Deciphering the function of sesaminol as an anti-obesity and anti-MAFLD molecule

Abstract

Obesity and its associated metabolic diseases, including type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) or metabolic dysfunction-associated liver disease (MAFLD), pose significant global health challenges. Adipocytes are key players in maintaining energy homeostasis and are classified into two different categories: white and brown adipocytes. While white adipocytes store energy as triacylglycerols in lipid droplets, brown adipocytes combust excess chemical energy and release it in the form of heat through uncoupled respiration. The unique properties of brown fat have drawn the attention of researchers and pharmaceutical industries, making it a promising target for treating obesity and related metabolic diseases. In this context, we screened and identified Sesaminol (SML), a lignan derived from sesame seeds, as a brown fat inducer. In the first part of our study, we investigated the effect of Sesaminol, a small molecule, on brown fat activity. We found that it induced the thermogenic program in mice. Administration of SML to mice challenged with high-fat diet (HFD) decreased weight gain, adiposity, and blood glucose levels in vivo by activating the thermogenic program in brown and white adipose depots. Mechanistically, SML repressed the myogenic gene program in C2C12 myoblasts and reprogrammed myoblast into brown adipose cells. In the second part of our study, we delved into the metabolic action of SML in obesity-induced MAFLD. Our findings suggested that SML administration induced OXPHOS proteins and mitochondrial function in the liver. Furthermore, our data showed that SML treatment reduced hepatic triacylglycerol accumulation and LDL-C levels. Notably, lipidomics analyses revealed that SML administration remodeled major phospholipids such as PC, PE, PI, CL, and PS to maintain membrane lipid homeostasis in the liver upon HFD challenge. Additionally, SML treatment reduced anti-inflammatory properties and fibrosis markers in the liver. Remarkably, SML lowered the hepatic levels of ALT and AST enzymes and alleviated MAFLD in diet-induced obese mice. In conclusion, our study demonstrated that Sesaminol is a potential small molecule that improved metabolic parameters and alleviated obesity-induced fatty liver disease in mice.