Regulating metabolism of fat is an important challenge for any animal,
from nematodes to humans. Central players in the regulatory network are
the nuclear hormone receptors (NHRs), which are transcription factors
that turn on or off a set of target genes when bound by specific lipid
molecules. In the premier open-access journal PLoS Biology, Keith
Yamamoto and colleagues show that the nuclear hormone receptor nhr-49
controls two different aspects of fat metabolism, which interact to
form a feedback system controlling the consumption and composition of
fats in the nematode.
Using RNAi to suppress gene expression, the researchers discovered
that when nhr-49 was absent, the lifespan of the nematode was reduced
by more than 50%, and the animal displayed numerous gross abnormalities
in the gut and gonad. This was accompanied by unusually high fat
content in the larvae. They further showed that deletion of nhr-49
changed expression of 13 genes related to fat and glucose metabolism,
with the most dramatic effects occurring within two metabolic pathways:
mitochondrial lipid oxidation and fatty acid desaturation.
Following up on these changes in gene expression, Yamamoto and
colleagues show that in its normal actions, nhr-49 sets in motion two
opposing pathways: it increases expression of a gene acs-2, which leads
to reduction of fat content, and it increases expression of another
gene fat-7, which, by reducing acs-2, increases fat content. In its
function, nhr-49 resembles a mammalian NHR, called peroxisome
proliferator-activated receptors (PPARs). Further investigation of this
link may lead to better understanding of the functions of PPARs and
provide opportunities for altering their function for treatment of fat
metabolism disorders such as diabetes and obesity.
Public Library Of Science. February 2005.