4-hydroxy-3-methoxycinnamic acid regulates orexigenic peptides and hepatic glucose homeostasis through phosphorylation of FoxO1

Abstract

4-hydroxy-3-methoxycinnamic acid (ferulic acid, FA) is known to have numerous beneficial health effects, including anti-obesity and anti-hyperglycemic properties. However, the molecular networks that modulate the beneficial FA-induced metabolic effects have not been well elucidated. In this study, we explored the molecular mechanisms mediating the beneficial metabolic effects of FA. In mice, FA protected against high-fat diet-induced weight gain, reduced food intake and exhibited an overall improved metabolic phenotype. The food intake suppression by FA was accompanied by a specific reduction in hypothalamic orexigenic neuropeptides, including agouti-related protein and neuropeptide Y, with no significant changes in the anorexigenic peptides pro-opiomelanocortin and cocaine and amphetamine-regulated transcript. FA treatment also inhibited fat accumulation in the liver and white adipose tissue and suppressed the expression of gluconeogenic genes, including phosphoenolpyruvate carboxylase and glucose-6-phosphatase. Furthermore, we show that FA phosphorylated and inactivated the transcription factor FoxO1, which positively regulates the expression of gluconeogenic and orexigenic genes, providing evidence that FA might exert its beneficial metabolic effects through inhibition of FoxO1 function in the periphery and the hypothalamus.

Dietary Ferulic Acid Ameliorates Metabolism Syndrome-Associated Hyperuricemia in Rats via Regulating Uric Acid Synthesis, Glycolipid Metabolism, and Hepatic Injury

“…The high dose of ferulic acid (HFFD with 0.1% of ferulic acid) showed even more efficiency in lowering abdominal obesity (perirenal fat index decreased 37.6% and epididymal fat index decreased 24.1%) than allopurinol and the low dose of ferulic acid. It has been reported that ferulic acid could reduce adipogenesis, stored lipid content in adipose tissue and adipose tissue expansion, and stimulate white-fat browning via regulating the expression of related genes, revealing the anti-obesity effect of ferulic acid (37)(38)(39). We found that allopurinol, a XO inhibitor, also exerted anti-obesity capacity, which was in line with the studies of Cho et al (40) and Zhang et al (41).…”

“…There was a dose correlation in glucose tolerance between low and high doses of ferulic acid. There is evidence to suggest that ferulic acid blunted HFFD-induced glucose production probably by an inactivation of forkhead box 1 in livers and a suppression of downstream enzymes, phosphoenolpyruvate carboxylase, and glucose-6-phosphatase, thus inhibiting the hepatic gluconeogenesis ( 38 ). In addition, administration of ferulic acid could cause a downregulation of glucose transporter 2 gene expression to weaken glucose output, ultimately reducing the FBG content ( 44 ).…”

Mulberry Bark Alleviates Effect of STZ Inducing Diabetic Mice through Negatively Regulating FoxO1

“…The p-AKT then phosphorylates FoxO1, causing nuclear exclusion. The translocation of FoxO1 from the nucleus to the cytoplasm suppresses the expression of FoxO1 gluconeogenic targets, phosphoenolpyruvate carboxylase (PEPCK), and glucose-6-phosphatase (G6Pase) in nuclear [35–37]. Proteins of PEPCK and G6Pase are rate-limiting enzymes for gluconeogenesis.…”

Carvedilol improves glucose tolerance and insulin sensitivity in treatment of adrenergic overdrive in high fat diet-induced obesity in mice

“…Glucose (GTT), insulin (ITT) and pyruvate (PTT) tolerance tests were performed as described previously [37] after the mice were challenged with HFD and treated with carvedilol for 4 weeks. Body weight were 48.98 ± 1.22 g for HFD-fed + vehicle treatment cohort (n = 6) and 47.62 ± 0.91 g for HFD-fed + carvedilol treatment cohort (n = 6), P = 0.392.…”