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SIRT7 couples light-driven body temperature cues to hepatic circadian phase coherence and gluconeogenesis

Abstract

The central pacemaker in the hypothalamic suprachiasmatic nucleus (SCN) synchronizes peripheral oscillators to coordinate physiological and behavioural activities throughout the body. How circadian phase coherence between the SCN and the periphery is controlled is not well understood. Here, we identify hepatic SIRT7 as an early responsive element to light that ensures circadian phase coherence in the mouse liver. The SCN-driven body temperature (BT) oscillation induces rhythmic expression of HSP70, which promotes SIRT7 ubiquitination and proteasomal degradation. Acute temperature challenge dampens the BT oscillation and causes an advanced liver circadian phase. Further, hepatic SIRT7 deacetylates CRY1, promotes its FBXL3-mediated degradation and regulates the hepatic clock and glucose homeostasis. Loss of Sirt7 in mice leads to an advanced liver circadian phase and rapid entrainment of the hepatic clock upon daytime-restricted feeding. These data identify a BT–HSP70–SIRT7–CRY1 axis that couples the mouse hepatic clock to the central pacemaker and ensures circadian phase coherence and glucose homeostasis.

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Fig. 1: A light-entrained BT oscillation induces SIRT7 rhythmicity in mouse liver.
Fig. 2: HSP70 mediates SIRT7 degradation via the ubiquitin–proteasome pathway.
Fig. 3: SIRT7 interacts with and deacetylates CRY1.
Fig. 4: SIRT7-mediated deacetylation destabilizes CRY1.
Fig. 5: SIRT7 regulates the circadian phase in mouse livers.
Fig. 6: Expression of clock components at different AT conditions.
Fig. 7: SIRT7 counteracts phase shifting of hepatic clocks induced by RF.
Fig. 8: Sirt7 deficiency leads to impaired hepatic gluconeogenesis.
Fig. 9: SIRT7 ensures phase coherence between the central and peripheral clocks and maintains glucose homeostasis.

Data availability

The authors declare that all of the data supporting the findings of this study are available from the corresponding authors upon reasonable request. Source Data are available online for Figs. 18, Extended Data Figs. 110 and Supplementary Figs. 2, 3 and 5–8.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (grant nos. 81571374, 91849208, 81871114 and 81601215), National Key R&D Program of China (grant no. 2017YFA0503900), Science and Technology Program of Guangdong Province (grant nos. 2014A030308011, 2015A030308007 and 2017B030301016), Shenzhen Municipal Commission of Science and Technology Innovation (grant nos. JCYJ20160226191451487, KQJSCX20180328093403969, JCYJ20180507182044945 and JCYJ20160520170240403; Discipline Construction Funding of Shenzhen 2016-1452). The authors are grateful to J. Tamanini (Shenzhen University and ETediting) for editing the manuscript prior to submission.

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Z.L. and M.Q. planned the experiments under guidance of B.L., performed biochemical, cellular and in vivo experiments and analyzed data. X.T., S.Z., F.M. and X.C. generated cell lines and plasmids used in this study. W.H., S.S., G.L., C.X., J.S. and B.T. did in vivo experiments. B.L. designed and supervised this study. Z.L., M.Q., Q.P., B.Z., Z.W., Y.G., X.R. and B.L. prepared and revised the manuscript.

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Correspondence to Baohua Liu.

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Extended data

Extended Data Fig. 1 Clock gene expression.

(a) Quantitative real time PCR (qRT-PCR) analysis of Sirt7, Bmal1 and Cry1 in mouse livers at the indicated circadian times. n = 3 per time point. (b) qRT-PCR analysis of Sirt7 expression in wild-type (WT) hypothalamus and livers. n = 3 per time point. (c) Representative immunoblots showing SIRT7 protein levels in WT hypothalamus (repeated three times with similar results). (d) qRT-PCR analysis of clock genes in WT liver tissues of mice maintained under normal feeding or no food (NF) from ZT0 conditions with or without a 2-h light exposure (L). n = 3 per time point. Data represent the means ± s.e.m. of three independent experiments. Source data

Extended Data Fig. 2 Light-entrained body temperature oscillation induces SIRT7 rhythmicity in mouse liver.

(a) Measurements of mouse rectal temperature during a light/dark (LD) or dark/dark (DD) cycle. n = 6 per time point per group. (b) Measurements of mouse rectal temperature in wild-type (WT) mice at ZT16. F, feeding; F+L, feeding plus light exposure; NF, no food available; and NF+L, no food available plus light exposure. n = 6 per time point, unpaired two-tailed Student’s t test. (c) Measurements of mouse rectal temperature in WT mice fasted from ZT0 to ZT16. n = 6 per time point per group, unpaired two-tailed Student’s t test. (d) Representative immunoblots showing SIRT7 and p-AKT in fasted or refed mice. n = 4 per group. (e) Measurements of mouse rectal temperature in WT mice fasted for 24 hr (food withdraw before light-off). n = 6 per time point per group, unpaired two-tailed Student’s t test. (f) Measurements of mouse rectal temperature in fasted or refed mice. Mice were fasted for 24 hr (food withdraw before light-off) and refed (food available before light-off). n = 6 per time point per group. (g) qRT-PCR analysis of heat shock protein genes in livers of mice maintained under room or high ambient temperature. n = 3 per time point, unpaired two-tailed Student’s t test. (h) qRT-PCR analysis of Hsp70 expression in mouse livers at ZT16. n = 3 per time point, unpaired two-tailed Student’s t test. (i) qRT-PCR analysis of Hsp70 expression in WT and Sirt7 knockout (KO) mice livers at ZT16 with or without light exposure (n = 3 mice per genotype per time point), unpaired two-tailed Student’s t test. (j) Representative immunoblots showing HSP70 protein levels in WT and Sirt7 KO mice liver at ZT16 with or without light exposure (repeated three times with similar results). Data represent the means ± s.e.m. of three independent experiments. Source data

Extended Data Fig. 3 Body temperature regulates SIRT7 levels via HSP70.

