4.8 Article

C-type natriuretic peptide is a pivotal regulator of metabolic homeostasis

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NATL ACAD SCIENCES
DOI: 10.1073/pnas.2116470119

关键词

natriuretic peptide; G protein-coupled receptor; cardiometabolic disease; adipogenesis; thermogenesis

资金

  1. British Heart Foundation [RG/16/7/32357, SCAF/17/02]
  2. Wellcome Trust [217543/Z/19/Z]
  3. Chief Scientist Office [SCAF/17/02]
  4. Medical Research Council [MRC G0802796]
  5. Wellcome Trust [217543/Z/19/Z] Funding Source: Wellcome Trust

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C-type natriuretic peptide (CNP) plays a crucial role in lipid homeostasis and energy balance by regulating the expression of uncoupling protein-1 and lipid utilization. CNP exerts these metabolic regulatory actions by inhibiting sympathetic thermogenic programming and reducing peroxisome proliferator-activated receptor-gamma coactivator-1 alpha expression, while driving adipogenesis via NPR-B/protein kinase-G.
Thermogenesis and adipogenesis are tightly regulated mechanisms that maintain lipid homeostasis and energy balance; dysfunction of these critical processes underpins obesity and contributes to cardiometabolic disease. C-type natriuretic peptide (CNP) fulfills a multimodal protective role in the cardiovascular system governing local blood flow, angiogenesis, cardiac function, and immune cell reactivity. Herein, we investigated a parallel, preservative function for CNP in coordinating metabolic homeostasis. Global inducible CNP knockout mice exhibited reduced body weight, higher temperature, lower adiposity, and greater energy expenditure in vivo. This thermogenic phenotype was associated with increased expression of uncoupling protein-1 and preferential lipid utilization by mitochondria, a switch corroborated by a corresponding diminution of insulin secretion and glucose clearance. Complementary studies in isolated murine and human adipocytes revealed that CNP exerts these metabolic regulatory actions by inhibiting sympathetic thermogenic programming via G(i)-coupled natriuretic peptide receptor (NPR)-C and reducing peroxisome proliferator-activated receptor-gamma coactivator-1 alpha expression, while concomitantly driving adipogenesis via NPR-B/protein kinase-G. Finally, we identified an association between CNP/NPR-C expression and obesity in patient samples. These findings establish a pivotal physiological role for CNP as a metabolic switch to balance energy homeostasis. Pharmacological targeting of these receptors may offer therapeutic utility in the metabolic syndrome and related cardiovascular disorders.

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