We have found that the C. elegans nuclear hormone receptor
nhr-49 is a key regulator of fatty acid metabolism. Worms lacking
nhr-49 function,
nhr-49(
nr2041), displayed two phenotypes, high fat content and reduced lifespan. Using a quantitative RT-PCR gene expression assay, we discovered that
nhr-49 affected the expression of 13 genes involved in fatty acid metabolism. Among the genes most significantly compromised by
nhr-49 deletion were the mitochondrial b -oxidation enzymes acetyl-CoA synthetase (
acs-2 ) and enoyl-CoA hydratase/3'OH acyl-CoA dehydrogenase (
ech-1 ), as well as the D 9 desaturases
fat-5 and
fat-7 , which convert saturated fatty acids to monounsaturated fatty acids. Therefore it is clear that
nhr-49 plays a prominent role in positively regulating genes involved in two fatty acid metabolism pathways, b -oxidation and desaturation. As mitochondrial b -oxidation is involved in the breakdown of fats for energy, we hypothesized that the high fat phenotype of
nhr-49(
nr2041) animals is due to an impaired ability to burn fat in mitochondria. Indeed, RNA interference of either
acs-2 or
ech-1 was sufficient to increase fat content, demonstrating that reduced mitochondrial b -oxidation alone could account lead to elevated fat content. Surprisingly, we also found RNAi of
fat-7 yielded a low fat phenotype, suggesting that
fat-7 is responsible for promoting fat storage. Consequently
nhr-49 stimulates the expression of genes that promote fat consumption (
acs-2 and
ech-1 ) and enhance fat storage (
fat-7 ). The functions of
nhr-49 are strikingly similar to those of the mammalian nuclear hormone receptor PPAR a , which also promotes fat consumption by activating mitochondrial b -oxidation, and at the same time stimulates expression of the mammalian ortholog of
fat-7 , stearoyl-CoA desaturase (SCD), an enzyme that exhibits lipogenic activity. Our findings highlight the fundamental importance of using a nuclear hormone receptor to govern fat usage and underscore an elegant feedback mechanism whereby both mammalian PPAR a and C. elegans
nhr-49 control pathways responsible for both consumption and storage of fat, with the potential to shift the balance in response to changing energy needs. Indeed, under conditions of starvation, we observed a dramatic increase in the expression of several genes involved in b -oxidation including, most prominently,
acs-2 . This adaptive response occurred in many tissues and was completely dependent upon
nhr-49 . Strikingly, although the expression of the fat consuming
acs-2 gene was induced by nearly 100-fold under conditions of starvation, expression of the fat storing
fat-7 gene was actually repressed. These results demonstrate that under changing dietary conditions,
nhr-49 selectively modulates the expression of its target genes to favor pathways that consume fat - presumably for the purpose of exploiting fat stores for energy supply under conditions where food intake is nonexistent. Thus
nhr-49 appears to be a key mediator of the metabolic response to starvation. Accordingly,
nhr-49(
nr2041) mutants were significantly compromised in their ability to thrive under conditions of starvation. Finally,
nhr-49(
nr2041) mutants also displayed significantly reduced lifespan. We found that RNAi of
fat-7 alone resulted in a shortened lifespan phenotype similar to that of
nhr-49(
nr2041) mutants. Thus we believe that the compromised longevity of
nhr-49(
nr2041) mutants is attributable, at least in part, to lowered
fat-7 expression. Biochemical analysis revealed that reduced FAT-7 activity in
nhr-49(
nr2041) mutants resulted in an abnormal accumulation of saturated fats in vivo . Thus we propose that improper fatty acid composition in
nhr-49(
nr2041) mutants precipitates a progressive decline in function that manifests as shortened longevity.