Gender difference in the leptin response to feeding in peroxisome-proliferator-activated receptor-alpha knockout mice

Ms, Lewitt; Brismar, Kerstin

doi:10.1038/sj.ijo.0802135

Cited by 15 publications

(16 citation statements)

References 47 publications

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“…applied CNTF. Even though the underlying mechanism for this sexually dimorphic phenotype remains unsolved, our data are in line with other studies using genetic mouse models of obesity (21)(22)(23) or analyzing the effect of centrally administered agents such as insulin and leptin on energy homeostasis (24) also finding different phenotypes and pharmacological responses depending on gender.…”

Section: Discussionsupporting

confidence: 78%

gp130 signaling in proopiomelanocortin neurons mediates the acute anorectic response to centrally applied ciliary neurotrophic factor

Janoschek

Plum

Koch

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Ciliary neurotrophic factor (CNTF) exerts anorectic effects by overcoming leptin resistance via activation of hypothalamic neurons. However, the exact site of CNTF action in the hypothalamus has not yet been identified. Using Cre-loxP-mediated recombination in vivo, we have selectively ablated the common cytokine signaling chain gp130, which is required for functional CNTF signaling, in proopiomelanocortin (POMC)-expressing neurons. POMC-specific gp130 knockout mice exhibit unaltered numbers of POMC cells and normal energy homeostasis under standard and high fat diet. Endotoxin (LPS) and stress-induced anorexia and adrenocorticotropin regulation were unaffected in these animals. Strikingly, the anorectic effect of centrally administered CNTF was abolished in POMC-specific gp130 knockout mice. Correspondingly, in these animals, CNTF failed to activate STAT3 phosphorylation in POMC neurons and to induce c-Fos expression in the paraventricular nucleus. These data reveal POMC neurons as a critical site of CNTF action in mediating its anorectic effect.

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Section: Discussionsupporting

confidence: 78%

gp130 signaling in proopiomelanocortin neurons mediates the acute anorectic response to centrally applied ciliary neurotrophic factor

Janoschek

Plum

Koch

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…It therefore appears that Pten deletion may produce some different physiological effects dependent on gender. Although the underlying mechanism for this phenomenon is not clear at this point, our data are consistent with multiple knockout experiments targeting signaling pathways involved in the regulation of energy homeostasis that yielded as-yet unexplained gender-specific phenotypes (41)(42)(43). Thus, this is an area that clearly deserves further detailed analysis.…”

Section: Discussionsupporting

confidence: 57%

Enhanced PIP3 signaling in POMC neurons causes KATP channel activation and leads to diet-sensitive obesity

Plum

Ma²,

Hampel³

et al. 2006

Journal of Clinical Investigation

288

270

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Leptin and insulin have been identified as fuel sensors acting in part through their hypothalamic receptors to inhibit food intake and stimulate energy expenditure. As their intracellular signaling converges at the PI3K pathway, we directly addressed the role of phosphatidylinositol 3,4,5 -trisphosphate-mediated (PIP 3 -mediated) signals in hypothalamic proopiomelanocortin (POMC) neurons by inactivating the gene for the PIP 3 phosphatase Pten specifically in this cell type. Here we show that POMC-specific disruption of Pten resulted in hyperphagia and sexually dimorphic diet-sensitive obesity. Although leptin potently stimulated Stat3 phosphorylation in POMC neurons of POMC cell-restricted Pten knockout (PPKO) mice, it failed to significantly inhibit food intake in vivo. POMC neurons of PPKO mice showed a marked hyperpolarization and a reduction in basal firing rate due to increased ATP-sensitive potassium (K ATP ) channel activity. Leptin was not able to elicit electrical activity in PPKO POMC neurons, but application of the PI3K inhibitor LY294002 and the K ATP blocker tolbutamide restored electrical activity and leptin-evoked firing of POMC neurons in these mice. Moreover, icv administration of tolbutamide abolished hyperphagia in PPKO mice. These data indicate that PIP 3 -mediated signals are critical regulators of the melanocortin system via modulation of K ATP channels.

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“…In addition, the induction of major transcriptional regulators of cholesterol homeostasis such as SREBP-2, FXR, LXR, and RXR was attenuated under a high-fat diet. On the other side, mice lacking PPAR␣ accumulated hepatic fat on a normal diet and were prone to obesity (25). They also exhibited increased leptin levels.…”

Section: Discussionmentioning

confidence: 99%

Dehydroepiandrosterone inhibits the amplification of glucocorticoid action in adipose tissue

Apostolova¹,

Schweizer²,

Balázs³

et al. 2005

American Journal of Physiology-Endocrinology and Metabolism

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Dehydroepiandrosterone (DHEA) exerts beneficial effects on blood glucose levels and insulin sensitivity in obese rodents and humans, resembling the effects of peroxisome proliferator-activated receptor-gamma (PPARgamma) ligands and opposing those of glucocorticoids; however, the underlying mechanisms remain unclear. Glucocorticoids are reactivated locally by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which is currently considered as a promising target for the treatment of obesity and diabetes. Using differentiated 3T3-L1 adipocytes, we show that DHEA causes downregulation of 11beta-HSD1 and dose-dependent reduction of its oxoreductase activity. The effects of DHEA were comparable with those of the PPARgamma agonist rosiglitazone but not additive. Furthermore, DHEA reduced the expression of hexose-6-phosphate dehydrogenase, which stimulates the oxoreductase activity of 11beta-HSD1. These findings were confirmed in white adipose tissue and in liver from DHEA-treated C57BL/6J mice. Analysis of the transcription factors involved in the DHEA-dependent regulation of 11beta-HSD1 expression revealed a switch in CCAAT/enhancer-binding protein (C/EBP) expression. C/EBPalpha, a potent activator of 11beta-HSD1 gene transcription, was downregulated in 3T3-L1 adipocytes and in liver and adipose tissue of DHEA-treated mice, whereas C/EBPbeta and C/EBPdelta, attenuating the effect of C/EBPalpha, were unchanged or elevated. Our results further suggest a protective effect of DHEA on adipose tissue by upregulating PPARalpha and downregulating leptin, thereby contributing to the reduced expression of 11beta-HSD1. In summary, we provide evidence that some of the anti-diabetic effects of DHEA may be caused through inhibition of the local amplification of glucocorticoids by 11beta-HSD1 in adipose tissue.

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Gender difference in the leptin response to feeding in peroxisome-proliferator-activated receptor-alpha knockout mice

Cited by 15 publications

References 47 publications

gp130 signaling in proopiomelanocortin neurons mediates the acute anorectic response to centrally applied ciliary neurotrophic factor

gp130 signaling in proopiomelanocortin neurons mediates the acute anorectic response to centrally applied ciliary neurotrophic factor

Enhanced PIP3 signaling in POMC neurons causes KATP channel activation and leads to diet-sensitive obesity

Dehydroepiandrosterone inhibits the amplification of glucocorticoid action in adipose tissue

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