Fasting Hormones Synergistically Induce Amino Acid Catabolism Genes to Promote Gluconeogenesis

Korenfeld, Noga; Finkel, Maya; Buchshtab, Nufar; Bar-Shimon, Meirav; Charni-Natan, Meital; Goldstein, Ido

doi:10.1016/j.jcmgh.2021.04.017

Cited by 15 publications

(21 citation statements)

References 71 publications

(166 reference statements)

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“…The synergistic group of genes was highly enriched in pathways related to gluconeogenesis and catabolic routes leading to gluconeogenesis (i. e. amino acid metabolism and urea cycle; Supplementary Table S2 ). This finding is in accordance with our previous studies showing that a dual treatment of glucagon and corticosterone leads to a synergistic increase in gluconeogenesis from both pyruvate and amino acid precursors ( 3 , 19 ). This also aligns with the observed synergistic glucose production following infusion of both hormones to dogs and humans ( 24 , 25 ).…”

Section: Resultssupporting

confidence: 94%

“…Synergy between GR and the cAMP-PKA pathway in regulating gene expression was shown ( 3 , 19 , 26–29 , 60 , 61 ). However, the mechanism behind it is unclear.…”

Section: Discussionmentioning

confidence: 99%

“…Enhancer clusters were analyzed in the vicinity of 91 assisted sites and 91 randomly-selected unassisted sites. Dnase hypersensitive sites that are found in fasted mice ( 3 , 19 ) and are located 12.5kb upstream and downstream of assisted or unassisted GRBS were isolated. GRBS with at least two Dnase hypersensitive sites in the +/- 12.5kb region were further analyzed.…”

Section: Methodsmentioning

confidence: 99%

“…All data is available in Gene Expression Omnibus (GEO) under accession number GSE72087. Lists of fasting-induced genes and fasting-activated Dnase hypersensitive sites were previously generated and are openly available ( 19 ). These lists were generated as follows: differential gene expression or Dnase accessibility were evaluated by DEseq2 ( 46 ) via the HOMER platform under default parameters.…”

Section: Methodsmentioning

confidence: 99%

“…The major transcription factor (TF) activated by glucagon is cAMP responsive element binding protein - CREB ( 17 ). Upon glucagon stimulation, CREB regulates gluconeogenic genes ( 18 ) as well as genes responsible for providing gluconeogenic precursors ( 19 ). In addition to glucagon, glucocorticoids are also secreted during fasting and dramatically affect hepatic gene expression and metabolism.…”

Section: Introductionmentioning

confidence: 99%

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Hormone-controlled cooperative binding of transcription factors drives synergistic induction of fasting-regulated genes

Goldberg

Charni-Natan

Buchshtab

et al. 2022

Nucleic Acids Research

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During fasting, hepatocytes produce glucose in response to hormonal signals. Glucagon and glucocorticoids are principal fasting hormones that cooperate in regulating glucose production via gluconeogenesis. However, how these hormone signals are integrated and interpreted to a biological output is unknown. Here, we use genome-wide profiling of gene expression, enhancer dynamics and transcription factor (TF) binding in primary mouse hepatocytes to uncover the mode of cooperation between glucagon and glucocorticoids. We found that compared to a single treatment with each hormone, a dual treatment directs hepatocytes to a pro-gluconeogenic gene program by synergistically inducing gluconeogenic genes. The cooperative mechanism driving synergistic gene expression is based on ‘assisted loading’ whereby a glucagon-activated TF (cAMP responsive element binding protein; CREB) leads to enhancer activation which facilitates binding of the glucocorticoid receptor (GR) upon glucocorticoid stimulation. Glucagon does not only activate single enhancers but also activates enhancer clusters, thereby assisting the loading of GR also across enhancer units within the cluster. In summary, we show that cells integrate extracellular signals by an enhancer-specific mechanism: one hormone-activated TF activates enhancers, thereby assisting the loading of a TF stimulated by a second hormone, leading to synergistic gene induction and a tailored transcriptional response to fasting.

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Section: Resultssupporting

confidence: 94%

“…Synergy between GR and the cAMP-PKA pathway in regulating gene expression was shown ( 3 , 19 , 26–29 , 60 , 61 ). However, the mechanism behind it is unclear.…”

Section: Discussionmentioning

confidence: 99%