Panax notoginseng saponins modulate the gut microbiota to promote thermogenesis and beige adipocyte reconstruction via leptin-mediated AMPKα/STAT3 signaling in diet-induced obesity

Abstract

Background: Activation of the thermogenic program in white and brown adipocytes presents a promising avenue for increasing energy expenditure during the treatment of obesity. The endogenous mechanism for promoting thermogenesis in brown adipocytes or browning in white adipocytes has indicated that the gut microbiota is a crucial regulator of the host energy balance. However, whether the effects of the therapeutic intervention-induced modulation of the gut microbiota on adipocyte browning involved the regulation of leptin remains unclear. Method: The adipose features were analyzed by body composition analysis, infrared camera observations, transmission electron microscopy and H&E staining. The gene and protein expression in adipose tissue were detected by qRT-PCR, immunoblotting, immunohistochemistry and immunofluorescence staining. The gut microbiome signature was identified by 16S rRNA gene amplicon sequencing, and both mice with high-fat diet-induced obesity (DIO) and mice with antibiotics-induced microbiome depletion were subjected to fecal microbiota transplantation. Results: Treatment with Panax notoginseng saponins (PNS) shaped the murine gut microbiome by increasing the abundances of Akkermansia muciniphila and Parabacteroides distasonis , and as a result, DIO mice harbored a distal gut microbiota with a significantly increased capacity to reduce host adiposity. The PNS-induced modulation of the gut microbiota in DIO mice could increase brown adipose tissue (BAT) thermogenesis and beige adipocyte reconstruction by activating the leptin-AMPK/STAT3 signaling pathway, which results in the promotion of energy expenditure. Leptin has an essential influence on the anti-obesity effects of PNS. In cases of leptin deficiency, the PNS-induced modulation of the gut microbiota exerts negative effects on thermogenesis and browning in white adipose tissue (WAT), which indicates that PNS fail to reduce obesity in leptin gene-deficient mice. The PNS-induced modulation of the gut microbiota exerted a minimal effect on DIO mice with antibiotic-induced microbiome depletion, which confirmed the correlation between altered gut microbiota and the remodeling of adipose tissues in DIO mice. The direct influence of leptin on browning via the AMPKα/STAT3 signaling pathway in C3H101/2 cells supported our in vivo results that signalling through the leptin-AMPK/STAT3 pathway induced by the PNS-modulated gut microbiota was involved in beige adipocyte reconstruction. Conclusion : Our results revealed that leptin signaling is critical for alterations in microbiota-fat crosstalk and provide promising avenues for therapeutic intervention in the treatment of obesity.

Bifidobacterium adolescentis Isolated from Different Hosts Modifies the Intestinal Microbiota and Displays Differential Metabolic and Immunomodulatory Properties in Mice Fed a High-Fat Diet

“…Parabacteroides is a commensal bacterium in the gut that is negatively related to obesity [ 42 , 43 , 44 , 45 ] and plays a role in anti-inflammatory processes [ 46 , 47 ]. Treatment with Parabacteroides distasonis has been reported to ameliorate metabolic dysfunction and alleviate obesity in HFD-fed mice [ 48 ].…”

MiR-22 modulates brown adipocyte thermogenesis by synergistically activating the glycolytic and mTORC1 signaling pathways

“…Notably, increasing evidence indicates that adult humans also possess Ucp1-positive BAT 4 , 5 , which contributes to metabolic homeostasis. Such findings have uncovered a viable therapeutic strategy, where these cells are exploited to treat obesity and diabetes 6 , 7 . Thus, understanding the regulatory mechanism that drives BAT thermogenic activity now has clinical implications.…”

Effect of Panax notoginseng Saponins and Major Anti-Obesity Components on Weight Loss

“…Interestingly, acute intraperitoneal injection of Rb1 activates the PI3K/Akt signaling pathway through the expression of c-FOS in brain regions involved in energy homeostasis, and inhibits the expression of NPY gene in the hypothalamus, thereby reducing appetite and food intake, body weight, and body fat content and increasing energy consumption ( Xiong et al, 2010 ; Park H. J. et al, 2019 ). Xu et al also found that PNS-induced regulation of intestinal flora in DIO mice can increase BAT thermogenesis and beige adipocyte reconstruction by activating the leptin-AMPK/STAT3 signaling pathway thus promoting energy consumption ( Xu et al, 2020 ).…”