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1.
Biochem Biophys Res Commun ; 612: 119-125, 2022 07 05.
Article in English | MEDLINE | ID: mdl-35523049

ABSTRACT

Kinases represent one of the largest druggable families of proteins. Importantly, many kinases are aberrantly activated/de-activated in multiple organs during obesity, which contributes to the development of diabetes and associated diseases. Previous results indicate that the complex between Extracellular-regulated kinase 3 (ERK3) and Mitogen-Activated Protein Kinase (MAPK)-activated protein kinase 5 (MK5) suppresses energy dissipation and promotes fatty acids (FAs) output in adipose tissue and, therefore promotes obesity and diabetes. However, the therapeutic potential of targeting this complex at the systemic level has not been fully explored. Here we applied a translational approach to target the ERK3/MK5 complex in mice. Importantly, deletion of ERK3 in the whole body or administration of MK5-specific inhibitor protects against obesity and promotes insulin sensitivity. Finally, we show that the expression of ERK3 and MK5 correlates with the degree of obesity and that ERK3/MK5 complex regulates energy dissipation in human adipocytes. Altogether, we demonstrate that ERK3/MK5 complex can be targeted in vivo to preserve metabolic health and combat obesity and diabetes.


Subject(s)
Diabetes Mellitus , Protein Serine-Threonine Kinases , Animals , Intracellular Signaling Peptides and Proteins , Mice , Mitogen-Activated Protein Kinase 6/metabolism , Obesity
2.
Genes Dev ; 34(7-8): 495-510, 2020 04 01.
Article in English | MEDLINE | ID: mdl-32139423

ABSTRACT

Obesity-induced diabetes affects >400 million people worldwide. Uncontrolled lipolysis (free fatty acid release from adipocytes) can contribute to diabetes and obesity. To identify future therapeutic avenues targeting this pathway, we performed a high-throughput screen and identified the extracellular-regulated kinase 3 (ERK3) as a hit. We demonstrated that ß-adrenergic stimulation stabilizes ERK3, leading to the formation of a complex with the cofactor MAP kinase-activated protein kinase 5 (MK5), thereby driving lipolysis. Mechanistically, we identified a downstream target of the ERK3/MK5 pathway, the transcription factor FOXO1, which promotes the expression of the major lipolytic enzyme ATGL. Finally, we provide evidence that targeted deletion of ERK3 in mouse adipocytes inhibits lipolysis, but elevates energy dissipation, promoting lean phenotype and ameliorating diabetes. Thus, ERK3/MK5 represents a previously unrecognized signaling axis in adipose tissue and an attractive target for future therapies aiming to combat obesity-induced diabetes.


Subject(s)
Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/physiopathology , Energy Metabolism/genetics , Lipolysis/genetics , Mitogen-Activated Protein Kinase 6/genetics , Mitogen-Activated Protein Kinase 6/metabolism , Obesity/complications , 3T3 Cells , Adipose Tissue/enzymology , Animals , Diabetes Mellitus, Type 2/drug therapy , Drug Evaluation, Preclinical , Forkhead Box Protein O1/metabolism , Gene Deletion , HEK293 Cells , Humans , Hypoglycemic Agents/therapeutic use , Intracellular Signaling Peptides and Proteins/metabolism , Lipase/genetics , Lipase/metabolism , Mice , Protein Serine-Threonine Kinases/metabolism , Signal Transduction/genetics
3.
Sci Signal ; 12(593)2019 08 06.
Article in English | MEDLINE | ID: mdl-31387939

ABSTRACT

Hepatic activation of protein kinase C (PKC) isoforms by diacylglycerol (DAG) promotes insulin resistance and contributes to the development of type 2 diabetes (T2D). The closely related protein kinase D (PKD) isoforms act as effectors for DAG and PKC. Here, we showed that PKD3 was the predominant PKD isoform expressed in hepatocytes and was activated by lipid overload. PKD3 suppressed the activity of downstream insulin effectors including the kinase AKT and mechanistic target of rapamycin complex 1 and 2 (mTORC1 and mTORC2). Hepatic deletion of PKD3 in mice improved insulin-induced glucose tolerance. However, increased insulin signaling in the absence of PKD3 promoted lipogenesis mediated by SREBP (sterol regulatory element-binding protein) and consequently increased triglyceride and cholesterol content in the livers of PKD3-deficient mice fed a high-fat diet. Conversely, hepatic-specific overexpression of a constitutively active PKD3 mutant suppressed insulin-induced signaling and caused insulin resistance. Our results indicate that PKD3 provides feedback on hepatic lipid production and suppresses insulin signaling. Therefore, manipulation of PKD3 activity could be used to decrease hepatic lipid content or improve hepatic insulin sensitivity.


Subject(s)
Cholesterol/biosynthesis , Hepatocytes/metabolism , Insulin/metabolism , Protein Kinase C/metabolism , Signal Transduction , Triglycerides/biosynthesis , Animals , Cholesterol/genetics , Insulin/genetics , Lipogenesis/genetics , Mice , Mice, Transgenic , Protein Kinase C/genetics , Triglycerides/genetics
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