HDAC3 inhibition protects against peripheral and central alterations in an animal model of obesity
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Franciéle Romero Machado1, Silvana Peterini Boeira1, Vandreza Cardoso Bortolotto1
1Laboratory of Pharmacological and Toxicological Evaluations Applied to Bioactive Molecules, LaftamBio Pampa, Federal University of Pampa, Campus Itaqui, Itaqui, RS, 97650-000, Brazil.
Background:
Obesity is a multifactorial disease with epigenetic manifestations that increases the prevalence of associated comorbidities such as metabolic syndrome, cardiovascular dysfunction, and major depression disorder. Given the aforementioned, a search for new pharmacological alternatives for the treatment of this disease is necessary. The current study aimed to evaluate the effects of histone deacetylase-3 (HDAC3) inhibition caused by RGFP966 (a benzamide-type HDAC inhibitor selective for HDAC3) administration, in an animal model of obesity induced by high-fat diet (HFD).
Methods:
Adult male mice C57BJ/6 were fed with a normal pellet diet (NPD) or HFD for 120 days. The HDAC3 inhibitor (RGFP966; 10 mg/kg; sc) was administered on the 91st to 120th day of the experiment (per 30 days). After the last inhibitor administration, animals were euthanized, blood was collected, and the hippocampus was removed for biochemical determinations.
Results:
In an overall manner, the administration of RGFP966 protected against changes in body weight gain, glucose, insulin, lipid profile, adipokines, and increase of hippocampal proinflammatory cytokines levels caused by HFD.
Conclusion:
Therefore, HDAC3 inhibition can represent a promising pharmacological target for the treatment of obesity.
Insights
Histone deacetylase-3 (HDAC3) inhibition using RGFP966 prevented weight gain and metabolic dysfunction in a high-fat diet obesity model. This suggests HDAC3 is a promising target for obesity treatment.
Area of Science:
- Pharmacology
- Epigenetics
- Metabolic Research
Background:
- Obesity is a complex disease with epigenetic factors contributing to comorbidities like metabolic syndrome and depression.
- Novel pharmacological treatments are needed to address the rising prevalence of obesity.
- This study investigates the role of histone deacetylase-3 (HDAC3) in diet-induced obesity.
Purpose of the Study:
- To evaluate the therapeutic effects of inhibiting HDAC3 with RGFP966 in a high-fat diet (HFD) induced obesity mouse model.
- To assess the impact of HDAC3 inhibition on metabolic parameters and neuroinflammation.
Main Methods:
- Adult male C57BJ/6 mice were fed a normal pellet diet (NPD) or HFD for 120 days.
- The HDAC3 inhibitor RGFP966 (10 mg/kg) was administered subcutaneously from day 91 to 120.
- Biochemical analyses of blood and hippocampus were performed post-treatment.
Main Results:
- RGFP966 administration significantly protected against HFD-induced increases in body weight gain.
- The inhibitor mitigated adverse changes in glucose, insulin, and lipid profiles.
- RGFP966 reduced HFD-induced increases in hippocampal proinflammatory cytokines and normalized adipokines.
Conclusions:
- HDAC3 inhibition demonstrates a protective effect against diet-induced obesity and associated metabolic disturbances.
- Targeting HDAC3 represents a potential pharmacological strategy for obesity treatment.
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