Abstract
C-type natriuretic peptide (CNP) is expressed in diverse tissues, including adipose and endothelium, and exerts its effects by binding to and activating its receptor, guanylyl cyclase B. Natriuretic peptides regulate intracellular cGMP and phosphorylated vasodilator-stimulated phosphoprotein (VASP). We recently revealed that overexpression of CNP in endothelial cells protects against high-fat diet (HFD)-induced obesity in mice. Given that endothelial CNP affects adipose tissue during obesity, CNP in adipocytes might directly regulate adipocyte function during obesity. Therefore, to elucidate the effect of CNP in adipocytes, we assessed 3T3-L1 adipocytes and transgenic (Tg) mice that overexpressed CNP specifically in adipocytes (A-CNP). We found that CNP activates the cGMP–VASP pathway in 3T3-L1 adipocytes. Compared with Wt mice, A-CNP Tg mice showed decreases in fat weight and adipocyte hypertrophy and increases in fatty acid β-oxidation, lipolysis-related gene expression, and energy expenditure during HFD-induced obesity. These effects led to decreased levels of the macrophage marker F4/80 in the mesenteric fat pad and reduced inflammation. Furthermore, A-CNP Tg mice showed improved glucose tolerance and insulin sensitivity, which were associated with enhanced insulin-stimulated Akt phosphorylation. Our results suggest that CNP overexpression in adipocytes protects against adipocyte hypertrophy, excess lipid metabolism, inflammation, and decreased insulin sensitivity during HFD-induced obesity.
Highlights
The growing public-health problem of obesity is characterized by the excessive accumulation of adipose tissue due to an imbalance between energy intake and energy expenditure[1]
This result indicates that C-type Natriuretic peptides (NPs) (CNP)–guanylyl cyclase B (GCB)-dependent cGMP production induced the phosphorylation of vasodilator-stimulated phosphoprotein (VASP) in 3T3-L1 adipocytes
We showed that the CNP–GCB–cGMP–VASP pathway is active in adipocytes and that overexpression of CNP in adipocytes suppresses adipocyte hypertrophy in fat pads, reduces fat weight, enhances energy expenditure, decreases inflammation, and improves insulin sensitivity in high-fat diet (HFD)-fed Tg mice
Summary
The growing public-health problem of obesity is characterized by the excessive accumulation of adipose tissue due to an imbalance between energy intake and energy expenditure[1]. White adipose tissue (WAT) stores excessive energy as triglycerides and secretes adipokines that mediate lipid metabolism, secretion of inflammatory cytokines, and insulin sensitivity[3]. Natriuretic peptides (NPs), which include atrial NP (ANP), brain NP (BNP), and C-type NP (CNP), are associated with obesity, insulin resistance, and metabolic syndrome[4,5,6,7]. Transgenic (Tg) mice with endothelial cell-specific overexpression of CNP are protected against visceral adipose tissue hypertrophy, systemic inflammation, and insulin resistance during the development of obesity due to feeding of a high-fat diet (HFD)[7]. The results revealed the CNP–GCB– cGMP–VASP pathway in adipocytes and showed that the overexpression of CNP in adipocytes decreased adipocyte hypertrophy in WAT and ameliorated metabolic disorders during HFD-induced obesity in mice
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