Preclinical and Clinical Evidence for a Distinct Regulation of Mu Opioid and Type 1 Cannabinoid Receptor Genes Expression in Obesity
Open accessAbstract
Among endogenous signaling networks involved in both rewarding and homeostatic mechanisms of obesity, a relevant role is played by the endocannabinoid (ECS) and the opioid (EOS) systems. We here studied the transcriptional regulation of ECS and EOS genes in the hypothalamus of Diet-induced obesity (DIO) rats, a preclinical model of obesity, as well as in humans with obesity and healthy controls. A significant and selective increase in type 1 cannabinoid receptor gene (Cnr1) expression was observed at the beginning of obesity development (5 weeks on high fat diet) as well as after 21 weeks of high diet exposure. After 5 weeks on high fat diet, selective up-regulation of mu opioid receptor gene (Oprm1) expression was also observed. Consistently, epigenetic studies showed a selective and significant decrease in DNA methylation at specific CpG sites at both gene promoters in overweight rats, but only after 5 weeks on high fat diet. Moreover, significantly lower levels of DNA methylation were observed at selected CpG sites of both receptor gene promoters, analyzed in peripheral blood mononuclear cells from younger (< 30 year old) humans with obesity, as well as in those with shorter time length from disease onset. Taken together, we here provide evidence of selective, synergistic and time-dependent transcriptional regulation of CNR1 and OPRM1 genes in overweight rats, as well as in human subjects. These alterations in genes regulation could contribute to the development of the obese phenotype, and we thus suggest CNR1 and OPRM1 epigenetic modulation as possible biomarkers of obesity development. Due to the reversible nature of the epigenetic hallmark, our data might also open new avenue to early environmental strategies of intervention.
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Methylation at the mu-opioid receptor (MOR) gene is most strongly associated with drug addiction as well as incentive motivation for processed food.
“While methylation at the mu-opioid receptor (MOR) gene is most strongly associated with drug addiction [144] as well as incentive motivation for processed food [145,146], decreased methylation at the kappa-opioid receptor (KOR) in the anterior insula has been shown in child abuse [147] (discussed further in Section 4.1).”
From Food Addiction and Psychosocial Adversity: Biological Embedding, Contextual Factors, and Public Health Implications (2020) · cites this paper as [146]
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- Authors
- Pucci, M., Micioni Di Bonaventura, M. V., Vezzoli, V., Zaplatic, E., Massimini, M., Mai, S., Sartorio, A., Scacchi, M., Persani, L., Maccarrone, M., Cifani, C., & D’Addario, C.
- Affiliations
- University of Teramo (IT)
- IRCCS Istituto Auxologico Italiano (IT)
- University of Milan (IT)
- Università Campus Bio-Medico (IT)
- Università di Camerino (IT)
- Corresponding author
- Cifani, Carlo
- D’Addario, Claudio
- ORCID
- Venue
- Frontiers in Genetics
- Publisher
- Frontiers Media SA
- Published
- 2019-06-14
- Volume
- 10
- Pages
- 523-523
- ISSN
- 1664-8021 (ISSN-L)
- PMC
- PMC6588048
- OpenAlex
- W2945140532
- Cited by
- 38
- References
- 85
- Citations by year
- 2025: 4 · 2024: 4 · 2023: 5 · 2022: 8 · 2021: 5 · 2020: 12
- FWCI
- 3.87
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
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- Frontiers in Genetics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, cc-by)
- Archivio Istituzionale della Ricerca - Università degli Studi dell Aquila (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Unicam Scientific Publications (University of Camerino) (submittedVersion, other-oa)
- UniTERAMO Research Catalog (University of Teramo) (submittedVersion, cc-by-nc-nd)
- Funders
- Ministero della Salute
- Horizon 2020 Framework Programme (713714)
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- obesity, mu-opioid receptor, cannabinoid type 1 receptor, CNR1, OPRM1, endocannabinoid system, opioid system, DNA methylation, epigenetic regulation, hypothalamus, high-fat diet, diet-induced obesity, gene expression, obesity biomarkers, peripheral blood mononuclear cells
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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