Premium
Profound Obesity Secondary to Hyperphagia in Mice Lacking Kinase Suppressor of Ras 2
Author(s) -
Revelli JeanPierre,
Smith Deon,
Allen Jason,
JeterJones Sabrina,
Shadoan Melanie K.,
Desai Urvi,
Schneider Matthias,
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.
Publication year - 2011
Publication title -
obesity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.438
H-Index - 199
eISSN - 1930-739X
pISSN - 1930-7381
DOI - 10.1038/oby.2010.282
Subject(s) - kinase , phenotype , biology , ampk , pi3k/akt/mtor pathway , protein kinase a , endocrinology , leptin , knockout mouse , gene , medicine , suppressor , obesity , microbiology and biotechnology , genetics , signal transduction
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.