Krajewska Maryla, Banares Steven, Zhang Eric E, Huang Xianshu, Scadeng Miriam, Jhala Ulupi S, Feng Gen-Sheng, Krajewski Stan
Burnham Institute for Medical Research, University of California San Diego, La Jolla, CA 92037, USA.
Am J Pathol. 2008 May;172(5):1312-24. doi: 10.2353/ajpath.2008.070594. Epub 2008 Apr 10.
Obesity and diabetes, termed "diabesity," are serious health problems that are increasing in frequency. However, the molecular mechanisms and neuronal regulation of these metabolic disorders are not fully understood. We show here that Shp2, a widely expressed Src homology 2-containing Tyr phosphatase, plays a critical role in the adult brain to control food intake, energy balance, and metabolism. Mice with a neuron-specific, conditional Shp2 deletion were generated by crossing a pan-neuronal Cre-line (CRE3) with Shp2(flox/flox) mice. These congenic mice, CRE3/Shp2-KO, developed obesity and diabetes and the associated pathophysiological complications that resemble those encountered in humans, including hyperglycemia, hyperinsulinemia, hyperleptinemia, insulin and leptin resistance, vasculitis, diabetic nephropathy, urinary bladder infections, prostatitis, gastric paresis, and impaired spermatogenesis. This mouse model may help to elucidate the molecular mechanisms that lead to the development of diabesity in humans and provide a tool to study the in vivo complications of uncontrolled diabetes.
肥胖症和糖尿病，即所谓的“糖尿病肥胖症”，是日益常见的严重健康问题。然而，这些代谢紊乱的分子机制和神经调节尚未完全明确。我们在此表明，Shp2，一种广泛表达的含Src同源2结构域的酪氨酸磷酸酶，在成年大脑中对控制食物摄入、能量平衡和新陈代谢起着关键作用。通过将泛神经元Cre系（CRE3）与Shp2（flox/flox）小鼠杂交，培育出具有神经元特异性、条件性Shp2缺失的小鼠。这些同源基因小鼠，即CRE3/Shp2-KO，出现了肥胖症和糖尿病以及相关的病理生理并发症，类似于人类所患的疾病，包括高血糖、高胰岛素血症、高瘦素血症、胰岛素和瘦素抵抗、血管炎、糖尿病肾病、膀胱感染、前列腺炎、胃轻瘫以及精子发生受损。这种小鼠模型可能有助于阐明导致人类糖尿病肥胖症发生的分子机制，并为研究未控制的糖尿病的体内并发症提供一种工具。
