Brain Melanocortin Control of Activity Energy Expenditure and Obesity Resistance

描述（由申请人提供）：大脑黑皮质素对活动能量消耗和肥胖抵抗力的控制人们越来越普遍地认为，日常体力活动水平的个体差异是遗传的，长期不活动会导致体重增加和代谢功能障碍。我们已经发现，在为高内在有氧能力（即，在没有事先训练的情况下跑长距离的能力; HCR）与他们的低能力同行（LCR）相比;这些差异不依赖于身体质量或组成。此外，HCR比LCR具有更高的每日总能量消耗，这是由于更高的非休息（非休息）能量消耗。在这里，我们假设在大脑黑皮质素系统的差异，特别是黑皮质素受体（MCR）表达的位点特异性变化，可能是高活性和低活性表型的基础。我们将让本科研究实习生来验证这一假设，利用通过人工选择以及通过删除特定MCR的基因表达获得的瘦/肥胖大鼠模型。首先，我们将确定MCR的脑表达模式的差异如何影响身体活动能量消耗，重点是MCR 3、4和5，以及量化MC 4 R缺陷大鼠中活动能量消耗如何改变。接下来，我们将探索大脑MC在体力活动期间增加骨骼肌燃料利用能力的分子机制，并确定这些机制在HCR和LCR之间是否存在差异。最后，我们将确定热量限制（即，高活性HCR比低活性LCR导致更多的体重减轻，与LCR相比，HCR差异性地改变了脑MCR和骨骼肌基因表达模式;我们还将使用MC 4 R缺陷大鼠来检验这一假设。专注于识别中枢（大脑）和外周（例如，骨骼肌）控制瘦型中的能量平衡可能产生肥胖症的新疗法。

DESCRIPTION (provided by applicant): Brain Melanocortin Control of Activity Energy Expenditure and Obesity Resistance It is becoming widely accepted that individual differences in daily physical activity levels are inherited, and that extended inactivity can lead to weight gan and metabolic dysfunction. We have found consistently high levels of physical activity and energy expenditure in rats selectively bred for high intrinsic aerobic capacity (i.e., the ability o run long distances without prior training; HCR) compared to their low-capacity counterparts (LCR); these differences are not dependent on body mass or composition. Moreover, HCR have higher total daily energy expenditure than LCR, a result of higher non-resting (not resting) energy expenditure. Here, we hypothesize that differences in the brain melanocortin system, specifically site-specific variations in melanocortin receptor (MCR) expression, may underlie the high- and low-activity phenotypes. We will engage undergraduate research trainees in testing this hypothesis, utilizing rat models of leanness/obesity derived through artificial selection as well as through deletion of gene expression for a specific MCR. First, we will determine how differences in brain expression patterns of MCR may contribute to physical activity energy expenditure, focusing on MCR 3, 4, and 5, as well quantify how activity energy expenditure is altered in MC4R- deficient rats. Next, we will probe the molecular mechanisms underlying the ability of brain MC to increase skeletal muscle fuel utilization during physical activity, and determine if these mechanisms differ between HCR and LCR. Lastly, we will determine if caloric restriction (i.e., dieting), which causes more weight loss in high- activity HCR than in low-activiy LCR, differentially alters brain MCR and skeletal muscle gene expression patterns in HCR compared to LCR; we will also test this hypothesis using MC4R-deficient rats. Focusing on identifying unique features of central (brain) and peripheral (e.g., skeletal muscle) control of energy balance in the lean phenotype may yield novel treatments for obesity.