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Cited by 243Circadian rhythm and melatoninAdipose Tissue and MetabolismLipid metabolism and biosynthesis

The DOI matches its Crossref record; 54 of the 54 references it cites were found in a registry or an index.

Circadian Regulation of Lipid Mobilization in White Adipose Tissues

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Shostak, Anton, Meyer-Kovac, Judit, Oster, Henrik·2013·Diabetes
DOI 10.2337/db12-1449PMC PMC3712056
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Abstract

In mammals, a network of circadian clocks regulates 24-h rhythms of behavior and physiology. Circadian disruption promotes obesity and the development of obesity-associated disorders, but it remains unclear to which extent peripheral tissue clocks contribute to this effect. To reveal the impact of the circadian timing system on lipid metabolism, blood and adipose tissue samples from wild-type, ClockΔ19, and Bmal1(-/-) circadian mutant mice were subjected to biochemical assays and gene expression profiling. We show diurnal variations in lipolysis rates and release of free fatty acids (FFAs) and glycerol into the blood correlating with rhythmic regulation of two genes encoding the lipolysis pacemaker enzymes, adipose triglyceride (TG) lipase and hormone-sensitive lipase, by self-sustained adipocyte clocks. Circadian clock mutant mice show low and nonrhythmic FFA and glycerol blood content together with decreased lipolysis rates and increased sensitivity to fasting. Instead circadian clock disruption promotes the accumulation of TGs in white adipose tissue (WAT), leading to increased adiposity and adipocyte hypertrophy. In summary, circadian modulation of lipolysis rates regulates the availability of lipid-derived energy during the day, suggesting a role for WAT clocks in the regulation of energy homeostasis.

