Profound obesity secondary to hyperphagia in mice lacking kinase suppressor of ras 2.
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.
Lexicon Pharmaceuticals, The Woodlands, Texas, USA. jrevelli@lexpharma.com
Jean-Pierre
JP
Revelli
Deon
D
Smith
Jason
J
Allen
Sabrina
S
Jeter-Jones
Melanie K
MK
Shadoan
Urvi
U
Desai
Matthias
M
Schneider
Isaac
I
van Sligtenhorst
Laura
L
Kirkpatrick
Kenneth A
KA
Platt
Adisak
A
Suwanichkul
Katerina
K
Savelieva
Brenda
B
Gerhardt
Jay
J
Mitchell
James
J
Syrewicz
Brian
B
Zambrowicz
Brian D
BD
Hamman
Peter
P
Vogel
David R
DR
Powell
D000091162:AMP-Activated Protein Kinase Kinases; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004435:Eating / Q000235:genetics; D006963:Hyperphagia / Q000378:metabolism*; D020738:Leptin / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
D020738:Leptin; D011494:Protein Kinases; C546843:mTOR protein, mouse; C542241:KSR2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D000091162:AMP-Activated Protein Kinase Kinases