ABSTRACT
Development of metabolic syndrome is associated with hyperactivity of the HPA axis characterized by elevated levels of circulating adrenal hormones including cortisol and aldosterone. However, the molecular mechanism leading to the dysregulation of the HPA axis is not well elucidated. In this study, we found that insulin regulates adrenal steroidogenesis by increasing the expression and activity of steroidogenic factor 1 (SF-1) both in vitro and in vivo and this insulin effect was partly through inhibition of FoxO1. Specifically, insulin increased the protein and RNA levels of SF-1 and steroidogenic target genes. Further, adrenal SF-1 expression was significantly increased by hyperactivation of insulin signaling in mice. Together with the elevated SF-1 expression in adrenal glands, hyperactivation of insulin signaling led to increased aldosterone and corticosterone levels. On the other hand, suppressing the insulin signaling using streptozotocin markedly reduced the expression of adrenal SF-1 in mice. In addition, overexpression of FoxO1 significantly suppressed SF-1 and its steroidogenic target genes implying that the positive effect of insulin on SF-1 activity might be through suppression of FoxO1 in the adrenal gland. Taken together, these results indicate that insulin regulates adrenal steroidogenesis through coordinated control of SF-1 and FoxO1.
Subject(s)
Adrenal Cortex/metabolism , Aldosterone/biosynthesis , Corticosterone/biosynthesis , Diabetes Mellitus, Experimental/metabolism , Forkhead Box Protein O1/metabolism , Insulin/metabolism , Steroidogenic Factor 1/metabolism , Adrenal Cortex/cytology , Aldosterone/blood , Animals , Biosynthetic Pathways/drug effects , Biosynthetic Pathways/physiology , Cell Line, Tumor , Corticosterone/blood , Diabetes Mellitus, Experimental/blood , Diabetes Mellitus, Experimental/etiology , Diet, High-Fat/adverse effects , Female , Gene Knockdown Techniques , HEK293 Cells , Humans , Hypothalamo-Hypophyseal System/drug effects , Hypothalamo-Hypophyseal System/physiology , Male , Mice , Mice, Inbred C57BL , Phosphorylation/physiology , Pituitary-Adrenal System/physiology , RNA, Small Interfering/metabolism , Steroidogenic Factor 1/genetics , Streptozocin/toxicityABSTRACT
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.
Subject(s)
Coumaric Acids/pharmacology , Forkhead Box Protein O1/metabolism , Glucose/metabolism , Homeostasis/drug effects , Liver/drug effects , Liver/metabolism , Neuropeptides/metabolism , Animals , Biomarkers , Cell Line , Diet, High-Fat , Energy Metabolism/drug effects , Energy Metabolism/genetics , Gene Expression Regulation/drug effects , Hypothalamus/drug effects , Hypothalamus/metabolism , Male , Mice , PhosphorylationABSTRACT
Activated in energy depletion conditions, AMP-activated protein kinase (AMPK) acts as a cellular energy sensor and regulator in both central nervous system and peripheral organs. Hypothalamic AMPK restores energy balance by promoting feeding behavior to increase energy intake, increasing glucose production, and reducing thermogenesis to decrease energy output. Besides energy state, many hormones have been shown to act in concert with AMPK to mediate their anorexigenic and orexigenic central effects as well as thermogenic influences. Here we explore the factors that affect hypothalamic AMPK activity and give the underlying mechanisms for the role of central AMPK in energy homeostasis together with the physiological effects of hypothalamic AMPK on energy balance restoration.
