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Neural clocks and Neuropeptide F/Y regulate circadian gene expression in a peripheral metabolic tissue.

Erion R, King AN, Wu G, Hogenesch JB, Sehgal A - Elife (2016)

Bottom Line: Interestingly, rhythmic expression of the cytochrome P450 transcripts, sex-specific enzyme 1 (sxe1) and Cyp6a21, which cycle in the fat body independently of the local clock, depends upon clocks in neurons expressing neuropeptide F (NPF).NPF signaling itself is required to drive cycling of sxe1 and Cyp6a21 in the fat body, and its mammalian ortholog, Npy, functions similarly to regulate cycling of cytochrome P450 genes in the mouse liver.These data highlight the importance of neuronal clocks for peripheral rhythms, particularly in a specific detoxification pathway, and identify a novel and conserved role for NPF/Npy in circadian rhythms.

View Article: PubMed Central - PubMed

Affiliation: Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, United States.

ABSTRACT
Metabolic homeostasis requires coordination between circadian clocks in different tissues. Also, systemic signals appear to be required for some transcriptional rhythms in the mammalian liver and the Drosophila fat body. Here we show that free-running oscillations of the fat body clock require clock function in the PDF-positive cells of the fly brain. Interestingly, rhythmic expression of the cytochrome P450 transcripts, sex-specific enzyme 1 (sxe1) and Cyp6a21, which cycle in the fat body independently of the local clock, depends upon clocks in neurons expressing neuropeptide F (NPF). NPF signaling itself is required to drive cycling of sxe1 and Cyp6a21 in the fat body, and its mammalian ortholog, Npy, functions similarly to regulate cycling of cytochrome P450 genes in the mouse liver. These data highlight the importance of neuronal clocks for peripheral rhythms, particularly in a specific detoxification pathway, and identify a novel and conserved role for NPF/Npy in circadian rhythms.

No MeSH data available.


NPF-expressing clock neurons regulate rhythmic expression of fat body genes, sxe1 and Cyp6a21.(A, B) Ablating the molecular clock by expressing CLKΔ or CYCΔ in either the LNvs (Pdf-GAL4) (A) or DN1s (911-GAL4) (B) does not eliminate rhythmic sxe1 expression in the fat body. (C, D) Expressing CLKΔ (C) or CYCΔ (D) using Npf-GAL4 abolishes rhythmic sxe1 expression in the fat body. (E) Expressing CLKΔ in a subset of LNds (Dvpdf-GAL4;Pdf-GAL80) also does not eliminate cycling but reduces sxe1 expression in the fat body. (F) Npf-GAL4>UAS-CLKΔ abolishes rhythmic Cyp6a21 expression in the fat body. (G) per expression is rhythmic in flies expressing UAS-CLKΔ under Npf-GAL4. (H, I) CLKΔ expression in NPF cells is restricted to adulthood using Tub-GAL80ts. (H) sxe1 expression is not affected with adult-specific clock ablation in NPF cells. (I) Rhythmic Cyp6a21 expression is affected in the fat body when Npf-GAL4>UAS-CLKΔ expression is induced in adult at 30°C. Each experiment was repeated independently at least twice. The average value for each timepoint is plotted with error bars denoting SEM. JTK_cycle p value <0.05 is indicated by an asterisk (*) next to the genotype label. See Table 3 for JTK_cycle p values. ZT- Zeitgeber Time.DOI:http://dx.doi.org/10.7554/eLife.13552.00910.7554/eLife.13552.010Figure 3—source data 1.Data for qPCR analysis of fat body clock-independent genes and clock genes in flies with ablated clock neurons.DOI:http://dx.doi.org/10.7554/eLife.13552.010
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fig3: NPF-expressing clock neurons regulate rhythmic expression of fat body genes, sxe1 and Cyp6a21.(A, B) Ablating the molecular clock by expressing CLKΔ or CYCΔ in either the LNvs (Pdf-GAL4) (A) or DN1s (911-GAL4) (B) does not eliminate rhythmic sxe1 expression in the fat body. (C, D) Expressing CLKΔ (C) or CYCΔ (D) using Npf-GAL4 abolishes rhythmic sxe1 expression in the fat body. (E) Expressing CLKΔ in a subset of LNds (Dvpdf-GAL4;Pdf-GAL80) also does not eliminate cycling but reduces sxe1 expression in the fat body. (F) Npf-GAL4>UAS-CLKΔ abolishes rhythmic Cyp6a21 expression in the fat body. (G) per expression is rhythmic in flies expressing UAS-CLKΔ under Npf-GAL4. (H, I) CLKΔ expression in NPF cells is restricted to adulthood using Tub-GAL80ts. (H) sxe1 expression is not affected with adult-specific clock ablation in NPF cells. (I) Rhythmic Cyp6a21 expression is affected in the fat body when Npf-GAL4>UAS-CLKΔ expression is induced in adult at 30°C. Each experiment was repeated independently at least twice. The average value for each timepoint is plotted with error bars denoting SEM. JTK_cycle p value <0.05 is indicated by an asterisk (*) next to the genotype label. See Table 3 for JTK_cycle p values. ZT- Zeitgeber Time.DOI:http://dx.doi.org/10.7554/eLife.13552.00910.7554/eLife.13552.010Figure 3—source data 1.Data for qPCR analysis of fat body clock-independent genes and clock genes in flies with ablated clock neurons.DOI:http://dx.doi.org/10.7554/eLife.13552.010

