Decreased PPAR gamma expression compromises perigonadal-specific fat deposition and insulin sensitivity.
Mutations and polymorphisms in PPARG have been linked to adiposity and partial lipodystrophy in humans. However, how disturbances in PPARG lead to depot-specific effects on adipose tissue, as shown by the characteristic aberrant fat distribution in patients, remains unclear. By manipulating the 3'-untranslated region of the Pparg gene, we have generated mice with peroxisome proliferator-activated receptor gamma (PPAR gamma) gene expression ranging from 25% to 100% normal. Basal levels of PPAR gamma transcripts between 50% and approximately 100% had no significant effect on body weight, fat mass, and insulin sensitivity. In contrast, mice with 25% normal PPAR gamma expression exhibited reduced body weight and total fat mass, insulin resistance, and dyslipidemia. Interestingly, fat mass was selectively reduced in perigonadal depot without significant changes in inguinal and other depots. Expression of adipogenic factor CCAAT enhancer binding protein-alpha and some other metabolic genes containing peroxisome proliferator response element were reduced in a perigonadal depot-specific fashion. This was further associated with depot-specific reduction in the expression of adipokines, increased expression of TNFalpha, and increased ectopic lipid deposition in muscles. Together, these results underscore the differential sensitivity of the individual fat depots on PPAR gamma availability as an underlying mechanism of partial lipodystrophy.
Tsai
Yau-Sheng
YS
Institute of Clinical Medicine, National Cheng Kung University, Tainan 701, Taiwan, Republic of China. yaustsai@mail.ncku.edu.tw
Tsai
Pei-Jane
PJ
Jiang
Man-Jin
MJ
Chou
Ting-Yu
TY
Pendse
Avani
A
Kim
Hyung-Suk
HS
Maeda
Nobuyo
N
D017667:Adipocytes / Q000166:cytology; D000483:Alleles; D000818:Animals; D001823:Body Composition; D004742:Enhancer Elements, Genetic; D005260:Female; D005786:Gene Expression Regulation; D005951:Glucose Tolerance Test; D006066:Gonads / Q000473:pathology; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008060:Lipodystrophy / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D047495:PPAR gamma / Q000096:biosynthesis* / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D047495:PPAR gamma; D014409:Tumor Necrosis Factor-alpha