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Inhibition of adipogenesis through MAP kinase-mediated phosphorylation of PPARgamma
1Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Abstract:
Adipocyte differentiation is an important component of obesity and other metabolic diseases. This process is strongly inhibited by many mitogens and oncogenes. Several growth factors that inhibit fat cell differentiation caused mitogen-activated protein (MAP) kinase-mediated phosphorylation of the dominant adipogenic transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma) and reduction of its transcriptional activity. Expression of PPARgamma with a nonphosphorylatable mutation at this site (serine-112) yielded cells with increased sensitivity to ligand-induced adipogenesis and resistance to inhibition of differentiation by mitogens. These results indicate that covalent modification of PPARgamma by serum and growth factors is a major regulator of the balance between cell growth and differentiation in the adipose cell lineage.
Insights
Growth factors inhibit fat cell differentiation by phosphorylating peroxisome proliferator-activated receptor gamma (PPARgamma). Mutating PPARgamma enhances adipogenesis, revealing its role in regulating cell growth versus differentiation.
Area of Science:
- Cellular biology
- Metabolic disease research
- Molecular endocrinology
Background:
- Adipocyte differentiation is crucial for metabolic health and implicated in obesity.
- Mitogens and oncogenes often impede fat cell differentiation.
- Growth factors play a significant role in regulating adipogenesis.
Purpose of the Study:
- To investigate the molecular mechanisms by which growth factors inhibit adipocyte differentiation.
- To determine the role of peroxisome proliferator-activated receptor gamma (PPARgamma) phosphorylation in this process.
Main Methods:
- Studied the effect of mitogens and growth factors on adipocyte differentiation.
- Analyzed mitogen-activated protein (MAP) kinase-mediated phosphorylation of PPARgamma.
- Utilized site-directed mutagenesis to create a nonphosphorylatable PPARgamma mutant (serine-112).
- Assessed ligand-induced adipogenesis and differentiation inhibition in cells expressing wild-type and mutant PPARgamma.
Main Results:
- Growth factors that inhibit differentiation induce MAP kinase-mediated phosphorylation of PPARgamma.
- This phosphorylation reduces PPARgamma's transcriptional activity.
- Cells expressing a nonphosphorylatable PPARgamma mutant showed increased sensitivity to ligand-induced adipogenesis.
- These cells were also resistant to differentiation inhibition by mitogens.
Conclusions:
- Covalent modification of PPARgamma is a key regulator of adipocyte differentiation.
- Phosphorylation of PPARgamma by growth factors balances cell growth and differentiation in adipose lineage.
- Targeting PPARgamma phosphorylation may offer therapeutic strategies for metabolic diseases.