The adrenergic-induced ERK3 pathway drives lipolysis and suppresses energy dissipation

El‐Merahbi, Rabih; Viera, Jonathan Trujillo; Loza‐Valdes, Angel; Kolczyńska, Katarzyna; Reuter, Saskia; Löffler, Mona C.; Erk, Manuela; Ade, Carsten P.; Karwen, Till; Mayer, Alexander; Eilers, Martin; Sumara, Grzegorz

doi:10.1101/gad.333617.119

Cited by 24 publications

(33 citation statements)

References 54 publications

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“…High throughput screen for kinases regulating lipolysis in adipocytes revealed ERK3 as a major factor promoting adipocyte function. Consistently, targeted deletion of ERK3 in mouse adipocytes inhibits lipolysis, but elevates energy dissipation, promoting lean phenotype and ameliorating diabetes [225]. Mechanistically, β-adrenergic stimulation stabilizes ERK3, leading to the formation of a complex with the cofactor MK5, and thereby driving lipolysis.…”

Section: The Atypical Mapksmentioning

confidence: 86%

“…However, ERK3 and NLK emerge as important regulators of adipocyte and pancreatic β-cell function ( Figure 5). ERK3 promotes lipolysis in adipose tissue and suppresses energy dissipation in this organ [225]. ERK3 also promotes insulin secretion from the pancreatic β cell [226].…”

Section: Discussionmentioning

confidence: 99%

“…Mechanistically, β-adrenergic stimulation stabilizes ERK3, leading to the formation of a complex with the cofactor MK5, and thereby driving lipolysis. ERK3/MK5 pathway promotes lipolysis by promoting the expression of a major lipase, adipose triglyceride lipase (ATGL), in a FOXO1-dependent manner [225]. On the other hand, depletion of ERK3 in adipocytes promotes UCP1 expression and energy dissipation by brown, as well as white, adipose tissue, thereby protecting against obesity and diabetes [225].…”

Section: The Atypical Mapksmentioning

confidence: 99%

“…ERK3/MK5 pathway promotes lipolysis by promoting the expression of a major lipase, adipose triglyceride lipase (ATGL), in a FOXO1-dependent manner [225]. On the other hand, depletion of ERK3 in adipocytes promotes UCP1 expression and energy dissipation by brown, as well as white, adipose tissue, thereby protecting against obesity and diabetes [225]. Pregnancy induces peripheral insulin resistance, which is normally compensated by increased β-cell proliferation, expansion of islet volume, and increased insulin synthesis and secretion.…”

Section: The Atypical Mapksmentioning

confidence: 99%

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Impact of Conventional and Atypical MAPKs on the Development of Metabolic Diseases

Kassouf

Sumara

2020

Biomolecules

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The family of mitogen-activated protein kinases (MAPKs) consists of fourteen members and has been implicated in regulation of virtually all cellular processes. MAPKs are divided into two groups, conventional and atypical MAPKs. Conventional MAPKs are further classified into four sub-families: extracellular signal-regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK1, 2 and 3), p38 (α, β, γ, δ), and extracellular signal-regulated kinase 5 (ERK5). Four kinases, extracellular signal-regulated kinase 3, 4, and 7 (ERK3, 4 and 7) as well as Nemo-like kinase (NLK) build a group of atypical MAPKs, which are activated by different upstream mechanisms than conventional MAPKs. Early studies identified JNK1/2 and ERK1/2 as well as p38α as a central mediators of inflammation-evoked insulin resistance. These kinases have been also implicated in the development of obesity and diabetes. Recently, other members of conventional MAPKs emerged as important mediators of liver, skeletal muscle, adipose tissue, and pancreatic β-cell metabolism. Moreover, latest studies indicate that atypical members of MAPK family play a central role in the regulation of adipose tissue function. In this review, we summarize early studies on conventional MAPKs as well as recent findings implicating previously ignored members of the MAPK family. Finally, we discuss the therapeutic potential of drugs targeting specific members of the MAPK family.

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Section: The Atypical Mapksmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: The Atypical Mapksmentioning

confidence: 99%

Section: The Atypical Mapksmentioning

confidence: 99%

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Impact of Conventional and Atypical MAPKs on the Development of Metabolic Diseases

Kassouf

Sumara

2020

Biomolecules

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“…Stromal vascular cells (SVC) from subcutaneous white adipose tissue (sWAT) were isolated and differentiated into mature adipocytes as described in El-Merahbi et al 45 . Briefly, sWAT of 8 weeks old mice were collected on a 10 cm Petri dish, washed with PBS, and cleaned from lymph-nodes and visible blood vessels.…”

Section: Methodsmentioning

confidence: 99%

A genome-wide transcriptomic analysis of embryos fathered by obese males in a murine model of diet-induced obesity

Bernhardt¹,

Dittrich

El‐Merahbi

et al. 2021

Sci Rep

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Paternal obesity is known to have a negative impact on the male’s reproductive health as well as the health of his offspring. Although epigenetic mechanisms have been implicated in the non-genetic transmission of acquired traits, the effect of paternal obesity on gene expression in the preimplantation embryo has not been fully studied. To this end, we investigated whether paternal obesity is associated with gene expression changes in eight-cell stage embryos fathered by males on a high-fat diet. We used single embryo RNA-seq to compare the gene expression profile of embryos generated by males on a high fat (HFD) versus control (CD) diet. This analysis revealed significant upregulation of the Samd4b and Gata6 gene in embryos in response to a paternal HFD. Furthermore, we could show a significant increase in expression of both Gata6 and Samd4b during differentiation of stromal vascular cells into mature adipocytes. These findings suggest that paternal obesity may induce changes in the male germ cells which are associated with the gene expression changes in the resulting preimplantation embryos.

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ERK3‐MK5 signaling regulates myogenic differentiation and muscle regeneration by promoting FoxO3 degradation

Soulez

Tanguay

Dô

et al. 2022

Journal Cellular Physiology

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The physiological functions and downstream effectors of the atypical mitogen‐activated protein kinase extracellular signal‐regulated kinase 3 (ERK3) remain to be characterized. We recently reported that mice expressing catalytically‐inactive ERK3 (Mapk6KD/KD) exhibit a reduced postnatal growth rate as compared to control mice. Here, we show that genetic inactivation of ERK3 impairs postnatal skeletal muscle growth and adult muscle regeneration after injury. Loss of MAPK‐activated protein kinase 5 (MK5) phenocopies the muscle phenotypes of Mapk6KD/KD mice. At the cellular level, genetic or pharmacological inactivation of ERK3 or MK5 induces precocious differentiation of C2C12 or primary myoblasts, concomitant with MyoD activation. Reciprocally, ectopic expression of activated MK5 inhibits myogenic differentiation. Mechanistically, we show that MK5 directly phosphorylates FoxO3, promoting its degradation and reducing its association with MyoD. Depletion of FoxO3 rescues in part the premature differentiation of C2C12 myoblasts observed upon inactivation of ERK3 or MK5. Our findings reveal that ERK3 and its substrate MK5 act in a linear signaling pathway to control postnatal myogenic differentiation.

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The adrenergic-induced ERK3 pathway drives lipolysis and suppresses energy dissipation

Cited by 24 publications

References 54 publications

Impact of Conventional and Atypical MAPKs on the Development of Metabolic Diseases

Impact of Conventional and Atypical MAPKs on the Development of Metabolic Diseases

A genome-wide transcriptomic analysis of embryos fathered by obese males in a murine model of diet-induced obesity

ERK3‐MK5 signaling regulates myogenic differentiation and muscle regeneration by promoting FoxO3 degradation

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