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 |
| |
Institution: | Lexicon Pharmaceuticals, The Woodlands, Texas, USA. jrevelli@lexpharma.com |
| |
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. |
| |
Keywords: | |
本文献已被 PubMed 等数据库收录! |
|