Disruption of neural signal transducer and activator of transcription 3 causes obesity, diabetes, infertility, and thermal dysregulation
Open accessAbstract
Signal transducer and activator of transcription (STAT)3 is widely expressed in the CNS during development and adulthood. STAT3 has been implicated in the control of neuron/glial differentiation and leptin-mediated energy homeostasis, but the physiological role and degree of involvement of STAT3 in these processes is not defined and controversial because of the lack of a direct genetic model. To address this, we created mice with a neural-specific disruption of STAT3 (STAT3 N-/- ). Surprisingly, homozygous mutants were born at the expected Mendelian ratio without apparent developmental abnormalities but susceptible to neonatal lethality. Mutants that survived the neonatal period were hyperphagic, obese, diabetic, and infertile. Administering a melanocortin-3/4 receptor agonist abrogated the hyperphagia and hypothalamic immunohistochemistry showed a marked reduction in proopiomelanocortin with an increase in neuropeptide Y and agouti-related protein. Mutants had reduced energy expenditure and became hypothermic after fasting or cold stress. STAT3 N-/- mice are hyperleptinemic, suggesting a leptin-resistant condition. Concomitant with neuroendocrine defects such as decreased linear growth and infertility with accompanying increased corticosterone levels, this CNS knockout recapitulates the unique phenotype of db / db and ob / ob obese models and distinguishes them from other genetic models of obesity. Thus, STAT3 in the CNS plays essential roles in the regulation of energy homeostasis and reproduction.
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Neural cell-specific STAT3 knockout causes obesity, diabetes, infertility, and thermal dysregulation.
“Obesity, diabetes, infertility, and thermal dysregulation”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Gao et al., 2004
STAT3 deletion in neurons decreases POMC and increases AgRP and neuropeptide Y levels, leading to hyperphagia, obesity, infertility, and thermal dysregulation.
“STAT3 deletion in neurons decreases POMC and increases AgRP and neuropeptide Y levels, leading to hyperphagia, obesity, infertility, and thermal dysregulation”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Gao et al., 2004
Only STAT3 deletion causes severe obesity and greatly attenuates the anorexic effect of leptin.
“Although genetic deletion of these CNS signalling pathways may increase adiposity, only STAT3 deletion causes severe obesity and greatly attenuates the anorexic effect of leptin141.”
From Obesity, kidney dysfunction and hypertension: mechanistic links (2019) · cites this paper as [141]
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- Authors
- Gao, Q., Wolfgang, M. J., Neschen, S., Morino, K., Horvath, T. L., Shulman, G. I., & Fu, X.-Y.
- Affiliations
- Howard Hughes Medical Institute (US)
- Departments of Pathology and Internal Medicine and Cellular and Molecular Physiology and Department of Obstetrics and Gynecology and Reproductive Science and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2004-03-22
- Volume
- 101
- Issue
- 13
- Pages
- 4661-4666
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC384803
- OpenAlex
- W2024802365
- Cited by
- 385
- References
- 56
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 12 · 2023: 8 · 2022: 15 · 2021: 13 · 2020: 16 · 2019: 12 · 2018: 14 · 2017: 13 · 2016: 16 · 2015: 18 · 2014: 14 · 2013: 33 · 2012: 18
- FWCI
- 9.36
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Eye Institute (R01EY013607, EY13607)
- National Institute of Allergy and Infectious Diseases (AI-34522, R01AI034522)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK45735, R01-DK40936, R01DK040936, DK 060711, R01DK060711, P30DK045735)
- National Center for Research Resources (RR014451, R01RR014451)
- 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 › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- STAT3, obesity, diabetes mellitus, infertility, hyperphagia, leptin resistance, energy homeostasis, melanocortin 3/4 receptor, proopiomelanocortin, neuropeptide Y, agouti-related protein, hypothalamus, corticosterone, cold stress, db/db mice, ob/ob mice
- MeSH terms
- Acute-Phase Proteins, Animals, Body Temperature Regulation, Adipose Tissue, Brown, Corticosterone, Diabetes Mellitus, DNA-Binding Proteins, Female, Infertility, Female, Infertility, Male, Intermediate Filament Proteins, Kinetics, Male, Mice, Transgenic, Nerve Tissue Proteins, Obesity, Time Factors, Trans-Activators, Mice, Knockout, Leptin, STAT3 Transcription Factor, Mice, Rats, Nestin
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