ArticleMolecular medicine (Cambridge, Mass.)2023
Microglia Sirt6 modulates the transcriptional activity of NRF2 to ameliorate high-fat diet-induced obesity.
Article in Molecular medicine (Cambridge, Mass.), 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 18 citations in OpenAlex.
- Obesity, Oxidative Stress, and Inflammation in Precocious Puberty: Do All Roads Lead to the Hypothalamus?International journal of molecular sciences · 2026Review
- Obesity-associated unfolded protein response, oxidative stress, and NRF2 signaling.International journal of obesity (2005) · 2026Review
- Microglial Feimin Alleviates Cognitive Impairment in High-Fat Diet-Fed Mice.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Anti-Metabolic Dysfunction-Associated Hepatic Steatosis Effects of Pickering Emulsion-Encapsulated Curcumin via Gut Microbiota and Short-Chain Fatty Acids Modulation in High-Fat-Diet Mice.Foods (Basel, Switzerland) · 2025Article
- Sirtuins as Therapeutic Targets for Treating Cancer, Metabolic Diseases, and Neurodegenerative Diseases.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Review
- Neuronutrition and Nrf2 Brain Resilience Signaling: Epigenomics and Metabolomics for Personalized Medicine in Nervous System Disorders from Bench to Clinic.International journal of molecular sciences · 2025Review
- SIRT7-mediated NRF2 deacetylation promotes antioxidant response and protects against chemodrug-induced liver injury.Cell death & disease · 2025Article
- SIRT6 modulates lesion microenvironment in LPC induced demyelination by targeting astrocytic CHI3L1.Journal of neuroinflammation · 2024Article
- ALKBH5 regulates chicken adipogenesis by mediating LCAT mRNA stability depending on mBMC genomics · 2024Article
- Metabolic mechanisms orchestrated by Sirtuin family to modulate inflammatory responses.Frontiers in immunology · 2024Review
- SIRT6 signaling as an underexplored mechanistic node in nanoformulation-based neuroinflammation therapy for Alzheimer's disease.Alzheimer's & dementia (New York, N. Y.)Article
Corrections and comments
- Erratum issued
Authors and funding
10 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundMicroglia play a pivotal role in neuroinflammation, while obesity triggers hypothalamic microglia activation and inflammation. Sirt6 is an important regulator of energy metabolism in many peripheral tissues and hypothalamic anorexic neurons. However, the exact mechanism for microglia Sirt6 in controlling high-fat diet-induced obesity remain unknown.
methodsMicroglia Sirt6 expression levels under various nutritional conditions were measured in the hypothalamus of mice. Also, microglia Sirt6-deficient mice were provided various diets to monitor metabolic changes and hypothalamic inflammatory response. Besides, RNA-seq and Co-IP of microglia with Sirt6 alterations were conducted to further investigate the detailed mechanism by which Sirt6 modulated microglia activity.
resultsWe found that Sirt6 was downregulated in hypothalamic microglia in mice given a high-fat diet (HFD). Additionally, knockout of microglia Sirt6 exacerbated high-fat diet-induced hypothalamic microglial activation and inflammation. As a result, mice were more prone to obesity, exhibiting a decrease in energy expenditure, impaired glucose tolerance, insulin and leptin resistance, and increased food intake. In vitro, Sirt6 overexpression in BV2 cells displayed protective effects against oleic acid and palmitic acid treatment-derived inflammatory response. Mechanically, Sirt6 deacetylated and stabilised NRF2 to increase the expression of anti-oxidative genes and defend against reactive oxygen species overload. Pharmacological inhibition of NRF2 eliminated the beneficial modulating effects of Sirt6 on microglial activity.
conclusionCollectively, our results revealed that microglial Sirt6 was a primary contributor of microglial activation in the central regulation of obesity. Thus, microglial Sirt6 may be an important therapeutic target for obesity.
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