Peptidoglycan inhibits beigeing of adipose tissue

Abstract Obesity, an epidemic metabolic disease characterized by excessive fat accumulation, causes a significant economic burden on families and the society. The discovery of beige adipocytes has provided us with a brand new approach for the intervention of obesity 1 . Beige adipocytes increase energy expenditure and improve the balance of glucose and lipid metabolism. Reduction of beige adipocytes is a hallmark of obesity. Mechanism underlying the decrement of beigeing remains largely unknown. Intestinal microflora is strongly associated with white adipose tissue beigeing. Removal of intestinal microflora with antibiotic treatment or germ-free mice can effectively promote beigeing of subcutaneous and visceral adipose tissue 2 . However, it is still unclear how the intestinal microflora influences white adipose tissue beigeing. Previous studies have suggested that bacterial products may affect the thermogenesis of white and brown adipose tissue 3 . For example, lipopolysaccharides (LPS) from Gram-negative bacteria have been reported to suppress adaptive thermogenesis 4 . However, studies have shown an increase in the ratio of Gram-positive firmicutes to Gram-negative bacteroidetes 5 . These observations suggest that products of intestinal Gram-positive bacterial may also contribute to modulation of beigeing. Peptidoglycan (PGN) is a unique and essential structural element in the cell wall of Gram-positive bacteria. It is embedded in a relatively thick cell wall with other polymers, such as lipoteichoic acids (LTAs). Our previous study suggests that PGN plays an important role in insulin resistance and metabolic inflammation 6 . Whether PGN affects the beigeing of adipose tissue remains unclear. PGNs from diverse bacteria function through Toll-like receptor (TLR) 2 to activate multiple signaling such as NFκB and JNK. As a critical molecule in innate immune response 7 , TLR2 may be involved in diet-induced metabolic syndrome. TLR2 deficiency improves insulin sensitivity, beta cell dysfunction and hepatic insulin signaling in mice 8 . It remains unclear whether the beneficial effects of TLR2 deficiency occur indirectly by suppressing inflammatory cells in metabolic tissues or directly by acting on parenchymal cells. Here we reported that PGN suppresses the white adipose tissue beigeing. This occurs through induction of inflammation in adipose tissue by promoting macrophage M1 polarization. In addition, PGN directly activates TLR2 receptor on adipocytes to suppress beigeing. Intervention of PGN-TLR2 signaling may thus provide a potential strategy for treatment of obesity.