Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Obesity in mice with adipocyte-specific deletion of clock component Arntl

Abstract

Adipocytes store excess energy in the form of triglycerides and signal the levels of stored energy to the brain. Here we show that adipocyte-specific deletion of Arntl (also known as Bmal1), a gene encoding a core molecular clock component, results in obesity in mice with a shift in the diurnal rhythm of food intake, a result that is not seen when the gene is disrupted in hepatocytes or pancreatic islets. Changes in the expression of hypothalamic neuropeptides that regulate appetite are consistent with feedback from the adipocyte to the central nervous system to time feeding behavior. Ablation of the adipocyte clock is associated with a reduced number of polyunsaturated fatty acids in adipocyte triglycerides. This difference between mutant and wild-type mice is reflected in the circulating concentrations of polyunsaturated fatty acids and nonesterified polyunsaturated fatty acids in hypothalamic neurons that regulate food intake. Thus, this study reveals a role for the adipocyte clock in the temporal organization of energy regulation, highlights timing as a modulator of the adipocyte-hypothalamic axis and shows the impact of timing of food intake on body weight.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Adipocyte-specific deletion of Arntl disrupts molecular rhythms in clock and clock-output gene expression.
Figure 2: Obesity in adipocyte-specific Arntl knockout (Ad-Arntl−/−) mice.
Figure 3: Attenuation of the diurnal rhythm in feeding activity and lower energy expenditure in adipocyte-specific Arntl knockout mice (Ad-Arntl−/−).
Figure 4: Higher food intake during the light period leads to obesity.
Figure 5: Lower concentrations of polyunsaturated fatty acids in adipose tissue, plasma and hypothalamus of adipocyte-specific Arntl knockout mice (Ad-Arntl−/−).
Figure 6: Polyunsaturated fatty acid–rich diets restore hypothalamic polyunsaturated fatty acid content and correct body weight, feeding behavior, energy homeostasis and hypothalamic neuropeptide expression in adipocyte-specific Arntl knockout mice (Ad-Arntl−/−).

Accession codes

Primary accessions

Gene Expression Omnibus

References

  1. 1

    Green, C.B., Takahashi, J.S. & Bass, J. The meter of metabolism. Cell 134, 728–742 (2008).

    CAS  Article  Google Scholar 

  2. 2

    Reppert, S.M. & Weaver, D.R. Coordination of circadian timing in mammals. Nature 418, 935–941 (2002).

    CAS  Article  Google Scholar 

  3. 3

    Marcheva, B. et al. Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes. Nature 466, 627–631 (2010).

    CAS  Article  Google Scholar 

  4. 4

    Lamia, K.A., Storch, K.F. & Weitz, C.J. Physiological significance of a peripheral tissue circadian clock. Proc. Natl. Acad. Sci. USA 105, 15172–15177 (2008).

    CAS  Article  Google Scholar 

  5. 5

    Oishi, K. et al. Disrupted fat absorption attenuates obesity induced by a high-fat diet in Clock mutant mice. FEBS Lett. 580, 127–130 (2006).

    CAS  Article  Google Scholar 

  6. 6

    Turek, F.W. et al. Obesity and metabolic syndrome in circadian Clock mutant mice. Science 308, 1043–1045 (2005).

    CAS  Article  Google Scholar 

  7. 7

    Rudic, R.D. et al. BMAL1 and CLOCK, two essential components of the circadian clock, are involved in glucose homeostasis. PLoS Biol. 2, e377 (2004).

    Article  Google Scholar 

  8. 8

    Ellingsen, T., Bener, A. & Gehani, A.A. Study of shift work and risk of coronary events. J. R. Soc. Promot. Health 127, 265–267 (2007).

    CAS  Article  Google Scholar 

  9. 9

    Karlsson, B., Knutsson, A. & Lindahl, B. Is there an association between shift work and having a metabolic syndrome? Results from a population based study of 27,485 people. Occup. Environ. Med. 58, 747–752 (2001).

    CAS  Article  Google Scholar 

  10. 10

    Spiegel, K., Tasali, E., Leproult, R. & Van Cauter, E. Effects of poor and short sleep on glucose metabolism and obesity risk. Nat. Rev. Endocrinol. 5, 253–261 (2009).

    CAS  Article  Google Scholar 

  11. 11

    Ahima, R.S. et al. Role of leptin in the neuroendocrine response to fasting. Nature 382, 250–252 (1996).

    CAS  Article  Google Scholar 

  12. 12

    Cowley, M.A. et al. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411, 480–484 (2001).

    CAS  Article  Google Scholar 

  13. 13

    Mizuno, T.M. & Mobbs, C.V. Hypothalamic agouti-related protein messenger ribonucleic acid is inhibited by leptin and stimulated by fasting. Endocrinology 140, 814–817 (1999).

    CAS  Article  Google Scholar 

  14. 14

    Lam, T.K. et al. Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis. Nat. Med. 11, 320–327 (2005).

    CAS  Article  Google Scholar 

  15. 15

    Pocai, A. et al. Restoration of hypothalamic lipid sensing normalizes energy and glucose homeostasis in overfed rats. J. Clin. Invest. 116, 1081–1091 (2006).

