The role of leptin-->STAT3 signaling in neuroendocrine function: an integrative perspective
Abstract
The hormone leptin is secreted by adipose tissue in proportion to fat mass to signal the repletion of body energy stores to the neuroendocrine system. Leptin acts on neurons in the hypothalamus and elsewhere in the brain to decrease appetite and regulate the activity of the thyroid, adrenal, growth, gonadal, and lactational axes. Conversely, absence of leptin signaling initiates the neuroendocrine starvation response. Leptin mediates these effects by activating the long form (LRb) of its receptor. One LRb signal, STAT3, has recently been shown to play a critical role in the regulation of body weight and some elements of neuroendocrine function (thyroid, adrenal, lactation), although the participation of STAT3 in the gonadal and growth axes is negligible. We discuss these findings in the context of the hypothalamic neuroendocrine system as it is presently understood.
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Mice with homozygous knock-in substitution of LepRb tyrosine residue Tyr1138 had decreased POMC and increased AgRP mRNA levels in the hypothalamus and displayed hyperphagia and decreased energy expenditure, leading to massive early-onset obesity associated with increased serum leptin levels.
“Mice with homozygous knock-in substitution of LepRb tyrosine residue Tyr1138”
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 Bates and Myers, 2004
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STAT3 signalling is required for leptin regulation of energy balance but not reproduction
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“Furthermore, the PVH CRH neuron may be regulated divergently by leptin in different species, as leptin increases CRH expression in the PVH in the rat [74, 75 ].”
BackgroundHuman Leptin Levels Are Pulsatile and Inversely Related to Pituitary–Ardenal Function
Licinio, J., Mantzoros, C., Negrão, A. B., Cizza, G., Wong, M.-L., Bongiorno, P. B., Chrousos, G. P., Karp, B., Allen, C., Flier, J. S., et al. (1997) · Nature Medicine · doi:10.1038/nm0597-575 · Cited by 632 · see citing works
Evidence That the Caudal Brainstem Is a Target for the Inhibitory Effect of Leptin on Food Intake
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“Leptin action on these hypothalamic neurons also regulates the activity of the autonomic nervous system, although direct leptin action on brainstem LRb-expressing neurons likely plays an important role as well [ 32 , 33].”
BackgroundDivergent Roles of SHP-2 in ERK Activation by Leptin Receptors
Bjørbæk, C., Buchholz, R. M., Davis, S. M., Bates, S. H., Pierroz, D. D., Gu, H., Neel, B. G., Myers, M. G., & Flier, J. S. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m007439200 · Cited by 364 · see citing works
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Diabetes, Obesity, and the Brain
Schwartz, M. W., & Porte, D. (2005) · Science · doi:10.1126/science.1104344 · Cited by 841 · see citing works
Bharadwaj, U., Kasembeli, M. M., Robinson, P., & Tweardy, D. J. (2020) · Pharmacological Reviews · doi:10.1124/pr.119.018440 · Cited by 314 · see citing works
“…and decreased energy expenditure, leading to massive early-onset obesity associated with increased serum leptin levels (Bates et al., 2003; Bates and Myers, 2004), which correlated with increased adipose mass in these mice and also indicated resistance to the normal energy homeostatic…”
BackgroundLRb-STAT3 Signaling Is Required for the Neuroendocrine Regulation of Energy Expenditure by Leptin
Bates, S. H., Dundon, T. A., Seifert, M., Carlson, M., Maratos-Flier, E., & Myers, M. G. (2004) · Diabetes · doi:10.2337/diabetes.53.12.3067 · Cited by 139 · see citing works
Self-citationSexually different actions of leptin in proopiomelanocortin neurons to regulate glucose homeostasis
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Gut Microbiota Restores Central Neuropeptide Deficits in Germ-Free Mice
Hamamah, S., & Covasa, M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231911756 · Cited by 25 · see citing works
Central Control of Glucose Homeostasis
Puglianiello, A., & Cianfarani, S. (2006) · The Review of Diabetic Studies · doi:10.1900/rds.2006.3.54 · Cited by 14 · see citing works
- Authors
- Bates, S. H., & Myers, M. G.
- Affiliations
- Joslin Diabetes Center (US)
- Corresponding author
- Myers, Martin G.
- ORCID
- Myers, Martin G.
- Venue
- Journal of Molecular Medicine
- Published
- 2004-01-01
- Volume
- 82
- Issue
- 1
- Pages
- 12-20
- ISSN
- 0946-2716 (ISSN-L)
- 1432-1440
- OpenAlex
- W2115005228
- Cited by
- 81
- References
- 5
- Citations by year
- 2025: 2 · 2024: 1 · 2022: 2 · 2021: 2 · 2020: 1 · 2019: 3 · 2018: 3 · 2017: 1 · 2016: 2 · 2015: 2 · 2014: 5 · 2013: 6 · 2012: 5
- FWCI
- 2.90
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Journal of Molecular Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK56731, DK 57768, R01DK057768)
- 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 › Oncology › Cytokine Signaling Pathways and Interactions
- Keywords
- leptin, STAT3 signaling, hypothalamus, neuroendocrine regulation, appetite regulation, energy homeostasis, hypothalamic-pituitary-thyroid axis, adrenal axis, lactation, gonadal axis, growth axis, starvation response, body weight regulation
- MeSH terms
- Animals, DNA-Binding Proteins, Homeostasis, Humans, Neuropeptides, Neurosecretory Systems, Obesity, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Receptors, Cell Surface, Signal Transduction, Trans-Activators, Protein Isoforms, Leptin, STAT3 Transcription Factor, Janus Kinase 2, Receptors, Leptin
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