Stimulation of adipose tissue thermogenesis is regarded as a promising avenue in the treatment of obesity. However, pharmacologic engagement of this process has proven difficult. Using the Connectivity Map (CMap) approach, we identified the phytochemical hyperforin (HPF) as an anti-obesity agent. We found that HPF efficiently promoted thermogenesis by stimulating AMPK and PGC-1α via a Ucp1-dependent pathway. Using LiP-SMap (limited proteolysis-mass spectrometry) combined with a microscale thermophoresis assay and molecular docking analysis, we confirmed dihydrolipoamide S-acetyltransferase (Dlat) as a direct molecular target of HPF. Ablation of Dlat significantly attenuated HPF-mediated adipose tissue browning both in vitro and in vivo. Furthermore, genome-wide association study analysis indicated that a variation in DLAT is significantly associated with obesity in humans. These findings suggest that HPF is a promising lead compound in the pursuit of a pharmacological approach to promote energy expenditure in the treatment of obesity.

YY1 transcriptionally represses TGFB1 in mice and may be a potential drug target for treating diabetic nephropathy.

Background: The simultaneous assessment of visceral adiposity and muscle mass might be useful to monitor the risk of non-alcoholic fatty liver disease (NAFLD) progression in large population. We aimed to investigate the value of serum creatinine-to-cystatin C ratio (CCR) in evaluating these two parameters and predicting liver steatosis and fibrosis.Methods: 154 overweight/obese inpatients (49 males, 105 females) scheduled for bariatric surgery and 49 non-overweight/obese volunteers (18 males, 31 females) responded to the hospital advertisement were involved in the cross-sectional study. Liver steatosis and fibrosis were diagnosed with transient elastography (TE). The psoas muscle area (PMA) and visceral fat area (VFA) were measured using magnetic resonance imaging.Results: The body mass index, insulin resistance, and lipid profiles showed significant differences between the CCR tertiles. Multiple regression analyses revealed that the CCR was significantly associated with the controlled attenuation parameter (β = −0.30, P = 0.006 in males; β = −0.19, P = 0.017 in females) and liver stiffness measurements in males (β = −0.246, P = 0.044). A low CCR was associated with moderate-to-severe steatosis (P < 0.001), significant liver fibrosis (P < 0.01), and excellent predictive power for these two conditions (P < 0.01). The CCR had a negative correlation with the VFA/PMA ratio (r = −0.584, P < 0.001 in males; r = −0.569, P < 0.001 in females).Conclusions: The CCR is a serum marker for muscle-adjusted visceral fat mass, and a low CCR is associated with an increased risk of progressive NAFLD.