C-type natriuretic peptide is a pivotal regulator of metabolic homeostasis.
Cristina Perez-TerneroAisah A AubdoolRaj MakwanaGareth John SangerRoland H StimsonLi F ChanAmie J MoyesAdrian J HobbsPublished in: Proceedings of the National Academy of Sciences of the United States of America (2022)
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 Gi-coupled natriuretic peptide receptor (NPR)-C and reducing peroxisome proliferator-activated receptor-γ coactivator-1α 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.
Keyphrases
- metabolic syndrome
- insulin resistance
- poor prognosis
- high fat diet induced
- blood flow
- body weight
- binding protein
- adipose tissue
- endothelial cells
- weight loss
- transcription factor
- type diabetes
- weight gain
- protein kinase
- oxidative stress
- case report
- uric acid
- cardiovascular disease
- physical activity
- blood pressure
- small molecule
- drug delivery
- reactive oxygen species
- cancer therapy
- body mass index
- blood glucose
- pluripotent stem cells
- nitric oxide synthase
- glycemic control
- case control