Saikosaponin D ameliorates obesity and metabolic disorders via the gut microbiota-SCFAs-thermogenic fat axis

Abstract

Activating thermogenic programs in brown adipose tissue (BAT) represents promising approaches to combat obesity through dissipating energy. Saikosaponin D (Sa-D), a major triterpenoid saponin derived from Radix bupleuri (a traditional herbal product) could ameliorate obesity. Here, our results showed that Sa-D treatment for 12 weeks significantly suppressed weight gain and improved glycolipid abnormalities in high-fat-diet (HFD)-fed mice. Importantly, Sa-D treatment increased the expression of uncoupling protein 1 (UCP1) along with other thermogenic factors, as well as enhanced phosphorylation of PKA, AMPK, and p38 in BAT and inguinal white adipose tissue (iWAT). 16S rRNA sequence analysis revealed that Sa-D restored HFD-induced microbial dysbiosis and specific bacterial genera such as unidentified_Lachnospiraceae, Tyzzerella, Romboutsia, Bilophila, Oscillibacter, Sphingomonas, and Companilactobacillus were strongly associated with obesity-related traits and brown/beige-related markers. Moreover, Sa-D markedly increased the concentration of short-chain fatty acids (SCFAs), induced gene expression of SCFAs-producing enzymes (acetate kinase (Ack), methylmalonyl-CoA decarboxylase (Mcd), butyryl-CoA (BCoA) and propionaldehyde dehydrogenase (PduP)), and upregulated expression of SCFAs receptors (Ffar3, Ffar2, or Hcar2) in colon, iWAT, and BAT. Collectively, our findings revealed that Sa-D could ameliorate obesity by activating thermogenic fat, which may be associated with the alteration in microflora profiles and increased SCFAs levels.