SIK2 regulates fasting-induced PPARα activity and ketogenesis through p300

Zhang, Zhenning; Gong, Lulu; Lv, Sihan; Li, Jian; Tai, Xiaolu; Cao, Wenqi; Peng, Bing; Qu, Shen; Li, Weida; Chao, Zhang; Luan, Bing

doi:10.1038/srep23317

Cited by 12 publications

(11 citation statements)

References 24 publications

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“…For examples, fasting stimulated the SIK2‐p300‐PPARα pathway to mediate glucagon signalling and regulated lipid metabolism (Zhang et al . ). Fasting also induced autophagy by activating AMPK and then directly activated phosphorylation of Forkhead box O3 (FoxO3) and the Unc‐51‐like kinase 1 (Ulk1) without repression of mTOR (Mammucari et al .…”

Section: Discussionmentioning

confidence: 97%

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

Wang

et al. 2019

The Journal of Physiology

108

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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.

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Section: Discussionmentioning

confidence: 97%

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

Wang

et al. 2019

The Journal of Physiology

108

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“…Von Meyenn and coworkers have shown that glucagon stimulation induced Lys259 acetylation of Foxa2, which plays an important role in glucagon-stimulated fatty acid oxidation (von Meyenn et al 2013). Our previous work also pointed out that glucagon could promote fatty acid oxidation through releasing the inhibitory effect of SIK2 on p300, which binds to PPARα and promotes PPARα activity (Zhang et al 2016). Thus, glucagon regulates fatty acid oxidation genes expression and PPARα activity through multiple mechanisms.…”

Section: :2mentioning

confidence: 90%

Glucagon-induced extracellular cAMP regulates hepatic lipid metabolism

Qiu

et al. 2017

Journal of Endocrinology

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Hormonal signals help to maintain glucose and lipid homeostasis in the liver during the periods of fasting. Glucagon, a pancreas-derived hormone induced by fasting, promotes gluconeogenesis through induction of intracellular cAMP production. Glucagon also stimulates hepatic fatty acid oxidation but the underlying mechanism is poorly characterized. Here we report that following the acute induction of gluconeogenic genes () and () expression through cAMP-response element-binding protein (CREB), glucagon triggers a second delayed phase of fatty acid oxidation genes () and () expression via extracellular cAMP. Increase in extracellular cAMP promotes PPARα activity through direct phosphorylation by AMP-activated protein kinase (AMPK), while inhibition of cAMP efflux greatly attenuates and expression. Importantly, cAMP injection improves lipid homeostasis in fasted mice and obese mice, while inhibition of cAMP efflux deteriorates hepatic steatosis in fasted mice. Collectively, our results demonstrate the vital role of glucagon-stimulated extracellular cAMP in the regulation of hepatic lipid metabolism through AMPK-mediated PPARα activation. Therefore, strategies to improve cAMP efflux could serve as potential new tools to prevent obesity-associated hepatic steatosis.

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“…In addition, transcription factor PPARα was likely activated in the liver of A. davidianus after prolonged fasting by Upstream Regulator Analysis in IPA. The activated PPARα by fasting promoted the expression of fatty acid oxidation and ketogenesis-related genes in synergy with other fastingrelated transcription factors, such as CREB3L3 (Nakagawa et al, 2016), p300 (Zhang et al, 2016), and PGC-1α (Rodgers and Puigserver, 2007). These results indicate that the enhanced fatty acid oxidation is needed to provide energy for the A. davidianus after prolonged fasting and can also explain why A. davidianus can survive for long periods of food deprivation.…”

Section: Fatty Acid β-Oxidation and Ketogenesis Are Up-regulated Durimentioning

confidence: 79%

Differential Proteomic Analysis of Chinese Giant Salamander Liver in Response to Fasting

et al. 2020

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Chinese giant salamander Andrias davidianus has strong tolerance to starvation. Fasting triggers a complex array of adaptive metabolic responses, a process in which the liver plays a central role. Here, a high-throughput proteomic analysis was carried out on liver samples obtained from adult A. davidianus after 3, 7, and 11 months of fasting. As a result, the expression levels of 364 proteins were significantly changed in the fasted liver. Functional analysis demonstrated that the expression levels of key proteins involved in fatty acid oxidation, tricarboxylic acid cycle, gluconeogenesis, ketogenesis, amino acid oxidation, urea cycle, and antioxidant systems were increased in the fasted liver, especially at 7 and 11 months after fasting. In contrast, the expression levels of vital proteins involved in pentose phosphate pathway and protein synthesis were decreased after fasting. We also found that fasting not only activated fatty acid oxidation and ketogenesis-related transcription factors PPARA and PPARGC1A, but also activated gluconeogenesis-related transcription factors FOXO1, HNF4A, and KLF15. This study confirms the central role of lipid and acetyl-CoA metabolism in A. davidianus liver in response to fasting at the protein level and provides insights into the molecular mechanisms underlying the metabolic response of A. davidianus liver to fasting.

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SIK2 regulates fasting-induced PPARα activity and ketogenesis through p300

Cited by 12 publications

References 24 publications

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

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

Glucagon-induced extracellular cAMP regulates hepatic lipid metabolism

Differential Proteomic Analysis of Chinese Giant Salamander Liver in Response to Fasting

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