Mild mitochondrial uncoupling induces HSL/ATGL-independent lipolysis relying on a form of autophagy in 3T3-L1 adipocytes
Open accessAbstract
Obesity is characterized by an excessive triacylglycerol accumulation in white adipocytes. Various mechanisms allowing the tight regulation of triacylglycerol storage and mobilization by lipid droplet-associated proteins as well as lipolytic enzymes have been identified. Increasing energy expenditure by inducing a mild uncoupling of mitochondria in adipocytes might represent a putative interesting anti-obesity strategy as it reduces the adipose tissue triacylglycerol content (limiting alterations caused by cell hypertrophy) by stimulating lipolysis through yet unknown mechanisms, limiting the adverse effects of adipocyte hypertrophy. Herein, the molecular mechanisms involved in lipolysis induced by a mild uncoupling of mitochondria in white 3T3-L1 adipocytes were characterized. Mitochondrial uncoupling-induced lipolysis was found to be independent from canonical pathways that involve lipolytic enzymes such as HSL and ATGL. Finally, enhanced lipolysis in response to mitochondrial uncoupling relies on a form of autophagy as lipid droplets are captured by endolysosomal vesicles. This new mechanism of triacylglycerol breakdown in adipocytes exposed to mild uncoupling provides new insights on the biology of adipocytes dealing with mitochondria forced to dissipate energy.
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The positive effect of mitochondrial uncoupling on autophagy has been established in many cellular and animal models, including adipocytes, MEFs, HeLa cells, HepG2 cells, SH-SY5Y neuroblastoma cells, and C57BL6 mice.
“The positive effect of mitochondrial uncoupling on autophagy has been established in many cellular and animal models, including adipocytes [91], MEFs [92], HeLa cells [93], HepG2 cells [90], SH-SY5Y neuroblastoma cells [93], or C57BL6 mice [94].”
From Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases (2019) · cites this paper as [91]
FCCP triggers a form of autophagy in 3T3-L1 murine white adipocytes, and a low concentration (0.5 μM) reduces adipocyte triacylglycerol content via lipolysis activation independent of HSL and ATGL.
“In this model, a low concentration (0.5 μM) in this mitochondrial uncoupler is sufficient to reduce adipocyte triacylglycerol (TAG) content, resulting from a lipolysis activation that is independent of the classical cytosolic lipases HSL (Hormone Sensitive Lipase) and ATGL (Adipose Triglyceride Lipase) [91].”
From Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases (2019) · cites this paper as [91]
The best-known effect of mitochondrial uncouplers is a drop in ATP/AMP levels, which induces activation of the AMPK signaling pathway.
“In terms of cell signaling, the best-known effect of mitochondrial uncouplers is probably a drop in ATP/AMP levels, which induces the activation of the AMPK signaling pathway (Figure 1).”
From Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases (2019) · cites this paper as [91]
The effect of mitochondrial uncouplers on ATP/AMP levels and AMPK activation has been found in multiple models and species, including white adipocytes, skeletal muscle cells, cancer cells, and neurons.
“This effect has been found in multiple models and species, including white adipocytes [91,251], skeletal muscle cells [252,253], cancer cells [54,254,255,256], and neurons [257].”
From Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases (2019) · cites this paper as [91]
By acting on white adipocyte mass, mitochondrial uncouplers could protect against diabetes.
“By acting on white adipocyte mass, mitochondrial uncouplers could protect against diabetes, as limiting hyperaccumulation of triacyglycerol (TAG) in these cells might limit organelle stress [91,273,274,275] and modifications in the expression pattern of genes encoding adipokines, which are known to communicate the level of adiposity to other organs [221,276].”
From Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases (2019) · cites this paper as [91]
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Metabolic Flux Analysis of Mitochondrial Uncoupling in 3T3-L1 Adipocytes
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A sensitive three-step protocol for fluorescence-based Western blot detection
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Flagged first, then by citations
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Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases
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- Authors
- Demine, S., Tejerina, S., Bihin, B., Thiry, M., Reddy, N., Renard, P., Raes, M., Jadot, M., & Arnould, T.
- Affiliations
- University of Namur (BE)
- University of Liège (BE)
- Corresponding author
- Arnould, Thierry
- ORCID
- Venue
- Journal of Cellular Physiology
- Publisher
- Wiley
- Published
- 2017-06-15
- Volume
- 233
- Issue
- 2
- Pages
- 1247-1265
- ISSN
- 0021-9541 (ISSN-L)
- 1097-4652
- OpenAlex
- W2615078207
- Cited by
- 21
- References
- 100
- Citations by year
- 2025: 5 · 2024: 1 · 2023: 1 · 2022: 2 · 2021: 3 · 2020: 3 · 2019: 3 · 2018: 3
- FWCI
- 1.25
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Cellular Physiology (publishedVersion)
- PubMed (publishedVersion)
- Open Repository and Bibliography (University of Liège) (submittedVersion, other-oa)
- Repository of the University of Namur (submittedVersion, other-oa)
- Funders
- FRS-FNRS (Fonds National de la Recherche Scientifique), 5, Rue d'Egmont, Brussels (Belgium) (Crédit de Recherche (CDR-2013): 19497337)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- mitochondrial uncoupling, lipolysis, HSL, adipose triglyceride lipase, autophagy, lipid droplets, 3T3-L1 adipocytes, triacylglycerol mobilization, obesity, adipocyte hypertrophy, energy expenditure
- MeSH terms
- Autophagy-Related Protein 5, Autophagy-Related Protein 7, Acyltransferases, Animals, Autophagy, Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone, Sterol Esterase, Lipase, Lipolysis, Lysosomes, Mitochondria, Transfection, Triglycerides, Uncoupling Agents, Adipocytes, Macrolides, RNA Interference, 3T3-L1 Cells, Mice, Lipid Droplets
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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