领导此次研究的是美国明尼苏达大学医学院的Kevin  Wickman。他和同事在进行大脑控制心脏功能的研究时无意中发现，移除小鼠体内的某个特定基因后，它们易患成年型肥胖（adult-onset  obesity）。

这一基因名为Girk4，研究人员发现它在视丘下部（hypothalamus）具有特别高的表达水平，而视丘下部与调节进食和能量消耗有关。Wickman推测，视丘下部中该基因的正常功能被破坏，可能是变异小鼠肥胖的潜在原因。不过他表示，还需要进行更多的研究以弄清其中的具体机制。

研究人员表示，小鼠模型中观察到的年龄依赖性肥胖与人类肥胖模式很相似。在人类中，20岁到60岁之间肥胖的可能性增加了1倍多。

论文合著者、明尼苏达大学食品科学与营养学系的Catherine  Kotz说：“这是一个新颖的发现，可能为理解影响肥胖的潜在细胞机制提供重要的新见解。”

原始出处：

PNAS，doi：10.1073/pnas.0803261105，Cydne A. Perry，Kevin Wickman

Predisposition to late-onset obesity in GIRK4 knockout mice

Cydne A. Perry*, Marco Pravetoni*, Jennifer A. Teske, Carolina Aguado, Darin J. Erickson, Juan F. Medrano¶, Rafael Luján, Catherine M. Kotz, and Kevin Wickman*,||

*Department of Pharmacology, University of Minnesota, 6-120 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455; Minnesota Obesity Center, Department of Food Science and Nutrition, Veterans Affairs Medical Center, Geriatric Research Education and Clinical Center, 11G, One Veterans Drive, Minneapolis, MN 55417; Departmento de Ciencias Médicas, Campus Biosanitario C/Almansa, Universidad de Castilla–La Mancha, 14, 02006 Albacete, Spain; Division of Epidemiology, School of Public Health, University of Minnesota, 1300 South Second Street, Suite 300, Minneapolis, MN 54454; and ¶Department of Animal Science, University of California, 1 Shields Avenue, Davis, CA 95616

Communicated by David E. Clapham, Harvard Medical School, Boston, MA, April 7, 2008 (received for review March 5, 2008)

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 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.