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, 7 (6), 533-44

Serotonin Regulates C. Elegans Fat and Feeding Through Independent Molecular Mechanisms

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Serotonin Regulates C. Elegans Fat and Feeding Through Independent Molecular Mechanisms

Supriya Srinivasan et al. Cell Metab.

Abstract

We investigated serotonin signaling in C. elegans as a paradigm for neural regulation of energy balance and found that serotonergic regulation of fat is molecularly distinct from feeding regulation. Serotonergic feeding regulation is mediated by receptors whose functions are not required for fat regulation. Serotonergic fat regulation is dependent on a neurally expressed channel and a G protein-coupled receptor that initiate signaling cascades that ultimately promote lipid breakdown at peripheral sites of fat storage. In turn, intermediates of lipid metabolism generated in the periphery modulate feeding behavior. These findings suggest that, as in mammals, C. elegans feeding behavior is regulated by extrinsic and intrinsic cues. Moreover, obesity and thinness are not solely determined by feeding behavior. Rather, feeding behavior and fat metabolism are coordinated but independent responses of the nervous system to the perception of nutrient availability.

Figures

Figure 1
Figure 1. 5-HT reduces fat content
(A) Images of Nile Red-stained wild-type and mod-5(n3314) animals treated with 5-HT or fluoxetine. In all images the anterior end of the animals is oriented towards the left. (B) Quantification of Nile Red fluorescence (n=8 animals per condition). The data are expressed as a percentage of vehicle-treated animals on OP50 bacteria. (**, p<0.005 when compared to vehicle-treated controls or indicated comparisons). (C) TLC measurement of extracted triacylglycerides (TAG) show that 5-HT treatment leads to fat loss (*, p<0.05).
Figure 2
Figure 2. Serotonergic feeding increase requires ser-1 and ser-7 whereas serotonergic fat decrease requires mod-1 and ser-6
(A) Feeding rates were measured in wild-type controls and indicated mutants (n=10) treated with either vehicle (gray bars) or 5mM 5-HT (black bars). Data are expressed as a percentage of vehicle-treated wild-type animals (**, p<0.005, when compared to 5HT-treated wild-type animals). (B) Representative images of Nile Red-stained animals treated with vehicle (top row) or 5mM 5-HT (bottom row). The anterior end of the animals is oriented towards the left. (C) The proportion of fat remaining in 5-HT-treated relative to vehicle-treated animals for each genotype (n=8). Nile Red fluorescence intensities are reported in Table 1. mod-1(ok103) and ser-6(tm2146) animals retained a significantly greater proportion of their fat upon 5-HT treatment when compared to wild-type (**, p<0.005).
Figure 3
Figure 3. β-oxidation genes are required for the fat-reducing effect of 5-HT
(A) Representative images of Nile Red-stained animals treated with the indicated RNAi clones exposed to either vehicle (top rows) or 5-HT (bottom rows). The anterior end of the animals is oriented towards the left. (B) The proportion of fat remaining in 5-HT-treated relative to vehicle-treated animals on HT115 bacteria exposed to each indicated RNAi (n=8). Nile Red fluorescence intensities are reported in Table 1. (**, p<0.005, when compared to wild type on vector control RNAi).
Figure 4
Figure 4. Expression patterns of β-oxidation genes
(A–H) Representative images of transgenic animals expressing GFP-reporter fusions for promoters of indicated genes. Inset panels show corresponding DIC images. (I) Change in transcript levels of indicated metabolic genes upon 5HT treatment in wild-type animals as determined by qRT-PCR. The data are reported as the average of two independent cDNA preparations ± s.e.m.
Figure 5
Figure 5. Effects of β-oxidation genes on oxygen consumption and feeding rate
(A) Oxygen consumption measurements (n=800 animals per condition) with or without 5-HT for vector and RNAi-treated animals. The data are expressed as a percentage of wild-type vehicle-treated animals, (**, p<0.005 when compared to 5-HT-treated animals on vector control). (B) Effects of 5-HT on feeding rate (n=10 animals per condition) (**, p<0.005 when compared to 5-HT-treated animals on vector control RNAi). For panels A and B, gray bars represent vehicle-treated animals and black bars, 5-HT-treated animals. The data are expressed as a percentage of wild-type vehicle-treated animals. (C) Effects of dietary oleic acid, Triascin C and inactivations of acs genes on feeding rate (**, p<0.005 when comparing the indicated treatments).
Figure 6
Figure 6. ser-6 and mod-1 mediate serotonergic fat regulation through distinct mechanisms
(A) Representative images of Nile Red-stained animals exposed to either vehicle (top row) or 5-HT (bottom row). The anterior end of the animals is oriented towards the left. (B) mod-1(ok103); ser-6(tm2146) double mutants block serotonergic fat reduction to a greater degree than either single mutant alone (n=8, and *, p<0.05). (C) RNAi inactivations of Y76A2B.3/acs-5 and F08A8.4/aco in mod-1(ok103) but not in ser-6(tm2146) animals cause a further block in serotonergic fat reduction (n=8, and *, p<0.05). Nile Red intensity measurements used to generate graphs (B) and (C) are reported in Table S3.

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