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.
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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.
The authors declare no competing financial interests.
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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
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