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Predisposition to late-onset obesity in GIRK4 knockout mice.

ABSTRACT: 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.

SUBMITTER: Perry CA

PROVIDER: S-EPMC2430374 | biostudies-literature | 2008 Jun

REPOSITORIES: biostudies-literature

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Predisposition to late-onset obesity in GIRK4 knockout mice.

Perry Cydne A CA Pravetoni Marco M Teske Jennifer A JA Aguado Carolina C Erickson Darin J DJ Medrano Juan F JF Luján Rafael R Kotz Catherine M CM Wickman Kevin K

Proceedings of the National Academy of Sciences of the United States of America 20080603 23

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 brai ...[more]

PMID: 18523006

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Project description:BackgroundPathogenic germline variants (PGVs) can play a vital role in the oncogenesis process in carriers. Previous studies have recognized that PGVs contribute to early onset of tumorigenesis in certain cancer types, for example, colorectal cancer and breast cancer. However, the reported prevalence data of cancer-associated PGVs were highly inconsistent due to nonuniform patient cohorts, sequencing methods, and prominent difficulties in pathogenicity interpretation of variants. In addition to the above difficulties, due to the rarity of cases, the prevalence of cancer PGV carriers in young cancer patients affected by late-onset cancer types has not been comprehensively evaluated to date.MethodsA total of 131 young cancer patients (1-29 years old at diagnosis) were enrolled in this study. The patients were affected by six common late-onset cancer types, namely, lung cancer, liver cancer, colorectal cancer, gastric cancer, renal cancer, and head-neck cancer. Cancer PGVs were identified and analyzed. based on NGS-based targeted sequencing followed by bioinformatic screening and strict further evaluations of variant pathogenicity.ResultsTwenty-three cancer PGVs in 21 patients were identified, resulting in an overall PGV prevalence of 16.0% across the six included cancer types, which was approximately double the prevalence reported in a previous pancancer study. Nine of the 23 PGVs are novel, thus expanding the cancer PGV spectrum. Seven of the 23 (30.4%) PGVs are potential therapeutic targets of olaparib, with potential implications for clinical manipulation. Additionally, a small prevalence of somatic mutations of some classic cancer hallmark genes in young patients, in contrast to all-age patients, was revealed.ConclusionThis study demonstrates the high prevalence of PGVs in young cancer patients with the common late-onset cancers and the potentially significant clinical implications of cancer PGVs, the findings highlight the value of PGV screening in young patients across lung cancer, liver cancer, colorectal cancer, gastric cancer, renal cancer, or head-neck cancer.

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Predisposition to late-onset obesity in GIRK4 knockout mice.

Publications

Predisposition to late-onset obesity in GIRK4 knockout mice.

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