Mentions: Rhythms of sxe1 expression are abolished in Clkjrk mutants in LD, and so we evaluated sxe1 regulation by other clocks in the presence of light cycles rather than under constant darkness (Figure 2C). Our initial discovery that PDF neurons regulate the fat body clock in constant darkness led us to hypothesize that these neurons may also regulate fat body clock-independent genes. Abolishing the clock in PDF cells by expressing CLKΔ under Pdf-GAL4, slightly decreased sxe1 transcript levels in the abdominal fat body, but did not abolish rhythmic expression (Figure 3A). This suggests that although the PDF neurons regulate the fat body clock, these neurons are not the primary drivers of rhythmic sxe1 expression.10.7554/eLife.13552.009Figure 3.NPF-expressing clock neurons regulate rhythmic expression of fat body genes, sxe1 and Cyp6a21.


Neural clocks and Neuropeptide F/Y regulate circadian gene expression in a peripheral metabolic tissue.

Erion R, King AN, Wu G, Hogenesch JB, Sehgal A - Elife (2016)

NPF-expressing clock neurons regulate rhythmic expression of fat body genes, sxe1 and Cyp6a21.(A, B) Ablating the molecular clock by expressing CLKΔ or CYCΔ in either the LNvs (Pdf-GAL4) (A) or DN1s (911-GAL4) (B) does not eliminate rhythmic sxe1 expression in the fat body. (C, D) Expressing CLKΔ (C) or CYCΔ (D) using Npf-GAL4 abolishes rhythmic sxe1 expression in the fat body. (E) Expressing CLKΔ in a subset of LNds (Dvpdf-GAL4;Pdf-GAL80) also does not eliminate cycling but reduces sxe1 expression in the fat body. (F) Npf-GAL4>UAS-CLKΔ abolishes rhythmic Cyp6a21 expression in the fat body. (G) per expression is rhythmic in flies expressing UAS-CLKΔ under Npf-GAL4. (H, I) CLKΔ expression in NPF cells is restricted to adulthood using Tub-GAL80ts. (H) sxe1 expression is not affected with adult-specific clock ablation in NPF cells. (I) Rhythmic Cyp6a21 expression is affected in the fat body when Npf-GAL4>UAS-CLKΔ expression is induced in adult at 30°C. Each experiment was repeated independently at least twice. The average value for each timepoint is plotted with error bars denoting SEM. JTK_cycle p value <0.05 is indicated by an asterisk (*) next to the genotype label. See Table 3 for JTK_cycle p values. ZT- Zeitgeber Time.DOI:http://dx.doi.org/10.7554/eLife.13552.00910.7554/eLife.13552.010Figure 3—source data 1.Data for qPCR analysis of fat body clock-independent genes and clock genes in flies with ablated clock neurons.DOI:http://dx.doi.org/10.7554/eLife.13552.010
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Related In: Results  -  Collection

