Leptin Interferes with Adrenocorticotropin/3′,5′-Cyclic Adenosine Monophosphate (cAMP) Signaling, Possibly through a Janus Kinase 2-Phosphatidylinositol 3-Kinase/Akt-Phosphodiesterase 3-cAMP Pathway, to Down-Regulate Cholesterol Side-Chain Cleavage Cytochrome P450 Enzyme in Human Adrenocortical NCI-H295 Cell Line

Hsu, Haoting; Chang, Yuan‐Ching; Chiu, Yi-Ning; Liu, Chien‐Liang; Chang, King‐Jen; Guo, Ing-Cherng

doi:10.1210/jc.2005-2383

Cited by 38 publications

(34 citation statements)

References 35 publications

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“…Thus, it could be speculated that hyperleptinemia dampens CRH expression and release in the face of selective sensitivity of the central HPA axis. It has also been shown in in vitro studies that leptin can reduce the sensitivity of adrenal cortex cells to ACTH, thereby reducing circulating corticosterone levels (Kruse et al 1998, Hsu et al 2006. However, the present data do not permit firm conclusions in this respect.…”

Section: Discussioncontrasting

confidence: 82%

The effects of high fat diet on the basal activity of the hypothalamus–pituitary–adrenal axis in mice

Auvinen

Romijn²,

Biermasz³

et al. 2012

Journal of Endocrinology

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Alterations in hypothalamus-pituitary-adrenal (HPA) axis activity have been linked to the development of the metabolic syndrome (MetS). Common features of the MetS, like insulin resistance and obesity, are reproducibly induced by high fat diet (HFD) in animal models of diet-induced obesity. These models, hampered by methodological differences, reveal conflicting results with respect to HPA axis activation. This study was aimed to evaluate in detail nonstressed diurnal HPA axis activity in mice during obesity development. Male C57Bl/6J mice were fed high or low fat diet for 12 weeks.

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Section: Discussioncontrasting

confidence: 82%

The effects of high fat diet on the basal activity of the hypothalamus–pituitary–adrenal axis in mice

Auvinen

Romijn²,

Biermasz³

et al. 2012

Journal of Endocrinology

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“…24 As leptin signaling has been suggested to involve another cAMP-specific PDE, PDE3B, a similar role could be speculated for Pde8b. 25 Apart from the adipose tissue, an early Pde8b labeling was detected in the liver and the heart ventricle. The type of labeling of Pde8b in these two tissues was suggestive of extracellular or membranous localization of the protein.…”

Section: Discussionmentioning

confidence: 95%

A cAMP-specific phosphodiesterase (PDE8B) that is mutated in adrenal hyperplasia is expressed widely in human and mouse tissues: a novel PDE8B isoform in human adrenal cortex

et al. 2008

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“…Our group previously reported that maternal food restriction as other types of systemic stress 45 results in elevated leptin levels most likely from placental and adipose tissue origin. 46 Elevated maternal leptin could also directly inhibit fetal adrenal steroidogenic enzymes as leptin was reported to have a direct adrenal suppressive effect on steroidogenic enzymes, 20,21,47 and on STAR protein expression. 48 Exposure to high levels of leptin would also enhance GC negative feedback in the brain through increased expression of GCR in the hippocampus and paraventricular nucleus as previously reported.…”

Section: Discussionmentioning

confidence: 99%

Maternal Undernutrition Programs Offspring Adrenal Expression of Steroidogenic Enzymes

et al. 2011

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The aim of this study was to determine the influence of maternal undernutrition (MUN) on maternal and offspring adrenal steoridogenic enzymes. Pregnant Sprague-Dawley rats were 50% food-restricted from day 10 of gestation until delivery. Control animals received ad libitum food. Offspring were killed on day 1 of life (P1) and at 9 months. We determined the messenger RNA (mRNA) expression of steroidogneic enzymes by real-time reverse transcriptase polymerized chain reaction (RT-PCR). Maternal undernutrition inhibited maternal adrenal expression of P450 cholesterol side-chain cleavage enzyme (CYP11A1), 11 betahydroxylase (CYP11B1), aldosterone synthase (CYP11B2), and adrenocorticotropic hormone (ACTH) receptor (ACTH-R; MC2 gene) compared with control offspring. There was a marked downregulation in the expression of CYP11B1, CYP11B2, 11 b-hydroxysteroid dehydrogenase type 1 and 2 (HSD1 and HSD2), CYP11A1, ACTH receptor, steroidogenic acute regulatory protein (STAR), and mineralocorticoid receptor (MCR; NR3C2 gene) mRNA in P1 MUN offspring (both genders), with no changes in glucocorticoid receptor (GCR). Quantitative immunohistochemical analysis confirmed the PCR data for GCR and MCR in P1 offspring and demonstrated lower expression of leptin receptor protein (Ob-Ra/Ob-Rb) and mRNA in P1 MUN offspring. In 9-month adult male MUN offspring, the expression of HSD1, CYP11A1, CYP11B2, Ob-Ra/Ob-Rb, and GCR mRNA were significantly upregulated with a trend toward an increase in ACTH-R and a decrease in 17 alpha-hydroxylase (CYP17A1) expression. In adult female MUN offspring, similar to males, the expression of CYP11A1, ACTH-R, and Ob-Rb mRNA were increased, whereas GCR and CYP17A1 mRNA were decreased. These results indicate that the adrenal gland is a target of nutritional programming. In utero undernutrition has a global suppressive effect on maternal and P1 offspring adrenal steroidogenic enzymes in association with reduced circulating corticosterone levels in P1 offspring, which may be secondary to a negative feedback from elevated maternal GC levels and or leptin levels in MUN dams. Gender-specific differences in steroidogenic enzyme expression were found in adult MUN offspring. The common finding of increased ACTH receptor expression in MUN adults of both genders suggests an increased sensitivity of these offspring to stress. Keywords adrenal, steroidogenesis, STAR protein, leptin receptor, ACTH receptor, maternal undernutrition, glucocorticoids, fetal programming An adverse intrauterine environment induces fetal growth restriction and is associated with development of metabolic syndrome in adult life. 1 These adverse intrauterine conditions are associated with maternal stress leading to excess glucocorticoid production which has significant impact on the fetus in terms of growth and later development of adult diseases. 2,3 Several studies have shown hyperactivity of offspring hypothalamic-pituitary-adrenal axis caused by maternal undernutrition. 4,5 Most of these studies have focused primarily on characterizat...

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Abstract: Leptin interferes with ACTH/cAMP signaling, possibly through a cAMP-degrading mechanism involving activation of JAK2, phosphatidylinositol 3-kinase, and PDE3, to down-regulate P450scc expression and consequent adrenal steroidogenesis.

Cited by 38 publications

References 35 publications

The effects of high fat diet on the basal activity of the hypothalamus–pituitary–adrenal axis in mice

The effects of high fat diet on the basal activity of the hypothalamus–pituitary–adrenal axis in mice

A cAMP-specific phosphodiesterase (PDE8B) that is mutated in adrenal hyperplasia is expressed widely in human and mouse tissues: a novel PDE8B isoform in human adrenal cortex

Maternal Undernutrition Programs Offspring Adrenal Expression of Steroidogenic Enzymes

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