Preferred Label : Obesity and Thermogenesis Pathway;
NCIt related terms : Role of PPAR-gamma Coactivators in Obesity and Thermogenesis;
Alternative definition : BIOCARTA: Nuclear hormone receptors are transcription factors that bind DNA and regulate
transcription in a ligand-dependent manner. PPAR-gamma is a member of this gene family
that is activated by fatty acids and thiazolidinedione drugs that plays a role in
insulin sensitivity and adipogenesis. Like PPAR-alpha and other members of this gene
family, PPAR-gamma activates transcription in concert with coactivators including
Src-1 and Tif2. Although these coactivators act for multiple members of this gene
family, coactivators may have specific functions in some settings. Deletion of the
Src-1 gene or Tif2 gene in mice reduced the response to steroid hormones and development
dependent on these hormones. Some PPAR-gamma ligands induce the specific recruitment
of coactivators, and might evoke different functional responses based on the interactions
they favor. The natural ligand 15-deoxy prostaglandin J2 stimulated PPAR-gamma interaction
with SRC-1, TIF2, TRAP220, and p300, while the synthetic PPAR-gamma ligand troglitazone,
an antidiabetic thiazolidinedione drug, did not promote these interactions, indicating
that other distinct coactivators may mediate the response to PPAR-gamma when it binds
this ligand. In normal rodents, a high-fat diet leads to high levels and free fatty
acids and PPAR-gamma activation in white adipose tissue, stimulating fat uptake, adipogenesis
and obesity. PPAR-gamma activation in brown adipose tissue depends mainly on Src-1
as a coactivator and Src-1 is essential for PGC-1 alpha to act as a coactivator to
stimulate thermogenesis. Regulation of energy use by PGC-1 in other tissues such as
muscle may contribute to weight loss associated with cancer and increased metabolism
induced by exercise. High-fat feeding and high plasma free fatty acids reduce thermogenesis
in brown fat due to the greater requirement of PPAR-gamma for Src-1 than Tif2 for
activation in these cells. In white adipose cells, Tif2 predominates as the PPAR-gamma
coactivator, stimulating fat uptake and adipogenesis in conditions of high-fat feeding.
Trap220, a component of the TRAP coactivator complex, is also required for adipogenesis.
Examining the metabolic consequences of coactivator deletion, Src-1 and Tif2 specifically
alter PPAR-gamma signaling. Compared to normal rodents, Mice lacking the Tif2 coactivator
are resistant to obesity when fed a high-fat diet, with increased lipolysis in adipocytes
and decreased fatty acid uptake in adipose tissue. A high-fat diet increases the expression
of Tif2 in both brown and white adipose cells, changing the Tif2 to Src-1 ratio. This
change in the ratio of coactivators favors increased adipogenesis in white adipose
while it blocks thermogenesis in brown adipose cells by opposing Src-1/PGC-1 alpha
dependent signaling. (This definition may be outdated - see the DesignNote.);
NCIt note : The BIOCARTA Definition (ALT_DEFINITION) for this pathway concept was provided by
BioCarta. This property was not created by, nor is it maintained by the NCI Thesaurus
staff. Additionally, BioCarta is no longer updating its pathway data; thus, the BIOCARTA
Definition might be outdated or inaccurate. Please see the Terms and Conditions for
Use at http://www.biocarta.com/.;
Biocarta ID : h_ppargPathway;
Origin ID : C39198;
UMLS CUI : C1518525;
Semantic type(s)
- has_gene_product_element
- pathway_has_gene_element
