A novel chemical uncoupler ameliorates obesity and related phenotypes in mice with diet-induced obesity by modulating energy expenditure and food intake
Abstract
Aims/hypothesis Decreasing mitochondrial coupling efficiency has been shown to be an effective therapy for obesity and related metabolic symptoms. Here we identified a novel mitochondrial uncoupler that promoted uncoupled respiration in a cell type-specific manner and investigated its effects on modulation of energy metabolism in vivo and in vitro.Methods We screened a collection of mitochondrial membrane potential depolarising compounds for a novel chemical uncoupler on isolated skeletal muscle mitochondria using a channel oxygen system. The effect on respiration of metabolic cells (L6 myotubes, 3T3-L1 adipocytes and rat primary hepatocytes) was examined and metabolic pathways sensitive to cellular ATP content were also evaluated. The chronic metabolic effects were investigated in high-fat diet-induced obese mice and standard diet-fed (SD) lean mice.Results The novel uncoupler, CZ5, promoted uncoupled respiration in a cell type-specific manner. It stimulated fuel oxidation in L6 myotubes and reduced lipid accumulation in 3T3-L1 adipocytes but did not affect gluconeogenesis or the triacylglycerol content in hepatocytes. The administration of CZ5 to SD mice increased energy expenditure (EE) but did not affect body weight or adiposity. Chronic studies in mice on high-fat diet showed that CZ5 reduced body weight and improved glucose and lipid metabolism via both increased EE and suppressed energy intake. The reduced adiposity was associated with the restoration of expression of key metabolic genes in visceral adipose tissue.Conclusions/interpretation This work demonstrates that a cell type-specific mitochondrial chemical uncoupler may have therapeutic potential for treating high-fat diet-induced metabolic diseases.
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CZ5 reduces body weight, total adipose tissue mass, fasting glucose levels, and insulin levels.
“CZ5, an orally bioavailable mitochondrial uncoupler271, also reduces body weight, total adipose tissue mass, fasting glucose levels and insulin levels271.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [271]
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- Authors
- Fu, Y.-Y., Zhang, M., Turner, N., Zhang, L.-N., Dong, T.-C., Gu, M., Leslie, S. J., Li, J.-Y., Nan, F.-J., & Li, J.
- Affiliations
- Chinese Academy of Sciences (CN)
- Garvan Institute of Medical Research (AU)
- Corresponding author
- Nan, F.-J.
- ORCID
- Venue
- Diabetologia
- Published
- 2013-08-05
- Volume
- 56
- Issue
- 10
- Pages
- 2297-2307
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- OpenAlex
- W1967694869
- Cited by
- 35
- References
- 50
- Citations by year
- 2025: 3 · 2023: 5 · 2022: 2 · 2021: 5 · 2020: 3 · 2019: 7 · 2018: 5 · 2017: 2 · 2016: 1 · 2014: 1
- FWCI
- 0.46
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Diabetologia (publishedVersion)
- PubMed (publishedVersion)
- Funders
- SLAC National Accelerator Laboratory
- Topics
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- mitochondrial uncouplers, uncoupled respiration, mitochondrial membrane potential, diet-induced obesity, energy expenditure, dietary intake, skeletal muscle mitochondria, adipocytes, hepatocytes, fuel oxidation, lipid accumulation, glucose metabolism, lipid metabolism, visceral adipose tissue, high-fat diet, obesity treatment
- MeSH terms
- Animals, Eating, Energy Metabolism, Humans, Hypoglycemic Agents, Male, Mice, Inbred C57BL, Obesity, Cell Respiration, Mice, Rats, Membrane Potential, Mitochondrial, Hep G2 Cells, Diet, High-Fat
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.
What counts as a claim ›How we measure confidence ›How we check this ›
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