ALTERED MELANOCORTIN RESPONE TO METABOLIC CUES IN AGING

衰老通常与食物摄取和新陈代谢之间的失衡有关，反映在中年时体重和脂肪增加，老年时食物摄入量减少。体重增加，特别是腹部脂肪增加，是II型糖尿病、心脏病和中风的主要风险因素，这些因素会显著降低寿命和生活质量。晚年食物摄入不足也会损害瘦体重和免疫力的维持。下丘脑黑素皮质素途径的中断与食欲失调以及高胰岛素血症、瘦素抵抗和体重增加有关，所有这些都已被报道与衰老有关。下丘脑前阿片黑素皮质素(POMC)是黑素皮质素受体配体的主要来源，被认为可以抑制食欲，在实验动物中已被证明随着年龄的增长而减少。糖皮质激素已被发现随着年龄的增长而增加，并以不依赖瘦素的方式促进食物摄取、胰岛素抵抗和脂肪沉积。我们假设，下丘脑POMC表达减少和糖皮质激素产生增加有助于瘦素抵抗，代表着对营养补充信号的敏感性降低。这种瘦素抵抗导致中年体重增加，而与年龄相关的大脑皮质类固醇受体丧失和对POMC表达不足的补偿可能是老年厌食症的原因。为了验证这一假设，我们将比较瘦素和皮质类固醇对年轻和老年小鼠的食物摄入量、身体成分、血浆激素以及皮质类固醇受体POMC和相关黑素皮质素配体和受体的基因表达的调节。这些研究将确定调节食物摄入和新陈代谢的神经药理学机制，这将有助于优化食欲和体重控制，以实现健康老龄化。

Aging is often associated with an imbalance between food intake and metabolism, reflected in increased body weight and fat at middle age and reduced food intake at old age. Weight gain, particularly as abdominal fat, is a major risk factor for type II diabetes, heart disease, and stroke, which can significantly reduce lifespan and quality of life. Inadequate food intake late in life can also impair maintenance of lean body mass and immunity. Disruption of hypothalamic melanocortin pathways has been implicated in appetite dysregulation, as well as hyperinsulinemia, leptin resistance, and weight gain, all of which have been reported in aging. Hypothalamic pro-opiomelanocortin (POMC), a major source of melanocortin receptor ligands proposed to inhibit appetite, has been shown to decrease during aging in experimental animals. Glucocorticoids have been found to increase with aging, and to promote food intake, insulin resistance and fat deposition in a leptin-independent manner. We hypothesize that decreased hypothalamic POMC expression and increased glucocorticoid production contribute to leptin resistance, representing reduced sensitivity to signals of nutritional repletion. This leptin resistance results in weight gain at middle age, while age-related loss of brain corticosteroid receptors and compensation for inadequate POMC expression may account for anorexia in old age. To test this hypothesis, we will compare leptin and corticosteroid regulation of food intake, body composition, plasma hormones, and gene expression of corticosteroid receptors, POMC and related melanocortin ligands and receptors, in young and aging mice. These studies will identify neuropharmacological mechanisms for regulating food intake and metabolism that will aid in optimizing appetite and body weight control for healthy aging.