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Mice lacking DUSP6/8 have enhanced ERK1/2 activity and resistance to diet-induced obesity
Ruijie Liu1, Monica Peters1, Nicholas Urban1
1Department of Biomedical Sciences, Grand Valley State University, Allendale, MI, 49401, USA.
Abstract:
Extracellular signal-regulated kinase 1 and 2 (ERK1/2) have been implicated as important regulators of metabolic homeostasis. Here we generated a new mouse model with genetic deletion of two ERK1/2 phosphatases, dual specificity phosphatase (DUSP) 6 and 8, to further define the role of ERK1/2 in obesity development. Dusp6/8 double-null mice demonstrated elevated ERK1/2 phosphorylation in multiple tissues, without any change of phosphorylation of p38 and c-Jun N-terminal kinases (JNKs). Elevated ERK1/2 activity in Dusp6/8 double-null mice was associated with larger hearts and other organs, consistent with greater rate of cell proliferation in these mice. However, ERK1/2 activation was not sufficient to protect the mouse hearts from pathological hypertrophy and interstitial fibrosis following angiotensin II and phenylephrine stimulation. Interestingly, mice lacking DUSP6/8 were resistant to high-fat diet-induced obesity. Serum triglyceride, lipid content in the liver and visceral adipose tissues was also dramatically reduced in Dusp6/8 double-null mice. Furthermore, Dusp6/8 double-null mice had improved glucose tolerance. Mechanistically, we found out that elevated ERK1/2 activity increased the expression levels of genes involved in lipid metabolism and glucose homeostasis. Together, our data suggest that ERK1/2 play an essential role for the management of metabolic homeostasis.
Insights
Genetic deletion of dual specificity phosphatase 6 and 8 (DUSP6/8) in mice enhances extracellular signal-regulated kinase 1 and 2 (ERK1/2) activity, leading to obesity resistance and improved metabolic homeostasis.
Area of Science:
- Cellular and Molecular Biology
- Metabolic Research
- Physiology
Background:
- Extracellular signal-regulated kinase 1 and 2 (ERK1/2) are crucial for metabolic homeostasis.
- Dual specificity phosphatases (DUSP) 6 and 8 regulate ERK1/2 activity.
- Understanding ERK1/2 regulation is key to addressing metabolic disorders like obesity.
Purpose of the Study:
- To investigate the role of ERK1/2 in obesity development by examining mice lacking DUSP6 and DUSP8.
- To determine the impact of elevated ERK1/2 activity on metabolic parameters and organ function.
Main Methods:
- Generated Dusp6/8 double-null mice to achieve sustained ERK1/2 activation.
- Assessed metabolic parameters including body weight, lipid profiles, and glucose tolerance.
- Analyzed tissue-specific ERK1/2 phosphorylation and gene expression related to metabolism.
Main Results:
- Dusp6/8 double-null mice exhibited increased ERK1/2 phosphorylation but not p38 or JNK.
- These mice were resistant to high-fat diet-induced obesity, with reduced triglycerides and liver/adipose tissue lipids.
- Improved glucose tolerance and enhanced expression of lipid/glucose metabolism genes were observed.
Conclusions:
- Elevated ERK1/2 activity, achieved through DUSP6/8 deletion, confers resistance to diet-induced obesity.
- ERK1/2 signaling is essential for regulating lipid and glucose metabolism.
- Targeting ERK1/2 pathways may offer therapeutic strategies for metabolic diseases.
