PI3K signaling effects in hypothalamic neurons mediated by estrogen

Malyala, Anna; Zhang, Chunguang; Bryant, Damani N.; Kelly, Martin J.; Rønnekleiv, Oline K.

doi:10.1002/cne.21584

Cited by 78 publications

(69 citation statements)

References 108 publications

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“…Thus, PPT effects are likely mediated directly via ERα expressed by MeA SIM1 neurons. These findings are consistent with earlier observations that estrogens directly activate other neural populations (12,35,36). Furthermore, we tested the physiological functions of MeA SIM1 neural activation via the DRE-ADD approach.…”

Section: Mea Erα Prevents Dio In Malessupporting

confidence: 93%

Estrogen receptor–α in medial amygdala neurons regulates body weight

Xu¹,

Cao²,

He³

et al. 2015

J. Clin. Invest.

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Section: Mea Erα Prevents Dio In Malessupporting

confidence: 93%

Estrogen receptor–α in medial amygdala neurons regulates body weight

Xu¹,

Cao²,

He³

et al. 2015

J. Clin. Invest.

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“…The present study does not address the mechanisms underlying the influence of PDK1 on neurotransmitter levels. It is noteworthy, though, that PI3K signaling has been shown to participate in the regulation of GABA transport [68,69], and the taurine transporter [68,[70][71][72]. Kinases activated by PDK1 include the serum and glucocorticoid inducible kinase (SGK) and protein kinase B PKB/Akt isoforms, which have been shown to regulate a wide variety of channels and transporters including glutamate transporters and glutamate receptors [33,[73][74][75][76][77][78][79][80][81][82].…”

Section: Discussionmentioning

confidence: 99%

Phosphatidylinositide Dependent Kinase Deficiency Increases Anxiety and Decreases GABA and Serotonin Abundance in the Amygdala

Ackermann¹,

Hörtnagl²,

Wolfer³

et al. 2008

Cell Physiol Biochem

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Pathological anxiety is paralleled by deficits in serotonergic and GABAergic neurotransmission in the amygdala. Conversely, anxiety disorders and depression may be reversed by brain-derived neurotrophic factor (BDNF). BDNF signaling involves Phosphatidylinositol 3-Kinase / 3-phosphoinositide-dependent protein kinase 1 (PI3K/PDK1). We thus hypothesized that impaired function of PDK1 might be associated with increased anxiety and concomitant neurotransmitter changes. Here we used the hypomorphic PDK1^hm mouse to investigate anxiety behavior in different settings: PDK1^hm mice differed from Wt littermates PDK1^WT in several behavioral measures related to anxiety and exploration, namely in the open field, dark-light box, O-maze and startle response. Further we analyzed the brain substrate underlying this phenotype and found significantly decreased GABA, taurine and serotonin concentrations in the amygdala and olfactory bulb of PDK1^hm mice, while BDNF and nerve growth factor (NGF) concentrations were not significantly different between PDK1^hm and PDK1^WT mice. These results suggest that impaired PI3K signaling in the PDK1^hm mouse reduces concentrations of GABA and serotonin in anxiety related brain regions and can serve as a molecular substrate for behavior indicative for anxious and depressive-like mood states.

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“…Both can activate STAT3 in various tissues, and hypothalamic leptin and insulin signaling are known to converge on the PI3K pathway (10)(11)(12)(13). Similarly, E 2 is now also known to activate STAT3 as well as PI3K signaling cascades, suggestive of possible cross-talk among these molecules and possibly representing a common neuronal signaling mechanism that may help explain the similarities in their central effects on energy homeostasis (14)(15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

Genetic rescue of nonclassical ERα signaling normalizes energy balance in obese Erα-null mutant mice

Park¹,

Zhao²,

et al. 2011

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In addition to its role in reproduction, estradiol-17β is critical to the regulation of energy balance and body weight. Estrogen receptor α-null (Erα -/-) mutant mice develop an obese state characterized by decreased energy expenditure, decreased locomotion, increased adiposity, altered glucose homeostasis, and hyperleptinemia. Such features are reminiscent of the propensity of postmenopausal women to develop obesity and type 2 diabetes. The mechanisms by which ERα signaling maintains normal energy balance, however, have remained unclear. Here we used knockin mice that express mutant ERα that can only signal through the noncanonical pathway to assess the role of nonclassical ERα signaling in energy homeostasis. In these mice, we found that nonclassical ERα signaling restored metabolic parameters dysregulated in Erα -/-mutant mice to normal or near-normal values. The rescue of body weight and metabolic function by nonclassical ERα signaling was mediated by normalization of energy expenditure, including voluntary locomotor activity. These findings indicate that nonclassical ERα signaling mediates major effects of estradiol-17β on energy balance, raising the possibility that selective ERα agonists may be developed to reduce the risks of obesity and metabolic disturbances in postmenopausal women. IntroductionIn addition to its critical functions as a reproductive hormone, estradiol-17β (E 2 ) plays a vital role in the regulation of energy balance and body weight (1). Estrogen deficiency at menopause is associated with an increased probability of obesity as well as increased risk for the development of type 2 diabetes (2). In experimental animals, reduction of circulating estrogen levels by ovariectomy leads to the development of obesity, which can be reversed or prevented by E 2 treatment (1). The effects of E 2 on energy balance bear many similarities to the actions of leptin and insulin, key molecules involved in energy homeostasis (3, 4). Genetic and pharmacological studies have demonstrated that leptin and insulin act directly on neural networks to modulate energy homeostasis, where the net effect is to decrease food intake and increase energy expenditure (5-9). Both can activate STAT3 in various tissues, and hypothalamic leptin and insulin signaling are known to converge on the PI3K pathway (10-13). Similarly, E 2 is now also known to activate STAT3 as well as PI3K signaling cascades, suggestive of possible cross-talk among these molecules and possibly representing a common neuronal signaling mechanism that may help explain the similarities in their central effects on energy homeostasis (14-17).That these metabolic actions of E 2 are mediated by estrogen receptor α (ERα) has been demonstrated in Erα-null (Erα -/-) mutant mice, in which the ablation of ERα signaling results in a metabolic syndrome characterized by increased body weight, adiposity, altered glucose homeostasis, decreased energy expenditure, hyperinsulinemia, and hyperleptinemia (18)(19)(20). However, these metabolic character-

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PI3K signaling effects in hypothalamic neurons mediated by estrogen

Cited by 78 publications

References 108 publications

Estrogen receptor–α in medial amygdala neurons regulates body weight

Estrogen receptor–α in medial amygdala neurons regulates body weight

Phosphatidylinositide Dependent Kinase Deficiency Increases Anxiety and Decreases GABA and Serotonin Abundance in the Amygdala

Genetic rescue of nonclassical ERα signaling normalizes energy balance in obese Erα-null mutant mice

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