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Figures

FIG. 1. Serum lipids change in ClockΔ19 mice. Diurnal profiles of cholesterol (A), TGs (B), FFAs (C), and glycerol (D) in the serum of wild-type (WT; closed circles) and ClockΔ19 (open circles) mice in DD (n = 3/time point). Time points indicate hours spent in DD after the last lights off. Diurnal profiles of FFAs (E) and glycerol (F) in the serum of wild-type (closed circles) and ClockΔ19 (open circles) mice in LD conditions (n = 3–5/time point). Time-of-day dependent variations in serum FFA and glycerol levels in WT (black bars) and Bmal1−/− (white bars) animals kept in DD (n = 3–5/time point). All data are shown as means ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001 by two-way ANOVA with Bonferroni posttest.
FIG. 1. Serum lipids change in ClockΔ19 mice. Diurnal profiles of cholesterol (A), TGs (B), FFAs (C), and glycerol (D) in the serum of wild-type (WT; closed circles) and ClockΔ19 (open circles) mice in DD (n = 3/time point). Time points indicate hours spent in DD after the last lights off. Diurnal profiles of FFAs (E) and glycerol (F) in the serum of wild-type (closed circles) and ClockΔ19 (open circles) mice in LD conditions (n = 3–5/time point). Time-of-day dependent variations in serum FFA and glycerol levels in WT (black bars) and Bmal1−/− (white bars) animals kept in DD (n = 3–5/time point). All data are shown as means ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001 by two-way ANOVA with Bonferroni posttest.CC BY-NC-ND · PubMed Central
FIG. 2. Increased body weight and adiposity in ClockΔ19 mice. Body weight (A) and adiposity (epididymal fat to body weight ratio) (B) in wild-type (WT; black bars) and ClockΔ19 (white bars) mice fed standard chow for 10 weeks (n = 14). C: Representative sections and adipocyte size of epididymal WAT after 10 weeks of standard diet (scale bars, 100 μm; n = 3). *P < 0.05; **P < 0.01; ***P < 0.001 by unpaired t test. All data are shown as means ± SEM.
FIG. 2. Increased body weight and adiposity in ClockΔ19 mice. Body weight (A) and adiposity (epididymal fat to body weight ratio) (B) in wild-type (WT; black bars) and ClockΔ19 (white bars) mice fed standard chow for 10 weeks (n = 14). C: Representative sections and adipocyte size of epididymal WAT after 10 weeks of standard diet (scale bars, 100 μm; n = 3). *P < 0.05; **P < 0.01; ***P < 0.001 by unpaired t test. All data are shown as means ± SEM.CC BY-NC-ND · PubMed Central
FIG. 3. Circadian clock controls TG metabolism in WAT. A: mRNA levels of genes involved in adipocyte TG metabolism from wild-type (WT) WAT samples isolated at two opposite circadian time points, 37 h (open bars) and 49 h (closed bars) in DD (n = 3 per time point [*P < 0.05; **P < 0.01 by unpaired t test]). Circadian expression profiles of candidate genes from (A) involved in FFA transport (B) and TG synthesis (C) in WAT samples from WT (closed circles) and ClockΔ19 (open circles) mice in DD (n = 3/time point [*P < 0.05; **P < 0.01; ***P < 0.001 by two-way ANOVA with Bonferroni posttest]). All data are shown as means ± SEM.
FIG. 3. Circadian clock controls TG metabolism in WAT. A: mRNA levels of genes involved in adipocyte TG metabolism from wild-type (WT) WAT samples isolated at two opposite circadian time points, 37 h (open bars) and 49 h (closed bars) in DD (n = 3 per time point [*P < 0.05; **P < 0.01 by unpaired t test]). Circadian expression profiles of candidate genes from (A) involved in FFA transport (B) and TG synthesis (C) in WAT samples from WT (closed circles) and ClockΔ19 (open circles) mice in DD (n = 3/time point [*P < 0.05; **P < 0.01; ***P < 0.001 by two-way ANOVA with Bonferroni posttest]). All data are shown as means ± SEM.CC BY-NC-ND · PubMed Central
FIG. 4. Circadian clock regulates lipid mobilization in WAT. A: Circadian expression profiles of genes involved in lipolysis in adipose tissue from wild-type (WT; closed circles) and ClockΔ19 (open circles) mice in DD (n = 3–4/time point). Profiles of glycerol excretion from WT (closed circles) and ClockΔ19 (open circles) epididymal WAT fat-pad explants harvested in DD (B) and LD (C) (n = 6–14/time point). D: Expression of Atgl and Hsl in WAT of WT (black bars) and Bmal1−/− (white bars) animals at 37 and 49 h after lights off (n = 2–3/time point). E: Changes in glycerol excretion from WT (black bars) and Bmal1−/− (white bars) epididymal WAT fat-pad explants harvested at 37 and 49 h after lights off (n = 8/time point). All data are shown as means ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001 by two-way ANOVA with Bonferroni posttest.
FIG. 4. Circadian clock regulates lipid mobilization in WAT. A: Circadian expression profiles of genes involved in lipolysis in adipose tissue from wild-type (WT; closed circles) and ClockΔ19 (open circles) mice in DD (n = 3–4/time point). Profiles of glycerol excretion from WT (closed circles) and ClockΔ19 (open circles) epididymal WAT fat-pad explants harvested in DD (B) and LD (C) (n = 6–14/time point). D: Expression of Atgl and Hsl in WAT of WT (black bars) and Bmal1−/− (white bars) animals at 37 and 49 h after lights off (n = 2–3/time point). E: Changes in glycerol excretion from WT (black bars) and Bmal1−/− (white bars) epididymal WAT fat-pad explants harvested at 37 and 49 h after lights off (n = 8/time point). All data are shown as means ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001 by two-way ANOVA with Bonferroni posttest.CC BY-NC-ND · PubMed Central
FIG. 5. Local WAT clocks regulate expression of Atgl and Hsl. A: Expression profiles of Bmal1, Per2, and Dbp mRNAs in WAT of wild-type (WT; closed circles) and ClockΔ19 (open circles) mice in DD (n = 3/time point). B: Representative baseline-subtracted luminescence recordings from epididymal, peritoneal, and subcutaneous WAT explants of PER2::LUCIFERASE circadian reporter mice. C: Rhythmic expression of Atgl and Hsl transcripts in WT (closed circles), but not ClockΔ19 (open circles), cultured fat-pad explants (n = 3/time point). D: Antiphasic expression of Per2 (open circles) and Bmal1 (closed circles) mRNAs in cultured WT fat-pad explants (n = 3/time point). All data are shown as means ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001 by two-way ANOVA with Bonferroni posttest. CPS, counts per second.
FIG. 5. Local WAT clocks regulate expression of Atgl and Hsl. A: Expression profiles of Bmal1, Per2, and Dbp mRNAs in WAT of wild-type (WT; closed circles) and ClockΔ19 (open circles) mice in DD (n = 3/time point). B: Representative baseline-subtracted luminescence recordings from epididymal, peritoneal, and subcutaneous WAT explants of PER2::LUCIFERASE circadian reporter mice. C: Rhythmic expression of Atgl and Hsl transcripts in WT (closed circles), but not ClockΔ19 (open circles), cultured fat-pad explants (n = 3/time point). D: Antiphasic expression of Per2 (open circles) and Bmal1 (closed circles) mRNAs in cultured WT fat-pad explants (n = 3/time point). All data are shown as means ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001 by two-way ANOVA with Bonferroni posttest. CPS, counts per second.CC BY-NC-ND · PubMed Central
FIG. 6. CLOCK and BMAL1 drive rhythmic transcription of Atgl and Hsl via E-boxes. A: Maps of the 5′ regions of the genomic loci of murine Atgl (top) and Hsl (bottom) on chromosome 7 (Chr.7). Putative E-box enhancers are indicated by ovals. Black arrows depict the genomic sequences cloned for promoter studies. Mutated E-boxes are indicated by gray arrowheads. B: Luciferase reporter assays in HEK293 cells for wild-type (WT) and mutated Atgl (left) and Hsl (right) promoters in response to cotransfection with Clock/Bmal1 and Cry1 (n = 3; ***P < 0.001 by one-way ANOVA with Bonferroni posttest). C: Time-dependent BMAL1 binding to Dbp, Atgl, and Hsl E-boxes and 500-bp downstream regions as identified by ChIP in WAT (n = 3/time point [*P < 0.05; **P < 0.01; ***P < 0.001 by two-way ANOVA with Bonferroni posttest]). All data are shown as means ± SEM.
FIG. 6. CLOCK and BMAL1 drive rhythmic transcription of Atgl and Hsl via E-boxes. A: Maps of the 5′ regions of the genomic loci of murine Atgl (top) and Hsl (bottom) on chromosome 7 (Chr.7). Putative E-box enhancers are indicated by ovals. Black arrows depict the genomic sequences cloned for promoter studies. Mutated E-boxes are indicated by gray arrowheads. B: Luciferase reporter assays in HEK293 cells for wild-type (WT) and mutated Atgl (left) and Hsl (right) promoters in response to cotransfection with Clock/Bmal1 and Cry1 (n = 3; ***P < 0.001 by one-way ANOVA with Bonferroni posttest). C: Time-dependent BMAL1 binding to Dbp, Atgl, and Hsl E-boxes and 500-bp downstream regions as identified by ChIP in WAT (n = 3/time point [*P < 0.05; **P < 0.01; ***P < 0.001 by two-way ANOVA with Bonferroni posttest]). All data are shown as means ± SEM.CC BY-NC-ND · PubMed Central
FIG. 7. Aberrant fasting responses in ClockΔ19 mice. Serum FFA (A) and glycerol (B) levels after 12 and 24 h of food deprivation in wild-type (WT; closed bars) and ClockΔ19 (open bars) mice (n = 3–5/time point). C: Normalized changes in liver glycogen content of WT and ClockΔ19 mice during 12-h fasting (n = 3 to 4). D: Rectal temperature in WT and ClockΔ19 animals during 12-h fasting (n = 6–12). All data are shown as means ± SEM. *P < 0.05; ***P < 0.001 by two-way ANOVA with Bonferroni posttest; #P < 0.001 by unpaired t test.
FIG. 7. Aberrant fasting responses in ClockΔ19 mice. Serum FFA (A) and glycerol (B) levels after 12 and 24 h of food deprivation in wild-type (WT; closed bars) and ClockΔ19 (open bars) mice (n = 3–5/time point). C: Normalized changes in liver glycogen content of WT and ClockΔ19 mice during 12-h fasting (n = 3 to 4). D: Rectal temperature in WT and ClockΔ19 animals during 12-h fasting (n = 6–12). All data are shown as means ± SEM. *P < 0.05; ***P < 0.001 by two-way ANOVA with Bonferroni posttest; #P < 0.001 by unpaired t test.CC BY-NC-ND · PubMed Central

