Fasting exacerbates hepatic growth differentiation factor 15 to promote fatty acid beta-oxidation and ketogenesis via activating XBP1 signaling in liver

Meiyuan Zhang, Weilan Sun, Jin Qian and Yan Tang

Redox Biology 2018. 16: 87-96.


Liver coordinates a series of metabolic adaptations to maintain systemic energy balance and provide adequate nutrients for critical organs, tissues and cells during starvation. However, the mediator(s) implicated in orchestrating these fasting-induced adaptive responses and the underlying molecular mechanisms are still obscure. Here we show that hepatic growth differentiation factor 15 (GDF15) is regulated by IRE1?-XBP1s branch and promotes hepatic fatty acids ?-oxidation and ketogenesis upon fasting. GDF15 expression was exacerbated in liver of mice subjected to long-term fasted or ketogenic diet feeding. Abrogation of hepatic Gdf15 dramatically attenuated hepatic ?-oxidation and ketogenesis in fasted mice or mice with STZ-initiated type I diabetes. Further study revealed that XBP1s activated Gdf15 transcription via binding to its promoter. Elevated GDF15 in liver reduced lipid accumulation and impaired NALFD development in obese mice through enhancing fatty acids oxidation in liver. Therefore, our results demonstrate a novel and critical role of hepatic GDF15 activated by IRE1?-XBP1s branch in regulating adaptive responses of liver upon starvation stress.

Our Thoughts on This Paper

The recent identification of GFRAL as a receptor for GDF15, mediating its anorexic effects has led to a flurry of recent work into the function of this hormone. The sources (at least in the absence of cancer) of this hormone are still not entirely clear, but in this recent paper, Zhang et al explored how fasting regulates hepatic GDF15 and some of the consequences of its production. They found that prolonged fasting, carbohydrate restriction, or beta cell destruction led to elevations in GDF15 production in the liver. They suggest hepatic ER stress as a mediator of this process, and show that knockdown of GDF15 by adenoviral siRNA impairs hepatic lipid oxidation. These data also suggest a novel hepatokine action of GDF15 in regulating adipocyte lipolysis. These data suggest that GDF15 may have roles in addition to appetite regulation, and may be a larger co-ordinator of nutrient homeostasis. These comments are crossposted on F1000 prime.

Written by Dave Bridges on July 24, 2018.


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