Manipulation of the process by which the body burns fat has long been a focus of efforts to treat obesity, but the underlying molecular pathways are not well understood. A recent paper published in Cell sheds light on this situation by showing that a ligand-activated transcription factor known as peroxisome-proliferator-activated receptor-δ (PPAR-δ) stimulates fat burning, which indicates that drugs that activate PPAR-δ might have potential for treating obesity.
Although two other PPARs — PPAR-α and PPAR-γ — are known to be important in fat metabolism, the role of PPAR-δ was unclear, and so Ronald Evans and colleagues set out to investigate its activity by using genetically modified mice. Selective expression of an activated form of PPAR-δ in adipose tissue resulted in mice with a lean phenotype, although their food intake on a standard diet was normal. And when these mice were fed a high-fat diet, weight gain and lipid accumulation were markedly reduced compared with control mice. Further experiments with Leprdb/db mice, which are predisposed to obesity, showed that expression of activated PPAR-δ reverses the obesity phenotype, and also that short-term treatment with a PPAR-δ agonist markedly depletes lipid accumulation.
All the mouse data are consistent with the idea that PPAR-δ activation upregulates fatty-acid combustion. But what is the molecular basis of this effect? To clarify this, the authors monitored the expression of genes involved in fatty acid metabolism, and found that PPAR-δ activation specifically induces the expression of genes required for fatty-acid oxidation and energy dissipation.
Overall, the authors' findings indicate that PPAR-δ is a key regulator of fat burning. PPAR-δ agonists might be particularly promising drug candidates for treating obesity as they can protect the body against both genetic and dietary obesity, and, furthermore, PPAR-γ — which is closely related to PPAR-δ — is already validated as the target of antidiabetes drugs of the thiazolidinedione class.
ORIGINAL RESEARCH PAPER
Wang, Y. -X. et al. Peroxisome-proliferator-activated receptor δ activates fat metabolism to prevent obesity. Cell 113, 159–170 (2003)
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Kirkpatrick, P. Turning on fat burning. Nat Rev Drug Discov 2, 422 (2003). https://doi.org/10.1038/nrd1120
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DOI: https://doi.org/10.1038/nrd1120