Vertical sleeve gastrectomy-derived gut metabolite licoricidin activates beige fat thermogenesis to combat obesity

Abstract

Obesity is a chronic metabolic disease, affecting individuals throughout the world. Bariatric surgery such as vertical sleeve gastrectomy (VSG) provides sustained weight loss and improves glucose homeostasis in obese mice and humans. However, the precise underlying mechanisms remain elusive. In this study, we investigated the potential roles and the mechanisms of action of gut metabolites in VSG-induced anti-obesity effect and metabolic improvement. Methods: High-fat diet (HFD)-fed C57BL/6J mice were subjected to VSG. Energy dissipation in mice was monitored using metabolic cage experiments. The effects of VSG on gut microbiota and metabolites were determined by 16S rRNA sequencing and metabolomics, respectively. The metabolic beneficial effects of the identified gut metabolites were examined in mice by both oral administration and fat pad injection of the metabolites. Results: VSG in mice greatly increased thermogenic gene expression in beige fat, which was correlated with increased energy expenditure. VSG reshaped gut microbiota composition, resulting in elevated levels of gut metabolites including licoricidin. Licoricidin treatment promoted thermogenic gene expression in beige fat by activating the Adrb3-cAMP-PKA signaling pathway, leading to reduced body weight gain in HFD-fed mice. Conclusions: We identify licoricidin, which mediates the crosstalk between gut and adipose tissue in mice, as a VSG-provoked anti-obesity metabolite. Identification of anti-obesity small molecules should provide new insights into treatment options for obesity and its associated metabolic diseases.

The association between Chinese visceral adiposity index and cardiometabolic multimorbidity among Chinese middle-aged and older adults: a national cohort study

“…Evidences from basic biological research and observational studies have identified poor socioeconomic factors (e.g., low income, low education, and a single civil status), unhealthy lifestyles (e.g., smoking, alcohol consumption, and unhealthy diet), and gut metabolite as important factors related to cardiometabolic multimorbidity (11)(12)(13)(14)(15)(16). Additionally, studies have explored the association between body measures, such as grip strength (17).…”

Gut microbiota turn up the heat after bariatric surgery

“…While both gut microbiota and bariatric surgery have been shown to activate thermogenesis in fat [14], their connection has, until recently, not been addressed. Two new studies by Jin et al [15] and Yadav et al [16] now provide causal evidence, using complementary approaches, that VSG and RYGB activate thermogenesis in fat through distinct microbiota-dependent mechanisms, to in turn promote metabolic health.…”

“…In the first study by Jin et al [15] VSG and sham surgery were performed on diet-induced obese mice. The authors found that VSG-operated mice displayed reduced body weight associated with increased oxygen consumption compared with sham-operated mice.…”

“…Jin et al [15] then reasoned that gut microbiota-derived products could mediate the activation of thermogenesis in subcutaneous white fat after VSG. Indeed, the authors could confirm that VSG increased the fecal abundance of Firmicutes and decreased the fecal abundance of Bacteriodetes, associated with stabilization of the intestinal epithelial barrier.…”

“…Next, Jin et al [15] determined if licoricidin given alone via oral gavage can at least recapitulate the metabolic benefits of VSG. Remarkably, licoricidin when admistered via this route prevented body weight gain, improved glycemic control, increased oxygen consumption and increased UCP1 expression in subcutaneous white fat.…”