Regulation of small ubiquitin-like modifier-1, nuclear receptor coreceptor, histone deacetylase 3, and peroxisome proliferator-activated receptor-γ in human adipose tissue.
BACKGROUND
This study investigated the regulation of peroxisome proliferator-activated receptor-γ (PPARγ), the histone deacetylase 3 (HDAC3)-nuclear receptor coreceptor (NCoR) complex (a corepressor of transcription used by PPARγ), and small ubiquitin-like modifier-1 (SUMO-1) (a posttranslational modifier of PPARγ) in human adipose tissue and both adipocyte and macrophage cell lines. The objective was to determine whether there were alterations in the human adipose tissue gene expression levels of PPARγ, HDAC3, NCoR, and SUMO-1 associated either with obesity or with treatment of impaired glucose tolerance (IGT) subjects with insulin-sensitizing medications.


METHODS
We obtained subcutaneous adipose tissue biopsies from 86 subjects with a wide range of body mass index (BMI) and insulin sensitivity (S(I)). Additionally, adipose tissue biopsies were obtained from a randomized subgroup of IGT subjects before and after 10 weeks of treatment with either pioglitazone or metformin.


RESULTS
The adipose mRNA levels of PPARγ, NCoR, HDAC3, and SUMO-1 correlated strongly with each other (P<0.0001); however, SUMO-1, NCoR, and HDAC3 gene expression were not significantly associated with BMI or S(I). Pioglitazone increased SUMO-1 expression by 23% (P<0.002) in adipose tissue and an adipocyte cell line (P<0.05), but not in macrophages. Small interfering RNA (siRNA)-mediated knockdown of SUMO-1 decreased PPARγ, HDAC3, and NCoR in THP-1 cells and increased tumor necrosis factor-α (TNF-α) induction in response to lipopolysaccharide (LPS).


CONCLUSIONS
These results suggest that the coordinate regulation of SUMO-1, PPARγ1/2, HDAC3, and NCoR may be more tightly controlled in macrophages than in adipocytes in human adipose and that these modulators of PPARγ activity may be particularly important in the negative regulation of macrophage-mediated adipose inflammation by pioglitazone.
The Department of Medicine, Division of Endocrinology, and the Barnstable Brown Diabetes and Obesity Center, University of Kentucky, Lexington, Kentucky 40536, USA. bfinlin@uky.edu
Brian S
BS
Finlin
Angela M
AM
Bodles-Brakhop
Aiwei
A
Yao-Borengasser
Beibei
B
Zhu
Catherine P
CP
Starnes
Robert E
RE
McGehee
Charlotte A
CA
Peterson
Philip A
PA
Kern
Neda
N
Rasouli
D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D001706:Biopsy; D015992:Body Mass Index; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005951:Glucose Tolerance Test; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008024:Ligands; D008297:Male; D008875:Middle Aged; D056971:Nuclear Receptor Co-Repressor 1 / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism*; D000077205:Pioglitazone; D034741:RNA, Small Interfering / Q000378:metabolism; D025842:SUMO-1 Protein / Q000378:metabolism*; D045162:Thiazolidinediones / Q000494:pharmacology; D000099186:Histone Deacetylase 3
D006655:Histone Deacetylases; D007328:Insulin; D008024:Ligands; D056971:Nuclear Receptor Co-Repressor 1; D047495:PPAR gamma; D000077205:Pioglitazone; D034741:RNA, Small Interfering; D025842:SUMO-1 Protein; D045162:Thiazolidinediones; D000099186:Histone Deacetylase 3; C539127:NCOR1 protein, human; C495501:SUMO1 protein, human