Editors' ChoicePhysiology

Fatty Rhythms

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Science Signaling  29 Oct 2013:
Vol. 6, Issue 299, pp. ec258
DOI: 10.1126/scisignal.2004847

When we eat, some calories are converted to fat (lipogenesis), which is then stored and used later for energy. Peroxisome proliferator–activated receptor δ (PPARδ) in the liver stimulates lipogenesis, whereas PPARα in the muscle promotes fatty acid breakdown. Liu et al. found that a lipid metabolite in mice serves as a signal from the liver to stimulate fat uptake and breakdown in the muscle in a circadian manner (see commentary by Moore). In mice, the expression of Ppard, which encodes PPARδ, oscillated diurnally with genes encoding circadian clock proteins, peaking in the dark, which is the feeding phase of the circadian cycle for mice. Daytime-restricted feeding reversed the expression pattern of Ppard, genes encoding lipogenesis enzymes, and genes encoding clock proteins. Compared with wild-type mice, fatty acid uptake in the soleus muscle in mice with liver-specific conditional Ppard knockout (LPPARDKO) was decreased during the dark phase, whereas liver-specific PPARδ overexpression decreased the abundance of serum triglycerides and fatty acids while increasing their abundance and amount of oxidation in muscle. Further, blood serum collected during the dark phase from wild-type mice promoted fat uptake in cultured C2C12 myotubes, but serum from LPPARDKO mice did not, suggesting that PPARδ in the liver induces fatty acid uptake and metabolism in muscle. Cluster analysis of lipids in the serum from wild-type versus LPPARDKO mice identified 14 lipid species as candidates to these effects. Of these, PPARδ regulated the circadian production of phosphatidylcholine 18:0 and 18:1 [PC(18:0/18:1)] in mice. Treating myotubes in culture or injecting mice intraperitoneally or intravascularly with PC(18:0/18:1), but not with other PC species, increased fatty acid uptake in muscle cells and, in mice, reduced serum fatty acid and triglyceride concentrations. These effects of PC(18:0/18:1) were abolished by PPARα knockdown in myotubes or by Ppara knockout in mice. A mouse model of diabetic obesity (db/db) or wild-type mice fed a high-fat diet had reduced production of PC(18:0/18:1). Treatment with this lipid decreased serum concentrations of triglycerides, fatty acids, and fasting glucose and improved glucose and insulin tolerance in both mice. The findings suggest that activating this liver-to-muscle lipid signaling mechanism may be beneficial in obesity and diabetes.

S. Liu, J. D. Brown, K. J. Stanya, E. Homan, M. Leidl, K. Inouye, P. Bhargava, M. R. Gangl, L. Dai, B. Hatano, G. S. Hotamisligil, A. Saghatelian, J. Plutzky, C.-H. Lee, A diurnal serum lipid integrates hepatic lipogenesis and peripheral fatty acid use. Nature 502, 550–554 (2013). [PubMed]

D. D. Moore, A metabolic minuet. Nature 502, 454–455 (2013). [PubMed]

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