Regulation of Natriuretic Peptide Signaling in Adipose Tissue and Energy Metabolism

脂肪组织和能量代谢中钠尿肽信号传导的调节

基本信息

  • 批准号:
    10246562
  • 负责人:
  • 金额:
    $ 25.95万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-09-10 至 2021-09-09
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY The epidemic of cardiometabolic disease occurring throughout the world is taking a heavy toll on individuals' quality of life, along with a huge economic impact Excess caloric intake leading to obesity is a major driver of the cardiometabolic syndrome. Brown adipose tissue (BAT) evolved in homeotherms as a mean to maintain body temperature by generating heat from stored calories. Brown adipocytes are highly enriched in mitochondria and express a unique protein called uncoupling protein-1 (UCP1). UCP1 `uncouples' the mitochondrial proton gradient from ATP production, thus avidly consuming glucose and fatty acids with the result being net energy expenditure. Active brown fat is present in adult humans and its amount is significantly correlated with reduced body fat and circulating triglycerides, greater insulin sensitivity, and lowered incidence of Type II diabetes. Increasing brown adipocyte amount and activity could reduce the risk of cardiometabolic disease. The sympathetic nervous system (SNS)-derived catecholamine norepinephrine, which act through β-adrenergic receptors and cAMP, is a well-established activator of BAT and the recruitment of UCP1-positive cells in white adipose tissue (WAT) depots (a process termed `browning' or `beiging'). We have shown in prior work that the cardiac hormones atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) also stimulate a similar `browning' program in mouse and human adipocytes, and protect against obesity-associated insulin resistance, hepatic steatosis and inflammation. This suggests that increasing NP signaling in adipose tissues is metabolically beneficial. NP activation of NP receptor A (NPRA) leads to cGMP production, while the NP `clearance receptor' NPRC removes NPs from circulation, and the ratio of NPRA to NPRC determines NP signaling capacity. Clinical studies show that compared to lean individuals, obese individuals have lower circulating NP level, increased NPRC level in adipose tissue, and blunted lipolytic responses to NPs. We observed similar patterns of receptor expression and physiological responses in mice. It has been postulated that higher adipose NPRC levels increases NP clearance, thus reducing NP availability in the circulation and efficacy in target tissues, resulting in a so-called `natriuretic handicap'. On the other hand, conditions such as fasting and cold temperature exposure reduce the level of NPRC expression, resulting in an increased NPRA/NPRC ratio and thus NP/cGMP signaling. Our studies with mouse models further support these observations. However, little is known about the regulation of the Npra and Nprc genes in either rodents or humans. The overall objective of this project is to: define the transcriptional regulatory mechanisms of the Nprc gene in human and mouse adipocytes; determine whether increased levels of NPRC in obesity serves as a `sink' to remove NPs from circulation, thus creating the `natriuretic handicap', and test the effects of selective NP ligands to modulate insulin sensitivity.
项目总结

项目成果

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SHEILA COLLINS其他文献

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{{ truncateString('SHEILA COLLINS', 18)}}的其他基金

Role of SIK3 in PKA/mTORC1 regulation of adipose browning
SIK3 在 PKA/mTORC1 调节脂肪褐变中的作用
  • 批准号:
    10736962
  • 财政年份:
    2023
  • 资助金额:
    $ 25.95万
  • 项目类别:
Natriuretic peptide and cGMP signaling in adipose tissue and energy metabolism
脂肪组织和能量代谢中的利钠肽和 cGMP 信号传导
  • 批准号:
    10445966
  • 财政年份:
    2022
  • 资助金额:
    $ 25.95万
  • 项目类别:
Pathophysiology of Metabolically Detrimental Changes in Adipose Distribution, Adipocyte Function, and Adipose Immune Environment on Antiretroviral Therapy
抗逆转录病毒治疗中脂肪分布、脂肪细胞功能和脂肪免疫环境代谢有害变化的病理生理学
  • 批准号:
    10570223
  • 财政年份:
    2022
  • 资助金额:
    $ 25.95万
  • 项目类别:
Pathophysiology of Metabolically Detrimental Changes in Adipose Distribution, Adipocyte Function, and Adipose Immune Environment on Antiretroviral Therapy
抗逆转录病毒治疗中脂肪分布、脂肪细胞功能和脂肪免疫环境代谢有害变化的病理生理学
  • 批准号:
    10364376
  • 财政年份:
    2022
  • 资助金额:
    $ 25.95万
  • 项目类别:
Natriuretic peptide and cGMP signaling in adipose tissue and energy metabolism
脂肪组织和能量代谢中的利钠肽和 cGMP 信号传导
  • 批准号:
    10609907
  • 财政年份:
    2022
  • 资助金额:
    $ 25.95万
  • 项目类别:
Dissecting PKA activation of mTORC1 and its function in adipose tissue
剖析 mTORC1 的 PKA 激活及其在脂肪组织中的功能
  • 批准号:
    9768476
  • 财政年份:
    2018
  • 资助金额:
    $ 25.95万
  • 项目类别:
Dissecting PKA activation of mTORC1 and its function in adipose tissue
剖析 mTORC1 的 PKA 激活及其在脂肪组织中的功能
  • 批准号:
    10091138
  • 财政年份:
    2018
  • 资助金额:
    $ 25.95万
  • 项目类别:
Dissecting PKA activation of mTORC1 and its function in adipose tissue
剖析 mTORC1 的 PKA 激活及其在脂肪组织中的功能
  • 批准号:
    10219236
  • 财政年份:
    2018
  • 资助金额:
    $ 25.95万
  • 项目类别:
Natriuretic peptide receptors, adipose browning and energy expenditure
利钠肽受体、脂肪褐变和能量消耗
  • 批准号:
    8768157
  • 财政年份:
    2014
  • 资助金额:
    $ 25.95万
  • 项目类别:
Natriuretic peptide receptors, adipose browning and energy expenditure
利钠肽受体、脂肪褐变和能量消耗
  • 批准号:
    8860180
  • 财政年份:
    2014
  • 资助金额:
    $ 25.95万
  • 项目类别:

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