D000409:Alanine / Q000235:genetics; D019943:Amino Acid Substitution; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015139:Blotting, Southern; D001835:Body Weight; D048429:Cell Size; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D015151:Immunoblotting; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D007333:Insulin Resistance; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic / Q000097:blood / Q000235:genetics; D009154:Mutation; D009765:Obesity / Q000097:blood / Q000139:chemically induced; D010766:Phosphorylation; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012694:Serine / Q000235:genetics; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D052242:Adiponectin; D001786:Blood Glucose; D017077:Culture Media, Conditioned; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin; D011506:Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D012694:Serine; D005947:Glucose; D000409:Alanine