Fasting enhances cold resistance in fish through stimulating lipid catabolism and autophagy

Abstract

Key points In a cold environment, mammals increase their food intake while fish decrease or stop feeding. However, the physiological value of fasting during cold resistance in fish is currently unknown. Fasting for more than 48 h enhanced acute cold resistance in zebrafish, which correlated with lipid catabolism and cell damage attenuation. Lipid catabolism and autophagy were necessary for cold resistance in fish and the inhibition of mitochondrial fatty acid β‐oxidation or autophagy weakened the fasting‐induced cold resistance. Repression of mechanistic target of rapamycin (mTOR) signalling pathway by rapamycin largely mimicked the beneficial effects of fasting in promoting cold resistance, suggesting mTOR signalling may be involved in the fasting‐induced cold resistance in fish. Our study demonstrates that fasting may be a protective strategy for fish to survive under cold stress. Abstract In cold environments, most homeothermic animals increase their food intake to supply more energy to maintain body temperature, whereas most poikilothermic animals such as fishes decrease or even stop feeding under cold stress. However, the physiological value of fasting during cold resistance in poikilotherms has not been explained. Here, we show that moderate fasting largely enhanced cold resistance in fish. By using pharmacological (fenofibrate, mildronate, chloroquine and rapamycin) and nutritional approaches (fatty acids diets and amino acids diets) in wild‐type or specific gene knock‐out zebrafish models (carnitine palmitoyltransferase‐1b‐deficient strain, CPT1b−/−, or autophagy‐related protein 12‐deficient strain, ATG12−/−), we verified that fasting‐stimulated lipid catabolism and autophagy played essential roles in the improved cold resistance. Moreover, suppression of the mechanistic target of rapamycin (mTOR) pathway by using rapamycin mostly mimicked the beneficial effects of fasting in promoting cold resistance as either the physiological phenotype or transcriptomic pattern. However, these beneficial effects were largely reduced when the mTOR pathway was activated through high dietary leucine supplementation. We conclude that fasting helps fish to resist cold stress by modulating lipid catabolism and autophagy, which correlates with the mTOR signalling pathway. Therefore, fasting can act as a protective strategy of fish in resisting coldness.

The role of autophagy and lipid catabolism in enhancing cold stress resistance in zebrafish

“…However, the work completed by Lu et al . () provides evidence that the processes of both autophagy and lipid catabolism could be responsible for this phenomenon as summarized in Fig. .…”

“…Since ATG12 is essential for phagophore extension, the assembly of autophagosomes in ATG12 −/− zebrafish was impaired (Zechner et al, 2017). As illustrated by Lu et al (2019), experimental conditions that increased or decreased autophagy were associated with an increase or decrease in zebrafish survival to cold stress, respectively. Therefore, this work provided evidence that highlighted autophagy as necessary for eliminating damage mediated by cold stress.…”

“…Unlike homeothermic animals that rely on a calorie rich diet to sustain body temperature (Lu et al. , 2019), it is hypothesized that zebrafish have adapted to manipulate mTOR signalling and lipid catabolism to survive cold climates.…”

“…Although it has been reported previously that fasting increases cold stress resistance using Drosophila melanogaster (Isabelle and Bourg, 2015), the mechanism of this phenomenon remained unknown. However, the work completed by Lu et al (2019) provides evidence that the processes of both autophagy and lipid catabolism could be responsible for this phenomenon as summarized in Fig. 1.…”

“…Natural selection favours organisms that develop biological and behavioural mechanisms to adapt to acute decreases in temperature, which is a known environmental stressor. Homeothermic animals maintain body temperature by increasing food intake whereas poikilothermic animals, such as fish, have evolved to adapt to cold temperatures by decreasing food intake (Lu et al, 2019). Although the physiological mechanism to explain this phenomenon remains unknown, it is hypothesized that fasting attenuates cellular damage mediated by stressors.…”