Induction of mitochondrial uncoupling enhances VEGF₁₂₀ but reduces MCP-1 release in mature 3T3-L1 adipocytes: Possible regulatory mechanism through endogenous ER stress and AMPK-related pathways
Abstract
Although white adipocytes contain a larger number of mitochondria per cytoplasmic volume, adipocyte mitochondrial uncoupling to reduce the efficiency of ATP production on cellular function including secretory regulation of bioactive molecules such as VEGF and MCP-1 remains to be elucidated. Here we induce mitochondrial uncoupling under hypoxia-independent conditions in mature 3T3-L1 adipocytes using a metabolic uncoupler, dinitrophenol (DNP). MCP-1 release was significantly decreased by 26% (p<0.01) in 24h DNP (30 μmol/L)-treated adipocytes compared to control cells. In contrast, secreted VEGF(120) lacking a heparin-binding domain was markedly increased 2.0-fold (p<0.01). CHOP content in these cells also were augmented (p<0.01), but no significant increase of endogenous oxidative stress was observed. Treatment with thapsigargin, which can induce exogenous endoplasmic reticulum (ER) stress, clearly attenuated MCP-1 release (p<0.01), but exhibited no effects on VEGF(120) secretion. On the other hand, exogenous H(2)O(2) amplified both MCP-1 and VEGF(120) secretion (p<0.05). In addition, under chronic activation of AMPK by AICAR, MCP-1 release was significantly diminished (p<0.05) but VEGF(120) secretion was increased (p<0.01). JNK phosphorylation in mature adipocytes was decreased by treatment with either DNP or AICAR (p<0.01). Enhanced VEGF(120) secretion with either DNP or AICAR was markedly suppressed by PI3K inhibitor LY294002 (p<0.01). Thus, induced mitochondrial uncoupling in adipocytes can reduce MCP-1 release through induction of endogenous ER stress and by reduced JNK activities via chronic activation of AMPK. Under this condition, VEGF(120) secretion was increased through PI3K-dependent pathways, which were chronically activated by AMPK, and not through ER stress. Because the decrease of MCP-1 secretion under mitochondrial uncoupling might attenuate chronic low-grade inflammation by suppressing macrophages recruitment to adipose tissue, clarification of the mechanism might reveal novel therapeutic targets for ameliorating obesity-associated insulin resistance in metabolic syndrome and type 2 diabetes.
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MCP-1 release was decreased by lower concentrations (1.5 μM) of DNP in murine 3T3-L1 adipocytes, an effect relying on endoplasmic reticulum stress induction and AMPK activation.
“MCP-1 release was also decreased by lower concentrations (1.5 μM) of DNP in murine 3T3-L1 adipocytes, an effect which relies on endoplasmic reticulum stress induction and AMPK activation [272].”
From Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases (2019) · cites this paper as [272]
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Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases
Demine, S., Renard, P., & Arnould, T. (2019) · Cells · doi:10.3390/cells8080795 · Cited by 476 · see citing works
- Authors
- Miyokawa-Gorin, K., Takahashi, K., Handa, K., Kitahara, A., Sumitani, Y., Katsuta, H., Tanaka, T., Nishida, S., Yoshimoto, K., Ohno, H., & Ishida, H.
- Affiliations
- Kyorin University (JP)
- Corresponding author
- Ishida, Hitoshi
- Venue
- Biochemical and Biophysical Research Communications
- Publisher
- Elsevier BV
- Published
- 2012-03
- Volume
- 419
- Issue
- 2
- Pages
- 200-205
- ISSN
- 0006-291X (ISSN-L)
- OpenAlex
- W2080343366
- Cited by
- 18
- References
- 35
- Citations by year
- 2021: 1 · 2019: 2 · 2018: 1 · 2017: 2 · 2016: 3 · 2015: 1 · 2014: 4 · 2013: 3 · 2012: 1
- FWCI
- 1.93
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical and Biophysical Research Communications (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Private School Promotion Foundation
- Ministry of Education, Culture, Sports, Science and Technology
- Topics
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Keywords
- mitochondrial uncoupling, 3T3-L1 adipocytes, endoplasmic reticulum stress, AMPK signaling, JNK phosphorylation, PI3K signaling, dinitrophenol, thapsigargin, hydrogen peroxide, CHOP, adipocyte inflammation
- MeSH terms
- AMP-Activated Protein Kinase Kinases, Animals, Diabetes Mellitus, Type 2, Mitochondria, Obesity, Protein Kinases, Adipocytes, Chemokine CCL2, Metabolic Syndrome, 3T3-L1 Cells, Vascular Endothelial Growth Factor A, Adipogenesis, Mice, Metabolic Networks and Pathways, Endoplasmic Reticulum Stress
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