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Profound obesity secondary to hyperphagia in mice lacking kinase suppressor of ras 2

Jean-Pierre Revelli1, Deon Smith, Jason Allen

  • 1Lexicon Pharmaceuticals, The Woodlands, Texas, USA. jrevelli@lexpharma.com

Obesity (Silver Spring, Md.)
|December 4, 2010
PubMed

Insights

Kinase suppressor of ras 2 (KSR2) gene knockout mice exhibit obesity and glucose intolerance due to overeating. This suggests KSR2 variants may contribute to human obesity and type 2 diabetes.

Area of Science:

  • Genetics
  • Metabolism
  • Endocrinology

Background:

  • The Kinase Suppressor of Ras 2 (KSR2) gene is located on chromosome 12q24, a region associated with obesity and type 2 diabetes (T2D).
  • Previous research has linked this chromosomal region to metabolic disorders, but the specific role of KSR2 remains unclear.

Purpose of the Study:

  • To investigate the role of KSR2 in regulating body weight and glucose homeostasis.
  • To determine the molecular mechanisms underlying KSR2-associated metabolic dysfunction.

Main Methods:

  • Phenotypic screening of KSR2 knockout (KSR2(-/-)) mice and comparison with melanocortin 4 receptor knockout (MC4R(-/-)) mice.
  • Assessment of hyperphagia, leptin responsiveness, and the involvement of AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) pathways.
  • Administration of rapamycin to evaluate its effect on food intake in KSR2(-/-) mice.

Main Results:

  • KSR2(-/-) mice displayed increased obesity and glucose intolerance compared to MC4R(-/-) mice.
  • The metabolic phenotype in KSR2(-/-) mice was characterized by hyperphagia, independent of leptin signaling and downstream of MC4R.
  • Increased mTOR activity was observed in the brains of KSR2(-/-) mice, and rapamycin treatment reduced their food intake.

Conclusions:

  • KSR2 plays a significant role in regulating appetite and metabolism, distinct from the MC4R pathway.
  • Dysregulation of the mTOR pathway in the brain contributes to KSR2-mediated hyperphagia and metabolic syndrome.
  • Human KSR2 variants may be implicated in the development of obesity and type 2 diabetes linked to chromosome 12q24.

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