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Region-Specific Reduction in Leptin-Induced Phosphorylation of Signal Transducer and Activator of Transcription-3 (STAT3) in the Rat Hypothalamus Is Associated with Leptin Resistance during Pregnancy
Abstract
Leptin concentrations increase during pregnancy, but this does not prevent the pregnancy-induced increase in food intake, suggesting a state of leptin resistance. This study investigated the response to intracerebroventricular leptin administration in pregnant rats. After fasting, nonpregnant, d-7 and d-14 pregnant rats received leptin (4 μg) or vehicle, then food intake was measured. Serial blood samples were collected in another group of rats to determine plasma leptin concentrations. Further groups of d-14 pregnant and nonpregnant rats were killed after leptin or vehicle treatment, and brains were collected. Hypothalamic nuclei were microdissected, and levels of signal transducer and activator of transcription (STAT)3 phosphorylation were measured using Western blot analysis. Fasting decreased leptin concentrations in both pregnant and nonpregnant rats. Leptin treatment significantly reduced food intake in nonpregnant and d-7 pregnant rats but not in d-14 pregnant rats. In addition, there was no postfasting hyperphagic response in the pregnant rats. In the pregnant rats, leptin-induced STAT3 phosphorylation was suppressed in the arcuate nucleus and, to a lesser extent, in the ventromedial hypothalamus (VMH), compared with nonpregnant rats. Unstimulated STAT3 levels were also decreased in the VMH during pregnancy. Leptin-induced phosphorylation of STAT3 in the dorsomedial and lateral hypothalamus was not different between pregnant and nonpregnant rats. These data indicate that pregnant rats become resistant to the satiety action of leptin. Furthermore, leptin-induced activation of the STAT3 is impaired during pregnancy, specifically in the arcuate nucleus and VMH. These data support the hypothesis that pregnancy is a state of hypothalamic leptin resistance.
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“Indeed, using a high-fat induced model of obesity in mice, leptin resistance measured by STAT-3 activation was shown to be restricted to the arcuate nucleus of the hypothalamus (60, 194), and this correlated with expression of the suppressor of leptin signaling SOCS-3 (248).”
From Cardiac remodeling in obesity (2008) · cites this paper as [194]
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STAT3 signalling is required for leptin regulation of energy balance but not reproduction
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Münzberg, H., Flier, J. S., & Bjørbæk, C. (2004) · Endocrinology · doi:10.1210/en.2004-0726 · Cited by 737
Abel, E. D., Litwin, S. E., & Sweeney, G. (2008) · Physiological Reviews · doi:10.1152/physrev.00017.2007 · Cited by 736
The expectant brain: adapting for motherhood
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Leptin Indirectly Regulates Gonadotropin-Releasing Hormone Neuronal Function
Quennell, J. H., Mulligan, A. C., Tups, A., Liu, X., Phipps, S. J., Kemp, C. J., Herbison, A. E., Grattan, D. R., & Anderson, G. M. (2009) · Endocrinology · doi:10.1210/en.2008-1693 · Cited by 385
Self-citation60 YEARS OF NEUROENDOCRINOLOGY: The hypothalamo-prolactin axis
Grattan, D. R. (2015) · Journal of Endocrinology · doi:10.1530/joe-15-0213 · Cited by 379
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Metadata
- Authors
- Ladyman, S. R., & Grattan, D. R.
- Affiliations
- University of Otago (NZ)
- Corresponding author
- Grattan, D. R.
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2004-08-01
- Volume
- 145
- Issue
- 8
- Pages
- 3704-3711
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- OpenAlex
- W2015900343
- Cited by
- 144
- References
- 52
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 2 · 2023: 2 · 2022: 6 · 2021: 5 · 2020: 7 · 2019: 12 · 2018: 5 · 2017: 7 · 2016: 9 · 2015: 3 · 2014: 9 · 2013: 8 · 2012: 5
- FWCI
- 2.77
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- leptin resistance, pregnancy, STAT3 phosphorylation, hypothalamus, arcuate nucleus, ventromedial hypothalamus, dietary intake, satiety, fasting, leptin, hypothalamic nuclei
- MeSH terms
- Animals, Arcuate Nucleus of Hypothalamus, DNA-Binding Proteins, Eating, Female, Hypothalamus, Injections, Intraventricular, Phosphorylation, Pregnancy, Pregnancy, Animal, Ventromedial Hypothalamic Nucleus, Signal Transduction, Trans-Activators, Rats, Sprague-Dawley, Leptin, STAT3 Transcription Factor, Rats
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