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- Title
Profound Obesity Secondary to Hyperphagia in Mice Lacking Kinase Suppressor of Ras 2.
- Authors
Revelli, Jean-Pierre; Smith, Deon; Allen, Jason; Jeter-Jones, Sabrina; Shadoan, Melanie K.; Desai, Urvi; Schneider, Matthias; van Sligtenhorst, Isaac; Kirkpatrick, Laura; Platt, Kenneth A.; Suwanichkul, Adisak; Savelieva, Katerina; Gerhardt, Brenda; Mitchell, Jay; Syrewicz, James; Zambrowicz, Brian; Hamman, Brian D.; Vogel, Peter; Powell, David R.
- 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.
- Subjects
OBESITY; DIABETES; HUMAN chromosomes; SUPPRESSOR cells; HYPERPHAGIA; RAPAMYCIN; GENES
- Publication
Obesity (19307381), 2011, Vol 19, Issue 5, p1010
- ISSN
1930-7381
- Publication type
Article
- DOI
10.1038/oby.2010.282