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fig3: NPF-expressing clock neurons regulate rhythmic expression of fat body genes, sxe1 and Cyp6a21.(A, B) Ablating the molecular clock by expressing CLKΔ or CYCΔ in either the LNvs (Pdf-GAL4) (A) or DN1s (911-GAL4) (B) does not eliminate rhythmic sxe1 expression in the fat body. (C, D) Expressing CLKΔ (C) or CYCΔ (D) using Npf-GAL4 abolishes rhythmic sxe1 expression in the fat body. (E) Expressing CLKΔ in a subset of LNds (Dvpdf-GAL4;Pdf-GAL80) also does not eliminate cycling but reduces sxe1 expression in the fat body. (F) Npf-GAL4>UAS-CLKΔ abolishes rhythmic Cyp6a21 expression in the fat body. (G) per expression is rhythmic in flies expressing UAS-CLKΔ under Npf-GAL4. (H, I) CLKΔ expression in NPF cells is restricted to adulthood using Tub-GAL80ts. (H) sxe1 expression is not affected with adult-specific clock ablation in NPF cells. (I) Rhythmic Cyp6a21 expression is affected in the fat body when Npf-GAL4>UAS-CLKΔ expression is induced in adult at 30°C. Each experiment was repeated independently at least twice. The average value for each timepoint is plotted with error bars denoting SEM. JTK_cycle p value <0.05 is indicated by an asterisk (*) next to the genotype label. See Table 3 for JTK_cycle p values. ZT- Zeitgeber Time.DOI:http://dx.doi.org/10.7554/eLife.13552.00910.7554/eLife.13552.010Figure 3—source data 1.Data for qPCR analysis of fat body clock-independent genes and clock genes in flies with ablated clock neurons.DOI:http://dx.doi.org/10.7554/eLife.13552.010
Mentions: Rhythms of sxe1 expression are abolished in Clkjrk mutants in LD, and so we evaluated sxe1 regulation by other clocks in the presence of light cycles rather than under constant darkness (Figure 2C). Our initial discovery that PDF neurons regulate the fat body clock in constant darkness led us to hypothesize that these neurons may also regulate fat body clock-independent genes. Abolishing the clock in PDF cells by expressing CLKΔ under Pdf-GAL4, slightly decreased sxe1 transcript levels in the abdominal fat body, but did not abolish rhythmic expression (Figure 3A). This suggests that although the PDF neurons regulate the fat body clock, these neurons are not the primary drivers of rhythmic sxe1 expression.10.7554/eLife.13552.009Figure 3.NPF-expressing clock neurons regulate rhythmic expression of fat body genes, sxe1 and Cyp6a21.

Bottom Line: Interestingly, rhythmic expression of the cytochrome P450 transcripts, sex-specific enzyme 1 (sxe1) and Cyp6a21, which cycle in the fat body independently of the local clock, depends upon clocks in neurons expressing neuropeptide F (NPF).NPF signaling itself is required to drive cycling of sxe1 and Cyp6a21 in the fat body, and its mammalian ortholog, Npy, functions similarly to regulate cycling of cytochrome P450 genes in the mouse liver.These data highlight the importance of neuronal clocks for peripheral rhythms, particularly in a specific detoxification pathway, and identify a novel and conserved role for NPF/Npy in circadian rhythms.

View Article: PubMed Central - PubMed

Affiliation: Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, United States.

ABSTRACT
Metabolic homeostasis requires coordination between circadian clocks in different tissues. Also, systemic signals appear to be required for some transcriptional rhythms in the mammalian liver and the Drosophila fat body. Here we show that free-running oscillations of the fat body clock require clock function in the PDF-positive cells of the fly brain. Interestingly, rhythmic expression of the cytochrome P450 transcripts, sex-specific enzyme 1 (sxe1) and Cyp6a21, which cycle in the fat body independently of the local clock, depends upon clocks in neurons expressing neuropeptide F (NPF). NPF signaling itself is required to drive cycling of sxe1 and Cyp6a21 in the fat body, and its mammalian ortholog, Npy, functions similarly to regulate cycling of cytochrome P450 genes in the mouse liver. These data highlight the importance of neuronal clocks for peripheral rhythms, particularly in a specific detoxification pathway, and identify a novel and conserved role for NPF/Npy in circadian rhythms.

No MeSH data available.