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

Abstract

The kinase suppressor of ras 2 (KSR2) gene resides at human chromosome 12q24, a region linked to obesity and type 2 diabetes (T2D). While knocking out and phenotypically screening mouse orthologs of thousands of druggable human genes, we found KSR2 knockout (KSR2(-/-)) mice to be more obese and glucose intolerant than melanocortin 4 receptor(-/-) (MC4R(-/-)) mice. The obesity and T2D of KSR2(-/-) mice resulted from hyperphagia which was unresponsive to leptin and did not originate downstream of MC4R. The kinases AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) are each linked to food intake regulation, but only mTOR had increased activity in KSR2(-/-) mouse brain, and the ability of rapamycin to inhibit food intake in KSR2(-/-) mice further implicated mTOR in this process. The metabolic phenotype of KSR2 heterozygous (KSR2(+/minus;)) and KSR2(-/-) mice suggests that human KSR2 variants may contribute to a similar phenotype linked to human chromosome 12q24.

• Authors: Jean-Pierre Revelli, Deon Smith, Jason Allen, Sabrina Jeter-Jones, Melanie K Shadoan, Urvi Desai, Matthias Schneider, Isaac van Sligtenhorst, Laura Kirkpatrick, Kenneth A Platt, Adisak Suwanichkul, Katerina Savelieva, Brenda Gerhardt, Jay Mitchell, James Syrewicz, Brian Zambrowicz, Brian D Hamman, Peter Vogel, David R Powell
• Journal: Obesity (Silver Spring, Md.) (Obesity (Silver Spring)) Vol. 19 Issue 5 Pg. 1010-8 (May 2011) ISSN: 1930-739X [Electronic] United States
• PMID: 21127480 (Publication Type: Journal Article)

Chemical References

• Leptin
• Protein Kinases
• mTOR protein, mouse
• KSR2 protein, mouse
• Protein Serine-Threonine Kinases
• TOR Serine-Threonine Kinases
• AMP-Activated Protein Kinase Kinases

Topics

• AMP-Activated Protein Kinase Kinases
• Adipose Tissue (metabolism)
• Animals
• Diabetes Mellitus, Type 2 (metabolism)
• Eating (genetics)
• Hyperphagia (metabolism)
• Leptin (metabolism)
• Mice
• Mice, Knockout
• Obesity (metabolism)
• Protein Kinases (metabolism)
• Protein Serine-Threonine Kinases (deficiency, genetics, metabolism)
• TOR Serine-Threonine Kinases (metabolism)