Functional Role of Suppressor of Cytokine Signaling 3 Upregulation in Hypothalamic Leptin Resistance and Long-Term Energy Homeostasis
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OBJECTIVE: Hypothalamic leptin resistance is found in most common forms of obesity, such as diet-induced obesity, and is associated with increased expression of suppressor of cytokine signaling 3 (Socs3) in the hypothalamus of diet-induced obese animals. This study aims to determine the functional consequence of Socs3 upregulation on leptin signaling and obesity, and to investigate whether Socs3 upregulation affects energy balance in a cell type–specific way. RESEARCH DESIGN AND METHODS: We generated transgenic mice overexpressing Socs3 in either proopiomelanocortin (POMC) or leptin receptor–expressing neurons, at levels similar to what is observed in diet-induced obesity. RESULTS: Upregulation of Socs3 in POMC neurons leads to impairment of STAT3 and mammalian target of rapamycin (mTOR)–S6K-S6 signaling, with subsequent leptin resistance, obesity, and glucose intolerance. Unexpectedly, Socs3 upregulation in leptin receptor neurons results in increased expression of STAT3 protein in mutant hypothalami, but does not lead to obesity. CONCLUSIONS: Our study establishes that Socs3 upregulation alone in POMC neurons is sufficient to cause leptin resistance and obesity. Socs3 upregulation impairs both STAT3 and mTOR signaling before the onset of obesity. The lack of obesity in mice with upregulated Socs3 in leptin receptor neurons suggests that Socs3's effect on energy balance could be cell type specific. Our study indicates that POMC neurons are important mediators of Socs3's effect on leptin resistance and obesity, but that other cell types or alteration of other signaling regulators could contribute to the development of obesity.
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Over-expression of SOCS-3 in leptin receptor-positive neurons does not cause leptin resistance or obesity.
“over-expression of SOCS-3 in leptin receptor-positive neurons did not (149).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [149]
Up-regulation of SOCS-3 selectively in POMC neurons causes leptin resistance and obesity.
“while up-regulation of SOCS-3 selectively in POMC neurons causes leptin resistance and obesity”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [149]
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“Moreover, while upregulation of SOCS-3 selectively in POMC neurons causes leptin resistance and obesity, somewhat surprisingly, overexpression of SOCS-3 in leptin receptor-positive neurons did not (149).”
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- Authors
- Reed, A. S., Unger, E. K., Olofsson, L. E., Piper, M. L., Myers, M. G., & Xu, A. W.
- Affiliations
- University of California, San Francisco (US)
- University of Michigan (US)
- Corresponding author
- Xu, Allison W.
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2010-01-12
- Volume
- 59
- Issue
- 4
- Pages
- 894-906
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC2844837
- OpenAlex
- W2164600485
- Cited by
- 176
- References
- 45
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 5 · 2023: 7 · 2022: 5 · 2021: 17 · 2020: 10 · 2019: 6 · 2018: 14 · 2017: 12 · 2016: 11 · 2015: 13 · 2014: 18 · 2013: 16 · 2012: 19
- FWCI
- 6.68
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Diabetes (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- American Diabetes Association
- Vetenskapsrådet
- National Institutes of Health (5t32dk007161-48, P30 DK)
- University of California, San Francisco
- National Institute of Diabetes and Digestive and Kidney Diseases (T32-DK-007161, R37DK056731, T32 DK-07161, P30DK063720, P30DK020572)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Keywords
- SOCS3, leptin resistance, hypothalamus, diet-induced obesity, POMC neurons, leptin receptor neurons, STAT3 signaling, energy homeostasis, impaired glucose tolerance, cell type-specific signaling, transgenic mice
- MeSH terms
- Suppressor of Cytokine Signaling 3 Protein, Animals, Blood Glucose, Female, Gene Amplification, Genotype, Hypothalamus, Insulin, Male, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Pro-Opiomelanocortin, Up-Regulation, Polymerase Chain Reaction, DNA Primers, Leptin, Suppressor of Cytokine Signaling Proteins, Mice, Receptors, Leptin
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