Obesity and the Regulation of Body Mass:- Diet Regulates the Expression of Genes Central to Maintaining Body Mass
Proteins in a family of ligand-activated transcription fac tors, the peroxisome proliferator-activated receptors (PPARs), respond to changes in dietary lipid by altering the expression of genes involved in fat and carbohydrate metabolism. These transcription factors were first recognized for their roles in peroxisome synthesis—thus their name. Their normal ligands are fatty acids or fatty acid derivatives, but they can also bind synthetic agonists and can be activated in the lab oratory by genetic manipulation. PPARα, PPARδ, and PPARγ are members of the nuclear receptor superfamily. They act in the nucleus by forming heterodimers with another nuclear receptor, RXR (retinoid X receptor), binding to regulatory regions of DNA near the genes under their control and changing the rate of transcription of those genes (Fig. 1).
PPARγ expressed primarily in liver and adipose tissue, is involved in turning on genes necessary to the differentiation of fibroblasts into adipocytes and genes that encode proteins required for lipid synthesis and storage in adipocytes. PPAR is activated by drugs of the thiazolidinedione class, which are used to treat type II diabetes. PPARα in hepatocytes turns on the genes necessary for β oxidation of fatty acids and formation of ketone bodies during fasting.
PPAR δ is a key regulator of fat oxidation, which acts by sensing changes in dietary lipid. It acts in liver and muscle, stimulating the transcription of at least nine genes encoding proteins for β oxidation and for energy dissipation through uncoupling of mitochondria. Normal mice overfed on high-fat diets accumulate massive amounts of both brown and white fat, and fat droplets accumulate in the liver. But when the same overfeeding experiment is done with mice that have a genetically altered, always active PPAR , this fat accumulation is prevented. In mice with a nonfunctioning leptin receptor (db/db), activated PPAR prevents the development of obesity that would otherwise occur . By stimulating fatty acid breakdown in uncoupled mitochondria, PPARδ causes fat depletion, weight loss, and thermogenesis. Seen in this light, thermogenesis is both a means of keeping warm and a defense against obesity. Clearly, PPARδ is a potential target for drugs to treat obesity.
FIGURE 1 Mode of action of PPARs. PPARs, when bound to their cognate ligand, form heterodimers with the nuclear receptor RXR. The dimer binds specific regions of DNA, response elements, stimulating transcription of genes in those regions.
