Interactions of Leptin and the Melanocortin System

瘦素和黑皮质素系统的相互作用

• 批准号: 10734976
• 负责人: JOEL K. ELMQUIST
• 金额: $ 47.66万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734976
• 关键词: Adipose tissue; Affect; Aminobutyric Acids; Attenuated; Blood Glucose; Body Weight; Brain; Cells; Dependovirus; Development; Diabetes Mellitus; Eating; Endocrine; Energy Metabolism; Enterobacteria phage P1 Cre recombinase; Exercise; Fasting; Food Energy; Genetic Engineering; Glutamates; Goals; Hepatic; Homeostasis; Hypothalamic structure; Impairment; Leptin; Leptin deficiency; Liver; LoxP-flanked allele; Maps; Mass Spectrum Analysis; Measures; Mediating; Melanocyte stimulating hormone; Metabolic; Metabolism; Modeling; Mus; Neurons; Obesity; Organ; Peptides; Physiological; Physiological Processes; Pituitary Gland; Point Mutation; Population; Population Heterogeneity; Pro-Opiomelanocortin; Production; Protein Isoforms; Proteins; Regulation; Role; Site; Structure of nucleus infundibularis hypothalami; System; Testing; Tissues; Transgenic Mice; alpha-Melanocyte stimulating hormone; beta-Endorphin; blood glucose regulation; cell type; energy balance; falls; glucose metabolism; glucose production; leptin receptor; mouse genetics; mouse model; neurotransmitter release; novel; optogenetics; pars intermedia; response

PROJECT SUMMARY The increasing rates of obesity and diabetes highlight the need to understand the brain circuits and cellular mechanisms regulating energy balance and glucose homeostasis. Prominent among these is the central leptin- melanocortin system, which includes the pro-opiomelanocortin (POMC) neurons, subsets of which express leptin receptors (LEPRs). While enormous strides have been made to understand the role of hypothalamic POMC neurons that produce α-MSH in metabolism, relatively little is known about how the three isoforms of - MSH produced in hypothalamus and pituitary gland POMC-expressing cells respond to metabolic challenges. The current application extends our previous discovery that LEPR-expressing POMC neurons are required for coordinating hepatic glucose production and responding to metabolic challenges. We will determine the roles for -MSH peptides produced from POMC neurons in the regulation of metabolism in dynamic challenges. This project is also significant because it will be the first to combine the power of mouse genetics with advanced mass spectrometry to quantitatively measure and map specific POMC-derived -MSH peptides in hypothalamic and pituitary tissues. We will also correlate -MSH peptide levels with parameters of energy and glucose homeostasis, and deermine which peptides underlie metabolic adaptation. These studies will broaden our understanding of the functional mechanism by which the leptin-melanocortin system regulates endocrine and autonomic functions, particularly at the level of liver and adipose tissues.

项目摘要 肥胖症和糖尿病发病率的增加突出了了解大脑回路和细胞的必要性。 调节能量平衡和葡萄糖稳态的机制。其中最突出的是中央瘦素- 黑皮质素系统，其包括阿黑皮素原（POMC）神经元，其子集表达 瘦素受体（LEPRs）。虽然在了解下丘脑的作用方面已经取得了巨大的进步， POMC神经元在代谢中产生α-MSH，关于β-MSH的三种亚型如何在POMC神经元中产生α-MSH， 下丘脑和垂体POMC表达细胞产生的MSH对代谢挑战作出反应。 目前的应用扩展了我们先前的发现，即表达LEPR的POMC神经元是 协调肝脏葡萄糖的产生和应对代谢挑战。我们将决定 对于POMC神经元产生的β-MSH肽在调节代谢中的动态挑战。这 该项目也很重要，因为它将是第一个将小鼠遗传学的力量与先进的联合收割机相结合的项目。 质谱定量测量和映射特定POMC衍生的MSH肽， 下丘脑和垂体组织。我们还将把β-MSH肽水平与能量参数和 葡萄糖稳态，并确定哪些肽是代谢适应的基础。这些研究将扩大 我们对瘦素-黑皮质素系统调节内分泌的功能机制的理解 和自主功能，特别是在肝脏和脂肪组织水平。

项目成果

Melanocortin regulation of histaminergic neurons via perifornical lateral hypothalamic melanocortin 4 receptors.

黑皮质素通过下丘脑外侧黑皮质素 4 受体对组胺能神经元的调节。

• DOI: 10.1016/j.molmet.2020.01.020
• 发表时间: 2020
• 期刊: Molecular metabolism
• 影响因子: 8.1
• 作者: Michael,NatalieJ;Caron,Alexandre;Lee,CharlotteE;Castorena,CarlosM;Lee,Syann;Zigman,JeffreyM;Williams,KevinW;Elmquist,JoelK
• 通讯作者: Elmquist,JoelK

Obesity: an evolutionary context.

• DOI: 10.1093/lifemeta/loac002
• 发表时间: 2022-08
• 期刊: Life metabolism
• 作者: Speakman, John R;Elmquist, Joel K
• 通讯作者: Elmquist, Joel K

Desacetyl-α-melanocyte stimulating hormone and α-melanocyte stimulating hormone are required to regulate energy balance.

• DOI: 10.1016/j.molmet.2017.11.008
• 发表时间: 2018-03
• 期刊: Molecular metabolism
• 影响因子: 8.1
• 作者: Mountjoy KG;Caron A;Hubbard K;Shome A;Grey AC;Sun B;Bould S;Middleditch M;Pontré B;McGregor A;Harris PWR;Kowalczyk R;Brimble MA;Botha R;Tan KML;Piper SJ;Buchanan C;Lee S;Coll AP;Elmquist JK
• 通讯作者: Elmquist JK

Electrophysiological Properties of Genetically Identified Histaminergic Neurons.

• DOI: 10.1016/j.neuroscience.2020.06.031
• 发表时间: 2020-09-15
• 期刊: Neuroscience
• 影响因子: 3.3
• 作者: Michael NJ;Zigman JM;Williams KW;Elmquist JK
• 通讯作者: Elmquist JK