Adipocyte expression of PU.1 transcription factor causes insulin resistance through upregulation of inflammatory cytokine gene expression and ROS production
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We have reported previously that ETS family transcription factor PU.1 is expressed in mature adipocytes of white adipose tissue. PU.1 expression is increased greatly in mouse models of genetic or diet-induced obesity. Here, we show that PU.1 expression is increased only in visceral but not subcutaneous adipose tissues of obese mice, and the adipocytes are responsible for this increase in PU.1 expression. To further address PU.1's physiological function in mature adipocytes, PU.1 was knocked down in 3T3-L1 cells using retroviral-mediated expression of PU.1-targeting shRNA. Consistent with previous findings that PU.1 regulates its target genes, such as NADPH oxidase subunits and proinflammatory cytokines in myeloid cells, the mRNA levels of proinflammatory cytokines (TNFα, IL-1β, and IL-6) and cytosolic components of NADPH oxidase (p47phox and p40phox) were downregulated significantly in PU.1-silenced adipocytes. NADPH oxidase is a main source for reactive oxygen species (ROS) generation. Indeed, silencing PU.1 suppressed NADPH oxidase activity and attenuated ROS in basal or hydrogen peroxide-treated adipocytes. Silencing PU.1 in adipocytes suppressed JNK1 activation and IRS-1 phosphorylation at Ser 307 . Consequently, PU.1 knockdown improved insulin signaling and increased glucose uptake in basal and insulin-stimulated conditions. Furthermore, knocking down PU.1 suppressed basal lipolysis but activated stimulated lipolysis. Collectively, these findings indicate that obesity induces PU.1 expression in adipocytes to upregulate the production of ROS and proinflammatory cytokines, both of which lead to JNK1 activation, insulin resistance, and dysregulation of lipolysis. Therefore, PU.1 might be a mediator for obesity-induced adipose inflammation and insulin resistance.
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By suppressing adipocyte oxidative stress, spirulina may lead to systemic anti-inflammatory and insulin-sensitising effects.
“Thus, by suppressing adipocyte oxidative stress, spirulina may lead to systemic anti-inflammatory and insulin-sensitising effects.12–20”
From Effects of spirulina on weight loss and blood lipids: A review (2020) · cites this paper as [18]
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Self-citation
- Authors
- Lin, L., Pang, W., Chen, K., Wang, F., Gengler, J., Sun, Y., & Tong, Q.
- Affiliations
- Agricultural Research Service (US)
- Corresponding author
- Tong, Qiang
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2012-06-15
- Volume
- 302
- Issue
- 12
- Pages
- E1550-E1559
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- PMC
- PMC3378156
- OpenAlex
- W2012427211
- Cited by
- 54
- References
- 76
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 3 · 2022: 7 · 2021: 6 · 2020: 4 · 2019: 7 · 2018: 7 · 2017: 1 · 2016: 1 · 2015: 5 · 2014: 3 · 2013: 5
- FWCI
- 3.10
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Agriculture
- American Heart Association
- National Institute of Diabetes and Digestive and Kidney Diseases (DK075978, R01DK075978)
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Keywords
- PU.1, ETS transcription factors, adipocytes, insulin resistance, obesity, adipose tissue inflammation, NADPH oxidase, reactive oxygen species, inflammatory cytokines, JNK1, IRS-1 phosphorylation, lipolysis, visceral adipose tissue, 3T3-L1 cells, shRNA knockdown
- MeSH terms
- Interferon Regulatory Factor-4, Animals, Cell Differentiation, Deoxyglucose, Insulin, Insulin Resistance, Lipolysis, Mice, Inbred C57BL, Obesity, Plasmids, Blotting, Western, Signal Transduction, Up-Regulation, Cytokines, 3T3 Cells, Reactive Oxygen Species, Adipocytes, NADPH Oxidases, Gene Silencing, RNA, Small Interfering, Interferon Regulatory Factors, Mice, Real-Time Polymerase Chain Reaction
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