Role of the Mixed-Lineage Protein Kinase Pathway in the Metabolic Stress Response to Obesity

Kant, Shashi; Barrett, Tamera; Vertii, Anastassiia; Noh, Yun Hee; Jung, Dae Young; Kim, Jason K.; Davis, Roger J.

doi:10.1016/j.celrep.2013.07.019

Cited by 32 publications

(29 citation statements)

References 28 publications

(47 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consuming a HFD increases the blood concentration of free fatty acids (Kahn et al, 2006) and causes JNK activation mediated by the mixed-lineage protein kinase pathway (Jaeschke and Davis, 2007; Kant et al, 2013). Activated JNK contributes to obesity development by increasing Activating Protein 1 (AP1)-dependent Dio2 gene expression in the anterior pituitary gland (Vernia et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

The PPARα-FGF21 Hormone Axis Contributes to Metabolic Regulation by the Hepatic JNK Signaling Pathway

et al. 2014

Self Cite

View full text Add to dashboard Cite

The cJun NH2-terminal kinase (JNK) stress signaling pathway is implicated in the metabolic response to the consumption of a high fat diet, including the development of obesity and insulin resistance. These metabolic adaptations involve altered liver function. Here we demonstrate that hepatic JNK potently represses the nuclear hormone receptor peroxisome proliferator-activated receptor α (PPARα). JNK therefore causes decreased expression of PPARα target genes that increase fatty acid oxidation / ketogenesis and promote the development of insulin resistance. We show that the PPARα target gene fibroblast growth factor 21 (Fgf21) plays a key role in this response because disruption of the hepatic PPARα - FGF21 hormone axis suppresses the metabolic effects of JNK-deficiency. This analysis identifies the hepatokine FGF21 as a critical mediator of JNK signaling in the liver.

show abstract

Section: Introductionmentioning

confidence: 99%

The PPARα-FGF21 Hormone Axis Contributes to Metabolic Regulation by the Hepatic JNK Signaling Pathway

et al. 2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…Indeed, obesity is associated with increased JNK activity in human omental adipose tissue (Bashan et al 2007). Obesity-induced JNK activation is mediated, in part, by free fatty acids (FFAs) that activate the mixed-lineage protein kinase pathway (Jaeschke and Davis 2007;Gadang et al 2013;Kant et al 2013). The mechanism of FFA signaling may involve G-proteincoupled receptors (Talukdar et al 2011) or nonreceptor mechanisms (Holzer et al 2011) that cause activation of the tyrosine kinase Src in lipid raft domains of the plasma membrane (Holzer et al 2011).…”

mentioning

confidence: 99%

Diet-induced obesity mediated by the JNK/DIO2 signal transduction pathway

et al. 2013

Self Cite

View full text Add to dashboard Cite

The cJun N-terminal kinase (JNK) signaling pathway is a key mediator of metabolic stress responses caused by consuming a high-fat diet, including the development of obesity. To test the role of JNK, we examined dietinduced obesity in mice with targeted ablation of Jnk genes in the anterior pituitary gland. These mice exhibited an increase in the pituitary expression of thyroid-stimulating hormone (TSH), an increase in the blood concentration of thyroid hormone (T4), increased energy expenditure, and markedly reduced obesity compared with control mice. The increased amount of pituitary TSH was caused by reduced expression of type 2 iodothyronine deiodinase (Dio2), a gene that is required for T4-mediated negative feedback regulation of TSH expression. These data establish a molecular mechanism that accounts for the regulation of energy expenditure and the development of obesity by the JNK signaling pathway.

show abstract

“…Analysis of Fgf21 mRNA expression demonstrated that both MKK4-deficiency and MKK7-deficiency caused increased Fgf21 expression, but compound MKK4 plus MKK7-deficiency strongly increased Fgf21 expression (Figure 1E). Similarly, compound deficiency of the mixed-lineage protein kinases MLK2 plus MLK3, that function as activators of MKK4 and MKK7 in response to metabolic stress (Kant et al, 2013), causes increased expression of FGF21 circulating in the blood (Figure 1D). Together, these data demonstrate that the JNK signaling pathway acts to suppress FGF21 expression.…”

Section: Resultsmentioning

confidence: 99%

Fibroblast Growth Factor 21 Mediates Glycemic Regulation by Hepatic JNK

et al. 2016

Self Cite

View full text Add to dashboard Cite

The cJun NH2-terminal kinase (JNK) signaling pathway is implicated in metabolic syndrome, including dysregulated blood glucose concentration and insulin resistance. Fibroblast growth factor 21 (FGF21) is a target of the hepatic JNK signaling pathway and may contribute to the regulation of glycemia. To test the role of FGF21, we established mice with selective ablation of the Fgf21 gene in hepatocytes. FGF21-deficiency in the liver caused marked loss of FGF21 protein circulating in the blood. Moreover, the protective effects of hepatic JNK-deficiency to suppress metabolic syndrome in high fat diet-fed mice were not observed in mice with hepatocyte-specific FGF21-deficiency, including reduced blood glucose concentration and reduced intolerance to glucose and insulin. Furthermore, we show that JNK contributes to the regulation of hepatic FGF21 expression during fasting /feeding cycles. These data demonstrate that the hepatokine FGF21 is a key mediator of JNK-regulated metabolic syndrome.

show abstract

Role of the Mixed-Lineage Protein Kinase Pathway in the Metabolic Stress Response to Obesity

Cited by 32 publications

References 28 publications

The PPARα-FGF21 Hormone Axis Contributes to Metabolic Regulation by the Hepatic JNK Signaling Pathway

The PPARα-FGF21 Hormone Axis Contributes to Metabolic Regulation by the Hepatic JNK Signaling Pathway

Diet-induced obesity mediated by the JNK/DIO2 signal transduction pathway

Fibroblast Growth Factor 21 Mediates Glycemic Regulation by Hepatic JNK

Contact Info

Product

Resources

About