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Mice lacking MAP kinase phosphatase-1 have enhanced MAP kinase activity and resistance to diet-induced obesity

J Julie Wu1, Rachel J Roth, Ethan J Anderson

  • 1Department of Pharmacology, Section of Endocrinology and Metabolism, Yale University School of Medicine, New Haven, Connecticut 06520, USA.

Cell Metabolism
|July 4, 2006
PubMed

Insights

Mice lacking nuclear MAPK phosphatase-1 (MKP-1) show increased MAPK activity but resist diet-induced obesity. Nuclear MKP-1 is crucial for metabolic homeostasis, distinct from its cytosolic functions.

Area of Science:

  • Cellular Biology
  • Metabolic Research
  • Signaling Pathways

Background:

  • Mitogen-activated protein kinases (MAPK) are implicated in diabetes and obesity pathogenesis.
  • MAPK activity is regulated by MAPK phosphatases (MKPs), found in both cytosol and nucleus.
  • MKP-1 is a key nuclear-localized MKP.

Purpose of the Study:

  • To investigate the role of nuclear MKP-1 in regulating MAPK activity and metabolic homeostasis.
  • To determine the impact of MKP-1 deficiency on insulin signaling, glucose homeostasis, and obesity development.

Main Methods:

  • Generation and analysis of MKP-1 knockout mice (mkp-1(-/-)).
  • Assessment of MAPK (Erk, p38, JNK) activities in insulin-responsive tissues.
  • Evaluation of insulin sensitivity, glucose homeostasis, and response to high-fat diet.

Main Results:

  • mkp-1(-/-) mice exhibit enhanced nuclear Erk, p38, and JNK activity.
  • Despite increased JNK activity, insulin signaling and glucose homeostasis remain unimpaired in mkp-1(-/-) mice.
  • mkp-1(-/-) mice are resistant to diet-induced obesity due to increased energy expenditure but develop glucose intolerance on a high-fat diet.

Conclusions:

  • Nuclear localization of MKP-1 is critical for managing metabolic homeostasis.
  • Nuclear MAPK regulation by MKP-1 is spatially distinct from cytosolic regulation and plays a key role in energy balance and obesity resistance.

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