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Peroxisome proliferator-activated receptor gamma modulation and lipogenic response in adipocytes of
Jennifer K Yee1, Wai-Nang Paul Lee, Michael G Ross
1Department of Pediatrics, Division of Endocrinology, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, David Geffen School of Medicine at UCLA, 1000 West Carson Street, Harbor Box 446, Torrance, CA 90509, USA. jyee@labiomed.org.
Insights
Small-for-gestational age (SGA) offspring exhibit enhanced fat cell development and lipid synthesis early in life. By postnatal day 21, SGA adipocytes show resistance to PPARγ repressors and a specific response to activators, impacting fatty acid metabolism.
Area of Science:
- Endocrinology
- Metabolic Research
- Developmental Biology
Background:
- Small-for-gestational age (SGA) birth is linked to increased risks of adult obesity and insulin resistance.
- SGA offspring exhibit elevated adipose tissue PPARγ and de novo fatty acid synthesis during nursing.
- Age-dependent lipogenesis in SGA adipocytes and the impact of PPARγ modulators remain unclear.
Purpose of the Study:
- To assess adipogenic and lipogenic potential in SGA adipocytes at postnatal days 1 and 21.
- To investigate the effects of PPARγ activators and repressors on SGA adipocyte lipogenesis.
- To determine the fatty acid metabolic response to PPARγ activator treatment in SGA adipocytes.
Main Methods:
- Primary adipocyte cultures from SGA and control rat offspring (postnatal days 1 and 21) were established.
- Cell proliferation, Oil Red O staining, and protein expression (PPARγ, SREBP1) were quantified.
- Lipogenesis was assessed using U13C-glucose tracing and GC/MS following treatment with rosiglitazone or BADGE.
Main Results:
- SGA adipocytes showed increased proliferation and lipid accumulation at both postnatal days 1 and 21.
- At postnatal day 21, SGA adipocytes exhibited heightened lipogenic gene expression and glucose-mediated de novo fatty acid synthesis.
- Rosiglitazone further enhanced glucose utilization for fatty acid synthesis in p21 SGA adipocytes, which were resistant to BADGE treatment.
Conclusions:
- SGA adipocytes possess enhanced early-life adipogenic and lipogenic capacity.
- By postnatal day 21, SGA adipocytes display resistance to PPARγ repressor ligands.
- High-dose PPARγ activator treatment selectively impacts gene expression, and p21 SGA adipocytes show increased de novo fatty acid synthesis linked to glucose metabolism.
Background:
Small-for-gestational age (SGA) at birth increases risk of development of adult obesity and insulin resistance. A model of SGA rat offspring has been shown to exhibit increased adipose tissue expression of a key adipogenic transcription factor, peroxisome proliferator-activated receptor gamma (PPARγ), and increased fatty acid de novo synthesis during the nursing period, prior to onset of obesity. PPARγ agonists have been studied for potential use in the prevention of insulin resistance. Moreover, SGA adipocytes exhibit age-dependent differences in lipogenesis as mediated by PPARγ. The effects of PPARγ modulators on lipogenic gene expression and de novo lipogenesis on the age-dependent changes in SGA adipocytes are not known. The objectives of this study were: 1) to determine the adipogenic and lipogenic potential in SGA adipocytes at postnatal day 1 (p1) and day 21 (p21), 2) to determine how the PPARγ activator- and repressor-ligands affect the lipogenic potential, and 3) to determine the fatty acid metabolic response to PPARγ activator-ligand treatment.
Methods:
Primary adipocyte cultures from p1 and p21 SGA and Control male offspring were established from a known maternal food-restriction model of SGA. Cell proliferation and Oil Red O (ORO) staining were quantified. Adipocytes were treated with increasing doses of rosiglitazone or bisphenol-A diglycidyl ether (BADGE). PPARγ and SREBP1 protein expression were determined. De novo lipogenesis with rosiglitazone treatment at p21 was studied using 50% U13C-glucose and gas chromatography/mass spectrometry.
Results:
At p1 and p21, SGA demonstrated increased cell proliferation and increased ORO staining. At p21, SGA demonstrated increased lipogenic gene expression and increased glucose-mediated fatty acid de novo synthesis compared with Controls. In response to rosiglitazone, SGA adipocytes further increased glucose utilization for fatty acid synthesis. SGA lipogenic gene expression demonstrated resistance to BADGE treatment.
Conclusions:
SGA adipocytes exhibit an enhanced adipogenic and lipogenic potential in early postnatal life. By p21, SGA demonstrated resistance to PPARγ repressor-ligand treatment, and selective response to high dose PPARγ activator-ligand treatment in adipogenic and lipogenic gene expression. p21 SGA adipocytes revealed increased fatty acid de novo synthesis through a complex relationship with glucose metabolism.
