Obesity causes various complications such as type 2 diabetes, hypertension, fatty liver, cardiovascular diseases, and cancer. In a pilot GWAS study, we screened the DNAJC6 gene which is significantly related to the resting metabolic rate (RMR) in childhood obesity. With DNAJC6-overexpressed 3T3-L1 cells (TgHsp), we investigated the new obesity mechanism caused by an energy imbalance. After differentiation, lipid droplets (Oil red O staining) were not formed in TgHsp cells compared to the control. TgHsp preadipocyte fibroblast morphology was also not clearly observed in the cell morphology assay (DAPI/BODIPY). In TgHsp cells, the expression of PPARγ, C/EBPα, and aP2 (adipogenesis-related biomarkers) decreased 3-, 39-, and 200-fold, respectively. The expression of the adipokines leptin and adiponectin from adipose tissues also decreased 2.4- and 840-fold, respectively. In addition, the levels of pHSL(Ser563) and free glycerol, which are involved in lipolysis, were significantly lower in TgHsp cells than in the control. The reduction in insulin receptor expression in TgHsp cells suppressed insulin signaling systems such as AKT phosphorylation, and GLUT4 expression. Degradation of IRS-1 in 3T3-L1 adipocytes was caused by chronic exposure to insulin, but not TgHsp. Mitochondrial functions such as oxygen consumption and ATP production, as well as proton leak and UCP1 protein expression, decreased in TgHsp cells compared to the control. Moreover, autophagy was observed by increasing autophagosomal proteins, LC3, on Day 8 of differentiation in TgHsp cells. Through our first report on the DNAJC6 gene related to RMR, we found a new mechanism related to energy metabolism in obesity. DNAJC6 expression positively suppressed adipogenesis, leading to the subsequent resistance of lipolysis, adipokine expression, insulin signaling, and mitochondrial functions.

Background: Chronic hepatitis B virus (HBV) infection is associated with a reduced risk of dyslipidaemia. Using a human faecal transplant mouse model, we compared changes in gut microbiota and lipid profiles in mice transplanted with human faeces from HBV-infected and non-infected individuals. Methods: A total of 19 mice received human faecal microbiota transplantation (FMT) from four HBV-infected individuals and were categorised into the HBV-positive mice group, while 20 mice received FMT from four HBV-non-infected individuals and were categorised into the HBV-negative mice group. Serial changes in the gut microbiota and lipid levels were compared between the two subgroups during 6 weeks of post-FMT period. Results: In the analysis of gut microbiota in FMT mice, we observed a robust increase in alpha diversity and abundance of taxa related to lipid metabolism, including Akkermansia muciniphila in HBV-positive mice, compared to that in HBV-negative mice. Functional inference analysis revealed that the pathways involved in glycerolipid metabolism were more enriched in HBV-positive mice. At 5 weeks of post-FMT, the reduced triglyceride (TG) level was predominantly observed in HBV-positive mice, compared to that in HBV-negative mice. Conclusions: In the experimental FMT mouse model, we found that altered gut microbiota accompanied by HBV infection was associated with a robust increase in alpha diversity and butyrate producers, which resulted in areduced level of TG at 5 weeks post-FMT. This indicates that the reduced risk of dyslipidaemia in chronic HBV infection may be due to the altered gut microbiota accompanied by HBV infection.