    CAS  Article  Google Scholar 

  16. 16

    Cintra, D.E. et al. Unsaturated fatty acids revert diet-induced hypothalamic inflammation in obesity. PLoS ONE 7, e30571 (2012).

    CAS  Article  Google Scholar 

  17. 17

    Bunger, M.K. et al. Mop3 is an essential component of the master circadian pacemaker in mammals. Cell 103, 1009–1017 (2000).

    CAS  Article  Google Scholar 

  18. 18

    Bunger, M.K. et al. Progressive arthropathy in mice with a targeted disruption of the Mop3/Bmal-1 locus. Genesis 41, 122–132 (2005).

    CAS  Article  Google Scholar 

  19. 19

    Kondratov, R.V., Kondratova, A.A., Gorbacheva, V.Y., Vykhovanets, O.V. & Antoch, M.P. Early aging and age-related pathologies in mice deficient in BMAL1, the core component of the circadian clock. Genes Dev. 20, 1868–1873 (2006).

    CAS  Article  Google Scholar 

  20. 20

    Westgate, E.J. et al. Genetic components of the circadian clock regulate thrombogenesis in vivo. Circulation 117, 2087–2095 (2008).

    Article  Google Scholar 

  21. 21

    He, W. et al. Adipose-specific peroxisome proliferator-activated receptor γ knockout causes insulin resistance in fat and liver but not in muscle. Proc. Natl. Acad. Sci. USA 100, 15712–15717 (2003).

    CAS  Article  Google Scholar 

  22. 22

    Clausen, B.E., Burkhardt, C., Reith, W., Renkawitz, R. & Forster, I. Conditional gene targeting in macrophages and granulocytes using LysMcre mice. Transgenic Res. 8, 265–277 (1999).

    CAS  Article  Google Scholar 

  23. 23

    Etchegaray, J.P., Lee, C., Wade, P.A. & Reppert, S.M. Rhythmic histone acetylation underlies transcription in the mammalian circadian clock. Nature 421, 177–182 (2003).

    CAS  Article  Google Scholar 

  24. 24

    Ueda, H.R. et al. System-level identification of transcriptional circuits underlying mammalian circadian clocks. Nat. Genet. 37, 187–192 (2005).

    CAS  Article  Google Scholar 

  25. 25

    Crumbley, C., Wang, Y., Kojetin, D.J. & Burris, T.P. Characterization of the core mammalian clock component, NPAS2, as a REV-ERBα/RORα target gene. J. Biol. Chem. 285, 35386–35392 (2010).

    CAS  Article  Google Scholar 

  26. 26

    Debruyne, J.P. et al. A clock shock: mouse CLOCK is not required for circadian oscillator function. Neuron 50, 465–477 (2006).

    CAS  Article  Google Scholar 

  27. 27

    Miller, B.H. et al. Circadian and CLOCK-controlled regulation of the mouse transcriptome and cell proliferation. Proc. Natl. Acad. Sci. USA 104, 3342–3347 (2007).

    CAS  Article  Google Scholar 

  28. 28

    Kornmann, B., Schaad, O., Bujard, H., Takahashi, J.S. & Schibler, U. System-driven and oscillator-dependent circadian transcription in mice with a conditionally active liver clock. PLoS Biol. 5, e34 (2007).

    Article  Google Scholar 

  29. 29

    Eguchi, J. et al. Transcriptional control of adipose lipid handling by IRF4. Cell Metab. 13, 249–259 (2011).

    CAS  Article  Google Scholar 

  30. 30

    Maffei, M. et al. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat. Med. 1, 1155–1161 (1995).

    CAS  Article  Google Scholar 

  31. 31

    El-Haschimi, K., Pierroz, D.D., Hileman, S.M., Bjorbaek, C. & Flier, J.S. Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity. J. Clin. Invest. 105, 1827–1832 (2000).

    CAS  Article  Google Scholar 

  32. 32

    Stunkard, A. et al. Binge eating disorder and the night-eating syndrome. Int. J. Obes. Relat. Metab. Disord. 20, 1–6 (1996).

    CAS  PubMed  Google Scholar 

  33. 33

    Hogenesch, J.B., Gu, Y.Z., Jain, S. & Bradfield, C.A. The basic-helix-loop-helix-PAS orphan MOP3 forms transcriptionally active complexes with circadian and hypoxia factors. Proc. Natl. Acad. Sci. USA 95, 5474–5479 (1998).

    CAS  Article  Google Scholar 

  34. 34

    Oh, D.Y. et al. GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell 142, 687–698 (2010).

    CAS  Article  Google Scholar 

  35. 35

    Wei, E. et al. Loss of TGH/Ces3 in mice decreases blood lipids, improves glucose tolerance, and increases energy expenditure. Cell Metab. 11, 183–193 (2010).

    CAS  Article  Google Scholar 

  36. 36

    Minokoshi, Y. et al. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 428, 569–574 (2004).