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Metadata

Authors
Shostak, A., Meyer-Kovac, J., & Oster, H.
Affiliations
  • Max Planck Institute for Biophysical Chemistry (DE)
  • Circadian Rhythms Group, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany
Corresponding author
Oster, Henrik
ORCID
Venue
Diabetes
Publisher
American Diabetes Association
Published
2013-06-14
Volume
62
Issue
7
Pages
2195-2203
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/db12-1449
PMC
PMC3712056
OpenAlex
W2098360522
Cited by
243
References
54
Citations by year
2026: 12 · 2025: 22 · 2024: 17 · 2023: 23 · 2022: 26 · 2021: 14 · 2020: 22 · 2019: 19 · 2018: 16 · 2017: 17 · 2016: 20 · 2015: 16 · 2014: 14 · 2013: 5
FWCI
9.90
Type
journal article
Language
en
Open access
Licence
Locations
  • Diabetes (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • MPG.PuRe (Max Planck Society) (submittedVersion)
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
  • Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
Keywords
circadian clock, white adipose tissue, lipolysis, lipid mobilization, free fatty acids, glycerol, adipose triglyceride lipase, hormone-sensitive lipase, Clock mutant mice, Bmal1, adipocyte hypertrophy, adiposity, energy homeostasis, circadian rhythm disruption
MeSH terms
Animals, Sterol Esterase, Circadian Rhythm, Fatty Acids, Nonesterified, Glycerol, Mice, Knockout, Adiposity, Lipid Metabolism, Mice, Adipose Tissue, White, CLOCK Proteins

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