(a) Representative immunoblots showing SIRT7, HSP70 and CRY1 protein levels in wild-type (WT) and Sirt7 KO liver tissues under room or high ambient temperatures at ZT4 and ZT16. n = 3 mice per genotype per time point. (b) Measurements of mice rectal temperatures when maintained under room or high ambient temperatures at ZT4 and ZT16. n = 6 mice per genotype per time point, unpaired two-tailed Student’s t test. (c) Representative immunoblots showing SIRT7, HSP70 and CRY1 protein levels in WT and Sirt7 KO mice liver tissues when maintained under room or cold ambient temperature at ZT16. n = 3 mice per genotype per time point. (d) Measurements of mice rectal temperatures when maintained under room or cold ambient temperatures at ZT16. n = 6 mice per genotype per time point, unpaired two-tailed Student’s t test. Data represent the means ± s.e.m. of three independent experiments. Source data

Extended Data Fig. 4 Deacetylation of CRY1 but not CRY2 by Sirtuins.

(a) Acetylation levels of FLAG-CRY1 and FLAG-CRY2 in HEK293 cells in the absence or presence of 10 mM NAM (repeated three times with similar results). (b) Acetylation levels of HA-CRY1 in the presence of over-expressed FLAG-SIRT1, FLAG-SIRT6 and FLAG-SIRT7 in HEK293 cells (repeated three times with similar results). Source data

Extended Data Fig. 5 Acetylation levels of CRY1 lysine/arginine (K/R) mutants.

Acetylation of FLAG-CRY1 and FLAG-CRY1-2KR in the absence or presence of 10 mM NAM (repeated three times with similar results). Source data

Extended Data Fig. 6 Clock mRNA and protein levels in unsynchronized cells.

(a,b) qRT-PCR analysis of mRNA levels of clock genes in two Sirt7 KO HEK293 cell lines (KO1 and KO2), unpaired two-tailed Student’s t test. (c) Representative immunoblots showing the protein levels of clock genes in Sirt7-KO HEK293 cells (repeated three times with similar results). (d) Representative immunoblots showing the protein levels of clock genes in cells over-expressing SIRT7 (repeated three times with similar results). (e,f) Quantification of CRY1 and BMAL1 protein levels in (c,d), unpaired two-tailed Student’s t test. Data represent the means ± s.e.m. of three independent experiments. Source data

Extended Data Fig. 7 Protein degradation of CRY1.

(a) Representative immunoblots showing the protein levels of endogenous CRY1 in Sirt7 knockout (KO) HEK293 cells treated with 50 μg/ml CHX and/or 20 μM MG132 (b) Representative immunoblots showing protein levels of CRY1 in HEK293 cells with ectopic SIRT7 or empty vector. (c,d) Quantification of CRY1 degradation assay in (a,b), unpaired two-tailed Student’s t test. (e) Representative immunoblots showing degradation of FLAG-CRY1 and FLAG-CRY1-2KR mutants in the presence or absence of over-expressed HA-SIRT7 H187Y in HEK293 cells (repeated three times with similar results). Data represent the means ± s.e.m. of three independent experiments. Source data

Extended Data Fig. 8 SIRT7 regulates endogenous circadian clocks.

(a) qRT-PCR analysis of core clock genes in synchronized wild-type (WT) and Sirt7-/- mouse embryonic fibroblasts (MEFs). MEFs were synchronized by 50% horse serum, and total mRNA and protein were extracted at 4-h intervals. (b) CRY1 and BMAL1 protein levels in synchronized WT and Sirt7-/- MEFs. Representative immunoblots are shown. (c) Quantification of CRY1 and BMAL1 protein levels in (b). Data represent the means ± s.e.m. of three independent experiments. Two-way ANOVA followed by Bonferroni’s multiple comparisons test. Source data

Extended Data Fig. 9 Circadian gene expression in WT and Sirt7-/- hypothalamus.

(a) qRT-PCR analysis of Bmal1, Cry1, Dbp and Per2 expression in wild-type (WT) and Sirt7 knockout (KO) hypothalamus. (b) Representative immunoblots showing expression of CRY1 in WT and Sirt7-KO hypothalamus. n = 3 mice per genotype per time point. Data represent the means ± s.e.m. of three independent experiments. Source data

Extended Data Fig. 10 Expression of clock components at different AT acclimated for one week.

(a) Measurements of mouse rectal temperature at different AT. n = 6 mice per time point. (b) Representative immunoblots showing CRY1 SIRT7 and HSP70 protein levels at different AT. n = 3 mice per time point. (c) Quantification of band intensity in (b). (d) Real-time PCR analysis of mRNA levels of core clock genes at different AT. n = 3 mice per time point. (e) The activity profiles of mice under different AT across a circadian LD cycle. n = 6 mice per time point. (f) The activity profiles of mice under different AT in DD cycle. n = 6 mice per time point. Data represent the means ± s.e.m. of three independent experiments. Two-way ANOVA followed by Bonferroni’s multiple comparisons test. Room: 22˚C, High: 32˚C, Cold: 4˚C. Purple P, Room vs High; blue P, Room vs Cold. Source data

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Liu, Z., Qian, M., Tang, X. et al. SIRT7 couples light-driven body temperature cues to hepatic circadian phase coherence and gluconeogenesis. Nat Metab 1, 1141–1156 (2019). https://doi.org/10.1038/s42255-019-0136-6

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