Kinase Suppressor of Ras 2 (KSR2) expression in the brain regulates energy balance and glucose homeostasis.
Kinase Suppressor of Ras 2 (KSR2) is a molecular scaffold coordinating Raf/MEK/ERK signaling that is expressed at high levels in the brain. KSR2 disruption in humans and mice causes obesity and insulin resistance. Understanding the anatomical location and mechanism of KSR2 function should lead to a better understanding of physiological regulation over energy balance.



Mice bearing floxed alleles of KSR2 (KSR2fl/fl) were crossed with mice expressing the Cre recombinase expressed by the Nestin promoter (Nes-Cre) to produce Nes-CreKSR2fl/flmice. Growth, body composition, food consumption, cold tolerance, insulin and free fatty acid levels, glucose, and AICAR tolerance were measured in gender and age matched KSR2-/-mice.



Nes-CreKSR2fl/flmice lack detectable levels of KSR2 in the brain. The growth and onset of obesity of Nes-CreKSR2fl/flmice parallel those observed in KSR2-/-mice. As in KSR2-/-mice, Nes-CreKSR2fl/flare glucose intolerant with elevated fasting and cold intolerance. Male Nes-CreKSR2fl/flmice are hyperphagic, but female Nes-CreKSR2fl/flmice are not. Unlike KSR2-/-mice, Nes-CreKSR2fl/flmice respond normally to leptin and AICAR, which may explain why the degree of obesity of adult Nes-CreKSR2fl/flmice is not as severe as that observed in KSR2-/-animals.



These observations suggest that, in the brain, KSR2 regulates energy balance via control of feeding behavior and adaptive thermogenesis, while a second KSR2-dependent mechanism, functioning through one or more other tissues, modulates sensitivity to leptin and activators of the energy sensor AMPK.
Eppley Institute for Research in Cancer and Allied Diseases, 985950 Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE 68198-5950, USA; Fred & Pamela Buffett Cancer Center, 987696 Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE 68198-7696, USA. Electronic address: liliguozhi@gmail.com.
Lili
L
Guo
Eppley Institute for Research in Cancer and Allied Diseases, 985950 Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE 68198-5950, USA; Fred & Pamela Buffett Cancer Center, 987696 Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE 68198-7696, USA. Electronic address: dcostanzo@unmc.edu.
Diane L
DL
Costanzo-Garvey
Eppley Institute for Research in Cancer and Allied Diseases, 985950 Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE 68198-5950, USA; Fred & Pamela Buffett Cancer Center, 987696 Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE 68198-7696, USA. Electronic address: deandra.smith@unmc.edu.
Deandra R
DR
Smith
Eppley Institute for Research in Cancer and Allied Diseases, 985950 Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE 68198-5950, USA; Fred & Pamela Buffett Cancer Center, 987696 Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE 68198-7696, USA. Electronic address: beth.clymer@unmc.edu.
Beth K
BK
Neilsen
Eppley Institute for Research in Cancer and Allied Diseases, 985950 Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE 68198-5950, USA; Fred & Pamela Buffett Cancer Center, 987696 Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE 68198-7696, USA; Department of Biochemistry and Molecular Biology, 985870 Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA. Electronic address: rgmacdon@unmc.edu.
Richard G
RG
MacDonald
Eppley Institute for Research in Cancer and Allied Diseases, 985950 Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE 68198-5950, USA; Fred & Pamela Buffett Cancer Center, 987696 Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE 68198-7696, USA. Electronic address: rlewis@unmc.edu.
Robert E
RE
Lewis
D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism*; D004734:Energy Metabolism; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000378:metabolism; D012265:Ribonucleotides / Q000378:metabolism; D015398:Signal Transduction
D005230:Fatty Acids, Nonesterified; D007328:Insulin; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; C542241:KSR2 protein, mouse; D017346:Protein Serine-Threonine Kinases; C031143:AICA ribonucleotide; D005947:Glucose
AMPK; Glucose metabolism; Insulin resistance; KSR2; Obesity