Abstract
Diurnal light-dark cycle resets the master clock, while timed food intake is another potent synchronizer of peripheral clocks in mammals. As the largest metabolic organ, the liver sensitively responds to the food signals and secretes hepatokines, leading to the robust regulation of metabolic and clock processes. However, it remains unknown which hepatokine mediates the food-driven resetting of the liver clock independent of the master clock. Here, we identify Angptl8 as a hepatokine that resets diurnal rhythms of hepatic clock and metabolic genes in mice. Mechanistically, the resetting function of Angptl8 is dependent on the signal relay of the membrane receptor PirB, phosphorylation of kinases and transcriptional factors, and consequently transient activation of the central clock gene Per1. Importantly, inhibition of Angptl8 signaling partially blocks food-entrained resetting of liver clock in mice. We have thus identified Angptl8 as a key regulator of the liver clock in response to food.
Highlights
Diurnal light-dark cycle resets the master clock, while timed food intake is another potent synchronizer of peripheral clocks in mammals
Mice lacking the gene encoding β-Klotho (Klb) in the suprachiasmatic nucleus (SCN) are refractory to these effects, suggesting that the diverse physiologic and pharmacologic actions of FGF21 are still mediated by the nervous system[16,17,18]
We found that the neutralization of Angptl[8] antagonized the effect of refeeding on the resetting of liver clock, evidenced by the decrease in the amplitudes of Per[2] and Dbp mRNA oscillation and the delay in the phase of Bmal[1] rhythmicity (Fig. 10d and Supplementary Table 11)
Summary
Diurnal light-dark cycle resets the master clock, while timed food intake is another potent synchronizer of peripheral clocks in mammals. As the largest metabolic organ, the liver sensitively responds to the food signals and secretes hepatokines, leading to the robust regulation of metabolic and clock processes It remains unknown which hepatokine mediates the food-driven resetting of the liver clock independent of the master clock. The entrainment of peripheral clocks is independent on the SCN, and complex foods show much stronger effects on the phase resetting compared to carbohydrate intake, indicating that other factors must be involved[19]. These remaining questions prompt us to identify hepatokines that mediate the food-driven resetting of the liver clock, independent of the master clock. Angptl[8] is a key regulator of the liver clock in response to food
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