Polygenic control of Caenorhabditis elegans fat storage

Abstract

Tubby mice and individuals with Bardet-Biedl syndrome have defects in ciliated neuron function and obesity, suggesting an as-yet unknown metabolic signaling axis from ciliated neurons to fat storage tissues. Here we show coordinate regulation of Caenorhabditis elegans fat storage by orthologues of these genes acting in ciliated neurons and by a 3-ketoacyl-coA thiolase (encoded by kat-1) that acts in fat storage tissue. A genetic screen for markedly enhanced fat storage in tub-1 mutants led to the isolation only of kat-1 alleles, which impair fatty acid beta-oxidation. kat-1 acts in the intestine, the major C. elegans fat storage tissue, and is transcriptionally upregulated in animals with high fat storage. A genetic screen for synergistic increase in fat storage of a kat-1 mutant identified bbs-1. bbs-1 acts in 15 ciliated neurons that are poised to sense external and internal nutrient levels, supporting a model in which bbs-1 and tub-1 in ciliated neurons form part of an ancient, conserved neuroendocrine axis. This pathway also includes genes encoding intraflagellar transport proteins and cyclic nucleotide gated channels, demonstrating that C. elegans fat storage is under polygenic control.

Generation and modulation of chemosensory behaviors in C. elegans

“…Animals with compromised chemosensory neuron structure and/or function are small and accumulate fat [25][26][27][28][29]. A TGF-β signaling pathway has been implicated in regulating body size [30], and the DBL-1 TGF-β ligand is neuronally expressed [31].…”

“…However, it is not yet clear whether chemosensory inputs function via modulation of the dbl-1 TGF-β pathway or via alternate pathways to regulate body size. A neuroendocrine signal from the chemosensory neurons released in response to external or internal nutrient signals has been proposed to regulate fat storage in the intestine [27][28][29], but pathway components have not yet been defined. As the requirement of chemosensation in regulating body size and fat storage may be independent of the ability of animals to locate food sources or the rate of food consumption and storage, internal metabolic state may be altered by chemosensory perception to regulate cell size and fat metabolism [26,27].…”

Caenorhabditis elegans as a model for obesity research

“…43 Mutation of the 3-ketoacyl-coA thiolase (kat-1) gene is associated with increased fat storage in tissue owing to impairment of fat oxidation, and decreased kat-1 activity appears to be responsible for the increased fat accumulation in tub-1-mutant C. elegans. 44 Specifically, tub-1 interacts with a Rab-GTPase-activating protein (RBG-3) to regulate fat storage by controlling receptor or sensory molecule degradation in neurons, and by upregulating the activity of a small C. elegans in obesity research J Zheng and FL Greenway Rab-GTPase (RAB-7) to mediate an endocytic pathway that increases fat storage. 45 Taken together, mutations of tub-1 result in increased fat storage in C. elegans through a decrease in KAT-1 activity, which impairs fat oxidation and through an increase in fat storage by enhanced endocytosis.…”

“…45 Taken together, mutations of tub-1 result in increased fat storage in C. elegans through a decrease in KAT-1 activity, which impairs fat oxidation and through an increase in fat storage by enhanced endocytosis. 44 The human adipose gene (Adp) dose dependently suppresses obesity. The othologs of the Adp gene are conserved in other species as well as in C. elegans (Y73E7A.9), in flies (adpr-1) and in mice (Wdtc1).…”

UNC-64 and RIC-4, the plasma membrane-associated SNAREs syntaxin and SNAP-25, regulate fat storage in nematode Caenorhabditis elegans

“…The bbs-1 gene, which could synergisticly increase fat storage in a kat-1 mutant, has been identified by genetic screen. This gene acts in 15 ciliated neurons, and regulates fat storage in the same pathway as that of tub-1 [9] . In addition, studies have revealed that the classical neurotransmitters have dramatic effects on fat regulation in nematodes [10,11] .…”