Mitochondrial uncoupling in the melanocortin system differentially regulates NPY and POMC neurons to promote weight-loss
Open accessAbstract
OBJECTIVE: The mitochondrial uncoupling agent 2,4-dinitrophenol (DNP), historically used as a treatment for obesity, is known to cross the blood-brain-barrier, but its effects on central neural circuits controlling body weight are largely unknown. As hypothalamic melanocortin neuropeptide Y/agouti-related protein (NPY/AgRP) and pro-opiomelanocortin (POMC) neurons represent key central regulators of food intake and energy expenditure we investigated the effects of DNP on these neurons, food intake and energy expenditure. METHOD: C57BL/6 and melanocortin-4 receptor (MC4R) knock-out mice were administered DNP intracerebroventricularly (ICV) and the metabolic changes were characterized. The specific role of NPY and POMC neurons and the ionic mechanisms mediating the effects of uncoupling were examined with in vitro electrophysiology performed on NPY hrGFP or POMC eGFP mice. RESULTS: Here we show DNP-induced differential effects on melanocortin neurons including inhibiting orexigenic NPY and activating anorexigenic POMC neurons through independent ionic mechanisms coupled to mitochondrial function, consistent with an anorexigenic central effect. Central administration of DNP induced weight-loss, increased BAT thermogenesis and browning of white adipose tissue, and decreased food intake, effects that were absent in MC4R knock-out mice and blocked by the MC4R antagonist, AgRP. CONCLUSION: These data show a novel central anti-obesity mechanism of action of DNP and highlight the potential for selective melanocortin mitochondrial uncoupling to target metabolic disorders.
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DNP can affect melanocortin-secreting neuron activity by inhibiting orexigenic NPY and activating anorexigenic POMC neurons.
“For instance, DNP can affect melanocortin-secreting neuron activity by inhibiting orexigenic NPY (Neuropeptide Y) and activating anorexigenic POMC (Proopiomelanocortin) neurons [270].”
From Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases (2019) · cites this paper as [270]
The DNP effect requires, at least partially, the melanocortin-4 receptor (MC4R).
“The DNP effect requires, at least partially, the melanocortin-4 receptor (MC4R) as observed in C57BL/6 MC4R KO mice [270].”
From Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases (2019) · cites this paper as [270]
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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
- Michael, N. J., Simonds, S. E., van den Top, M., Cowley, M. A., & Spanswick, D.
- Affiliations
- Monash University (AU)
- University of Warwick (GB)
- Corresponding author
- Spanswick, David
- Venue
- Molecular Metabolism
- Publisher
- Elsevier BV
- Published
- 2017-10
- Volume
- 6
- Issue
- 10
- Pages
- 1103-1112
- ISSN
- 2212-8778 (ISSN-L)
- PMC
- PMC5641603
- OpenAlex
- W2727527593
- Cited by
- 21
- References
- 51
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 1 · 2023: 3 · 2022: 2 · 2021: 3 · 2020: 1 · 2019: 1 · 2018: 3
- FWCI
- 0.84
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Metabolism (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Monash University Research Portal (Monash University) (acceptedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Warwick Research Archive Portal (University of Warwick) (submittedVersion)
- Funders
- National Health and Medical Research Council (NHMRC) (APP1063955, APP1084600, APP1079422, APP1065641)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Pharmacology › Pharmacology and Obesity Treatment
- Keywords
- mitochondrial uncoupling, 2,4-dinitrophenol, melanocortin system, NPY neurons, POMC neurons, agouti-related protein, melanocortin-4 receptor, hypothalamus, dietary intake, energy expenditure, brown adipose tissue thermogenesis, white adipose tissue browning, weight loss, anti-obesity mechanisms, ionic mechanism
- MeSH terms
- Uncoupling Protein 1, Animals, Body Weight, Adipose Tissue, Brown, Eating, Energy Metabolism, Male, Mice, Inbred C57BL, Mitochondria, Neurons, Neuropeptide Y, Obesity, Pro-Opiomelanocortin, Weight Loss, Mice, Knockout, 2,4-Dinitrophenol, Thermogenesis, Receptors, Melanocortin, Receptor, Melanocortin, Type 4, Mice, Melanocortins
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