Microglia Sirt6 modulates the transcriptional activity of NRF2 to ameliorate high-fat diet-induced obesity.

BACKGROUND: Microglia 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. METHODS: Microglia 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. RESULTS: We 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. CONCLUSION: Collectively, 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.

Harnessing the Therapeutic Potential of Ginsenoside Rd for Activating SIRT6 in Treating a Mouse Model of Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is a prevalent global condition and a common precursor to liver cancer, yet there is currently no specific medication available for its treatment. Ginseng, renowned for its medicinal and dietary properties, has been utilized in NAFLD management, although the precise underlying mechanism remains elusive. To investigate the effectiveness of ginsenoside Rd, we employed mouse and cell models to induce NAFLD using high-fat diets, oleic acid, and palmitic acid. We explored and confirmed the specific mechanism of ginsenoside Rd-induced hepatic steatosis through experiments involving mice with a liver-specific knockout of SIRT6, a crucial protein involved in metabolic regulation. Our findings revealed that administration of ginsenoside Rd significantly reduced the inflammatory response, reactive oxygen species (ROS) levels, lipid peroxide levels, and mitochondrial stress induced by oleic acid and palmitic acid in primary hepatocytes, thereby mitigating excessive lipid accumulation. Moreover, ginsenoside Rd administration effectively enhanced the mRNA content of key proteins involved in fatty acid oxidation, with a particular emphasis on SIRT6 and its target proteins. We further validated that ginsenoside Rd directly binds to SIRT6, augmenting its deacetylase activity. Notably, we made a significant observation that the protective effect of ginsenoside Rd against hepatic disorders induced by a fatty diet was almost entirely reversed in mice with a liver-specific SIRT6 knockout. Our findings highlight the potential therapeutic impact of Ginsenoside Rd in NAFLD treatment by activating SIRT6. These results warrant further investigation into the development of Ginsenoside Rd as a promising agent for managing this prevalent liver disease.

Emodin palliates high-fat diet-induced nonalcoholic fatty liver disease in mice via activating the farnesoid X receptor pathway.

BACKGROUND: Cassia mimosoides Linn (CMD) is a traditional Chinese herb that clears liver heat and dampness. It has been widely administered in clinical practice to treat jaundice associated with damp-heat pathogen and obesity. Emodin (EMO) is a major bioactive constituent of CMD that has apparent therapeutic efficacy against obesity and fatty liver. Here, we investigated the protective effects and underlying mechanisms of EMO against high-fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD). OBJECTIVE: We aimed to investigate whether EMO activates farnesoid X receptor (FXR) signaling to alleviate HFD-induced NAFLD. MATERIALS AND METHODS: In vivo assays included serum biochemical indices tests, histopathology, western blotting, and qRT-PCR to evaluate the effects of EMO on glucose and lipid metabolism disorders in wild type (WT) and FXR knockout mice maintained on an HFD. In vitro experiments included intracellular triglyceride (TG) level measurement and Oil Red O staining to assess the capacity of EMO to remove lipids induced by oleic acid and palmitic acid in WT and FXR knockout mouse primary hepatocytes (MPHs). We also detected mRNA expression of FXR signaling genes in MPHs. RESULTS: After HFD administration, body weight and serum lipid and inflammation levels were dramatically increased in the WT mice. The animals also presented with impaired glucose tolerance, insulin resistance, and antioxidant capacity, liver tissue attenuation, and pathological injury. EMO remarkably reversed the foregoing changes in HFD-induced mice. EMO improved HFD-induced lipid accumulation, insulin resistance, inflammation, and oxidative stress in a dose-dependent manner in WT mice by inhibiting FXR expression. EMO also significantly repressed TG hyperaccumulation by upregulating FXR expression in MPHs. However, it did not improve lipid accumulation, insulin sensitivity, or glucose tolerance in HFD-fed FXR knockout mice. CONCLUSIONS: The present study demonstrated that EMO alleviates HFD-induced NAFLD by activating FXR signaling which improves lipid accumulation, insulin resistance, inflammation, and oxidative stress.