    CAS  Article  Google Scholar 

  37. 37

    Ropelle, E.R. et al. IL-6 and IL-10 anti-inflammatory activity links exercise to hypothalamic insulin and leptin sensitivity through IKKβ and ER stress inhibition. PLoS Biol. 8, e1000465 (2010).

    Article  Google Scholar 

  38. 38

    Kiessling, S., Eichele, G. & Oster, H. Adrenal glucocorticoids have a key role in circadian resynchronization in a mouse model of jet lag. J. Clin. Invest. 120, 2600–2609 (2010).

    CAS  Article  Google Scholar 

  39. 39

    Pietiläinen, K.H. et al. Association of lipidome remodeling in the adipocyte membrane with acquired obesity in humans. PLoS Biol. 9, e1000623 (2011).

    Article  Google Scholar 

  40. 40

    Arble, D.M., Bass, J., Laposky, A.D., Vitaterna, M.H. & Turek, F.W. Circadian timing of food intake contributes to weight gain. Obesity (Silver Spring) 17, 2100–2102 (2009).

    Article  Google Scholar 

  41. 41

    Stucchi, P. et al. Circadian feeding drive of metabolic activity in adipose tissue and not hyperphagia triggers overweight in mice: is there a role of the pentose-phosphate pathway? Endocrinology 153, 690–699 (2012).

    CAS  Article  Google Scholar 

  42. 42

    Hatori, M. et al. Time-restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high-fat diet. Cell Metab. 15, 848–860 (2012).

    CAS  Article  Google Scholar 

  43. 43

    Masaki, T. et al. Involvement of hypothalamic histamine H1 receptor in the regulation of feeding rhythm and obesity. Diabetes 53, 2250–2260 (2004).

    CAS  Article  Google Scholar 

  44. 44

    Salgado-Delgado, R., Angeles-Castellanos, M., Saderi, N., Buijs, R.M. & Escobar, C. Food intake during the normal activity phase prevents obesity and circadian desynchrony in a rat model of night work. Endocrinology 151, 1019–1029 (2010).

    CAS  Article  Google Scholar 

  45. 45

    Fonken, L.K. et al. Light at night increases body mass by shifting the time of food intake. Proc. Natl. Acad. Sci. USA 107, 18664–18669 (2010).

    CAS  Article  Google Scholar 

  46. 46

    Scheer, F.A., Hilton, M.F., Mantzoros, C.S. & Shea, S.A. Adverse metabolic and cardiovascular consequences of circadian misalignment. Proc. Natl. Acad. Sci. USA 106, 4453–4458 (2009).

    CAS  Article  Google Scholar 

  47. 47

    Reyes, T.M., Walker, J.R., DeCino, C., Hogenesch, J.B. & Sawchenko, P.E. Categorically distinct acute stressors elicit dissimilar transcriptional profiles in the paraventricular nucleus of the hypothalamus. J. Neurosci. 23, 5607–5616 (2003).

    CAS  Article  Google Scholar 

  48. 48

    Roberts, L.D. et al. Increased hepatic oxidative metabolism distinguishes the action of peroxisome proliferator-activated receptor δ from peroxisome proliferator-activated receptor γ in the ob/ob mouse. Genome Med. 1, 115 (2009).

    Article  Google Scholar 

  49. 49

    Irizarry, R.A. et al. Summaries of Affymetrix GeneChip probe level data. Nucleic Acids Res. 31, e15 (2003).

    Article  Google Scholar 

  50. 50

    Grant, G.R., Liu, J. & Stoeckert, C.J. Jr. A practical false discovery rate approach to identifying patterns of differential expression in microarray data. Bioinformatics 21, 2684–2690 (2005).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

This work was supported by US National Institutes of Health (NIH) grant RO1 HL097800 and Medical Research Council grant UD99999906. We thank M. Lazar for help with the ChIP experiments (funded by NIH R01 DK45586). We thank R. Ahima and the Mouse Phenotyping, Physiology and Metabolism Core of the Penn Diabetes Research Center (P30 DK19525) for performing body composition and behavioral analysis; D. Baldwin's Microarray Core Facility for performing the microarray analysis; and R. Freer and M. Adam for technical assistance. G.A.F. is the McNeil Professor of Translational Medicine and Therapeutics.

Author information

Affiliations

Authors

Contributions

G.K.P., S.I., W.-L.S., T.K., C.H.V. and F.W. contributed to the acquisition, analysis and interpretation of the data. G.K.P. and G.A.F. initiated and designed the study. G.G. performed statistical analyses and analysis of the microarray data. T.M.R. performed indirect calorimetric analyses. C.A.B. provided the mice with the conditional Arntl allele. M.E., M.M., J.L.G. and J.A.L. performed the liquid chromatography mass spectrometry (LC-MS) analysis. G.K.P. and G.A.F. wrote the paper.

Corresponding author

Correspondence to Garret A FitzGerald.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8 and Supplementary Methods (PDF 6800 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Paschos, G., Ibrahim, S., Song, WL. et al. Obesity in mice with adipocyte-specific deletion of clock component Arntl. Nat Med 18, 1768–1777 (2012). https://doi.org/10.1038/nm.2979

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing