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Sphingolipid-mediated dysregulation of glucose and energy homeostasis by POMC neurons

POMC 神经元鞘脂介导的葡萄糖和能量稳态失调

基本信息

批准号：
9050560
负责人：
Joshua Johnson
金额：
$ 3.1万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9050560
关键词：
1,2-diacylglycerol Acids Adipose tissue Adult Amides Amidohydrolases Ants Automobile Driving Biological Assay Blood Glucose Body Weight Body Weight Changes Brain Cell Line Cells Ceramide glucosyltransferase Ceramides Complement Cues Diabetes Mellitus Diet Diglycerides Doxycycline Drug Targeting Eating Enzymes Evolution Fatty Acids Fatty acid glycerol esters Gangliosides Genetic Glucose Glucosylceramides Homeostasis Hormonal Hormones Hypothalamic structure Individual Insulin Insulin Receptor Insulin Resistance Ions Knockout Mice Leptin Lipids Liver Mediating Mentors Modeling Molecular Mus Nature Neurons Nutritional Obesity Partner in relationship Pathogenesis Pathway interactions Peripheral Pharmaceutical Preparations Population Population Heterogeneity Pro-Opiomelanocortin Process Proteins Receptor Signaling Regulation Resistance Response Elements Role Signal Transduction Slice Sphingolipids Structure of beta Cell of islet Tern Testing Tetracyclines Tissues Transgenic Mice United States Weight Weight Gain Work amidase attenuation blood glucose regulation diabetic fight against galactosylgalactosylglucosylceramidase impaired driving performance improved in vivo insulin signaling novel novel strategies overexpression prevent public health relevance saturated fat tetraiodothyroacetic acid tool

项目摘要

DESCRIPTION (provided by applicant): It has been well-established that in the evolution of obesity and diabetes, hypothalamic weight- and glucose-regulatory neurons become insensitive to signals (including hormones such as leptin or insulin) that work to inhibit incremental weight gain and increased circulating glucose. However, the specific mechanisms of these insensitivities are not well-understood. We postulate that hypothalamic accumulation of the sphingolipid ceramide can drive attenuation of hypothalamic leptin and insulin signaling. Ceramide accumulation has been demonstrated to drive insulin resistance in a number of peripheral tissues, and some evidence suggests it may antagonize central leptin/insulin receptor signaling also. One set of neurons within the hypothalamus known to regulate both body weight and circulating glucose and that become insensitive to leptin/insulin in the obese state are characterized by expression of proopiomelanocortin (POMC). We hypothesize that POMC neurons accumulate ceramides in the obese state, and these ceramides drive resistance of these cells to leptin/insulin signal transduction. To test this, we will inducibly overexpress an enzyme which degrades ceramides, acid ceramidase, in POMC neurons of adult mice. The construct used will be a tetracycline response element- driven acid ceramidase, which when mated to a mouse containing both flox-stop-flox-Rosa26-rtTA and POMC- Cre cassettes, will produce acid ceramidase in the POMC neuron upon administration of doxycycline in the chow. This will be complemented with similar mice which force ceramide glucosylation or knockout mice which prevent ceramide glucosylation, as glucosylceramide derivatives may have independent effects on glucose and energy homeostasis. We will use these mice to interrogate whether ceramides have a causative role in the pathogenesis of obesity, whether reducing ceramides in POMC neurons can improve glucose homeostasis independent of weight change, and the molecular pathways which ceramides modulate within the POMC neuron. This work will thus demonstrate a possible novel drug target in the brain to decrease both body weight gain and blood glucose in obese or diabetic individuals, respectively.