Predisposition to late-onset obesity in GIRK4 knockout mice.
G protein-gated inwardly rectifying potassium (GIRK/Kir3) channels mediate the inhibitory effects of many neurotransmitters on excitable cells. Four Girk genes have been identified (Girk1-4). Whereas GIRK4 is associated with the cardiac GIRK channel, Girk4 expression has been detected in a few neuron populations. Here, we used a transgenic mouse expressing enhanced green fluorescent protein (EGFP) under the control of the Girk4 gene promoter to clarify the expression pattern of Girk4 in the brain. Although small subsets of EGFP-positive neurons were evident in some areas, prominent labeling was seen in the hypothalamus. EGFP expression was most pronounced in the ventromedial, paraventricular, and arcuate nuclei, neuron populations implicated in energy homeostasis. Consistent with a contribution of GIRK4-containing channels to energy balance, Girk4 knockout -/- mice were predisposed to late-onset obesity. By 9 months, Girk4-/- mice were approximately 25% heavier than wild-type controls, a difference attributed to greater body fat. Before the development of overweight, Girk4-/- mice exhibited a tendency toward greater food intake and an increased propensity to work for food in an operant task. Girk4-/- mice also exhibited reduced net energy expenditure, despite displaying elevated resting heart rates and core body temperatures. These data implicate GIRK4-containing channels in signaling crucial to energy homeostasis and body weight.
Department of Pharmacology, University of Minnesota, 6-120 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455, USA.
Cydne A
CA
Perry
Marco
M
Pravetoni
Jennifer A
JA
Teske
Carolina
C
Aguado
Darin J
DJ
Erickson
Juan F
JF
Medrano
Rafael
R
Luján
Catherine M
CM
Kotz
Kevin
K
Wickman
D017668:Age of Onset; D000818:Animals; D001831:Body Temperature; D001835:Body Weight; D003216:Conditioning, Operant; D004198:Disease Susceptibility; D004734:Energy Metabolism; D005247:Feeding Behavior / Q000502:physiology; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000172:deficiency* / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006339:Heart Rate; D007031:Hypothalamus / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000378:metabolism* / Q000503:physiopathology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015430:Weight Gain
D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C484273:Kcnj5 protein, mouse; D011993:Recombinant Fusion Proteins; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins