mTOR signaling in the arcuate nucleus of the hypothalamus mediates the anorectic action of estradiol

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Abstract

Current evidence suggests that estradiol (E2), the main ovarian steroid, modulates energy balance by regulating both feeding and energy expenditure at the central level, through the energy sensor AMP-activated protein kinase (AMPK). We hypothesized that the hypothalamic mechanistic target of rapamycin (mTOR) pathway, a well-established nutrient sensor and modulator of appetite and puberty, could also mediate the anorectic effect of E2. Our data showed that ovariectomy (OVX) elicited a marked downregulation of the mTOR signaling in the arcuate nucleus of the hypothalamus (ARC), an effect that was reversed by either E2 replacement or central estrogen receptor alpha (ERα) agonism. The significance of this molecular signaling was given by the genetic inactivation of S6 kinase B1 (S6K1, a key downstream mTOR effector) in the ARC, which prevented the E2-induced hypophagia and weight loss. Overall, these data indicate that E2 induces hypophagia through modulation of mTOR pathway in the ARC.

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Most cited references 27

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Distribution of androgen and estrogen receptor mRNA-containing cells in the rat brain: an in situ hybridization study.

R Simerly, C. Chang, M Muramatsu … (1990)

The distribution of cells that express mRNA encoding the androgen (AR) and estrogen (ER) receptors was examined in adult male and female rats by using in situ hybridization. Specific labeling appeared to be largely, if not entirely, localized to neurons. AR and ER mRNA-containing neurons were widely distributed in the rat brain, with the greatest densities of cells in the hypothalamus, and in regions of the telencephalon that provide strong inputs in the medial preoptic and ventromedial nuclei, each of which is thought to play a key role in mediating the hormonal control of copulatory behavior, as well as in the lateral septal nucleus, the medial and cortical nuclei of the amygdala, the amygdalohippocampal area, and the bed nucleus of the stria terminalis. Heavily labeled ER mRNA-containing cells were found in regions known to be involved in the neural control of gonadotropin release, such as the anteroventral periventricular and the arcuate nuclei, but only a moderate density of labeling for AR mRNA was found over these nuclei. In addition, clearly labeled cells were found in regions with widespread connections throughout the brain, including the lateral hypothalamus, intralaminar thalamic nuclei, and deep layers of the cerebral cortex, suggesting that AR and ER may modulate a wide variety of neural functions. Each part of Ammon's horn contained AR mRNA-containing cells, as did both parts of the subiculum, but ER mRNA appeared to be less abundant in the hippocampal formation. Moreover, AR and ER mRNA-containing cells were also found in olfactory regions of the cortex and in both the main and accessory olfactory bulbs. AR and ER may modulate nonolfactory sensory information as well since labeled cells were found in regions involved in the central relay of somatosensory information, including the mesencephalic nucleus of the trigeminal nerve, the ventral thalamic nuclear group, and the dorsal horn of the spinal cord. Furthermore, heavily labeled AR mRNA-containing cells were found in the vestibular nuclei, the cochlear nuclei, the medial geniculate nucleus, and the nucleus of the lateral lemniscus, which suggests that androgens may alter the central relay of vestibular and auditory information as well. However, of all the regions involved in sensory processing, the heaviest labeling for AR and ER mRNA was found in areas that relay visceral sensory information such as the nucleus of the solitary tract, the area postrema, and the subfornical organ. We did not detect ER mRNA in brainstem somatic motoneurons, but clearly labeled AR mRNA-containing cells were found in motor nuclei associated with the fifth, seventh, tenth, and twelfth cranial nerves. Similarly, spinal motoneurons contained AR but not ER mRNA.(ABSTRACT TRUNCATED AT 400 WORDS)

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AMP-activated protein kinase suppresses protein synthesis in rat skeletal muscle through down-regulated mammalian target of rapamycin (mTOR) signaling.

Douglas Bolster, Stephen Crozier, Scot Kimball … (2002)

AMP-activated protein kinase (AMPK) is viewed as an energy sensor that acts to modulate glucose uptake and fatty acid oxidation in skeletal muscle. Given that protein synthesis is a high energy-consuming process, it may be transiently depressed during cellular energy stress. Thus, the intent of this investigation was to examine whether AMPK activation modulates the translational control of protein synthesis in skeletal muscle. Injections of 5-aminoimidazole-4-carboxamide 1-beta-d-ribonucleoside (AICAR) were used to activate AMPK in male rats. The activity of alpha1 AMPK remained unchanged in gastrocnemius muscle from AICAR-treated animals compared with controls, whereas alpha2 AMPK activity was significantly increased (51%). AICAR treatment resulted in a reduction in protein synthesis to 45% of the control value. This depression was associated with decreased activation of protein kinases in the mammalian target of rapamycin (mTOR) signal transduction pathway as evidenced by reduced phosphorylation of protein kinase B on Ser(473), mTOR on Ser(2448), ribosomal protein S6 kinase on Thr(389), and eukaryotic initiation factor eIF4E-binding protein on Thr(37). A reduction in eIF4E associated with eIF4G to 10% of the control value was also noted. In contrast, eIF2B activity remained unchanged in response to AICAR treatment and therefore would not appear to contribute to the depression in protein synthesis. This is the first investigation to demonstrate changes in translation initiation and skeletal muscle protein synthesis in response to AMPK activation.

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Meta-analysis: effect of hormone-replacement therapy on components of the metabolic syndrome in postmenopausal women.

E. Salpeter, Christine S. Walsh, E Greyber … (2006)

To quantify the effects of hormone-replacement therapy (HRT) on components of the metabolic syndrome in postmenopausal women. Comprehensive searches of electronic databases were performed from April 1966 to October 2004. We included randomized controlled trials that were of at least 8 weeks duration and evaluated the effect of HRT on metabolic, inflammatory or thrombotic components. Insulin resistance was calculated by homeostasis model assessment (HOMA-IR). Subgroup analysis evaluated the effects for transdermal and oral treatment and for diabetic and non-diabetic women. Pooled results of 107 trials showed that HRT reduced abdominal fat [-6.8% (CI, -11.8 to -1.9%)], HOMA-IR [-12.9% (CI, -17.1 to -8.6%)] and new-onset diabetes [relative risk 0.7 (CI, 0.6-0.9)] in women without diabetes. In women with diabetes, HRT reduced fasting glucose [-11.5% (CI, -18.0 to -5.1%)] and HOMA-IR [-35.8% (CI, -51.7 to -19.8%)]. HRT also reduced low-density lipoprotein/high-density lipoprotein cholesterol ratio [-15.7% (CI, -18.0 to -13.5%)], lipoprotein(a) [Lp(a)] [-25.0% [CI, -32.9 to -17.1%)], mean blood pressure [-1.7% (CI, -2.9 to -0.5%)], E-selectin [-17.3% (CI, -22.4 to -12.1%)], fibrinogen [-5.5% (CI, -7.8 to -3.2%)] and plasminogen activator inhibitor-1 [-25.1% (CI, -33.6 to -15.5%)]. Oral agents produced larger beneficial effects than transdermal agents, but increased C-reactive protein (CRP) [37.6% (CI, 17.4-61.3%)] and decreased protein S [-8.6% CI, -13.1 to -4.1%)], while transdermal agents had no effect. HRT reduces abdominal obesity, insulin resistance, new-onset diabetes, lipids, blood pressure, adhesion molecules and procoagulant factors in women without diabetes and reduced insulin resistance and fasting glucose in women with diabetes. Oral agents adversely affected CRP and protein S, while transdermal agents had no effects.

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Author and article information

Journal

Journal ID (nlm-ta): J Endocrinol

Journal ID (iso-abbrev): J. Endocrinol

Journal ID (hwp): JOE

Title: The Journal of Endocrinology

Publisher: Bioscientifica Ltd (Bristol )

ISSN (Print): 0022-0795

ISSN (Electronic): 1479-6805

Publication date Collection: September 2018

Publication date (Electronic): 18 June 2018

Volume: 238

Issue: 3

Pages: 177-186

Affiliations

[1 ]Department of Physiology CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain

[2 ]CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn) Santiago de Compostela, Spain

[3 ]Hormone Laboratory Haukeland University Hospital, Bergen, Norway

[4 ]KG Jebsen Center for Diabetes Research Department of Clinical Science, University of Bergen, Bergen, Norway

[5 ]Department of Cell Biology Physiology and Immunology, University of Córdoba, Córdoba, Spain

[6 ]Instituto Maimónides de Investigación Biomédica (IMIBIC)/Hospital Reina Sofía Córdoba, Spain

[7 ]FiDiPro Program University of Turku, Turku, Finland

Author notes

Correspondence should be addressed to S Tovar or M López: sulay.tovar@ 123456usc.es or m.lopez@ 123456usc.es

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Publisher ID: JOE180190

DOI: 10.1530/JOE-18-0190

PMC ID: 6055430

PubMed ID: 29914932

SO-VID: a8bbb6c5-e0fc-4541-a2d7-4d9a831114fc

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This work is licensed under a Creative Commons Attribution 4.0 Unported License.

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mTOR signaling in the arcuate nucleus of the hypothalamus mediates the anorectic action of estradiol

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Most cited references 27

Distribution of androgen and estrogen receptor mRNA-containing cells in the rat brain: an in situ hybridization study.

AMP-activated protein kinase suppresses protein synthesis in rat skeletal muscle through down-regulated mammalian target of rapamycin (mTOR) signaling.

Meta-analysis: effect of hormone-replacement therapy on components of the metabolic syndrome in postmenopausal women.

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