Previous studies suggested that fecal short-chain fatty acids (SCFAs) and branched short-chain fatty acids (BCFAs) are associated with glucose regulation. However, the potential relationship between circulating SCFAs and BCFAs with incident diabetes risk in both men and women remains unidentified in prospective cohort studies. In this study, we examined a panel of nine serum SCFAs and BCFAs in 3414 subjects with incident diabetes, and matched normoglycemic controls from the China Cardiometabolic Disease and Cancer Cohort study. In fully adjusted conditional logistic regression models, total SCFAs, total BCFAs, and isovaleric acid were significantly associated with incident type 2 diabetes mellitus (T2DM) (P < 0.05). Interestingly, gender-specific analysis showed that per standard deviation (SD) increment of SCFAs were positively associated with incident T2DM among women, with the odds ratio (95% confidence interval) of 1.16 (1.05–1.29) for total SCFAs and 1.18 (1.07–1.31) for propionate, respectively (P < 0.05, false discovery rate (FDR) < 0.05). No significant associations were observed in men. A significant interaction was detected between men and women for propionate (P_interaction < 0.001, FDR < 0.01). After further adjustment of insulin measurements, the associations of serum propionate with diabetes remained significant (P < 0.05, FDR < 0.05). Meanwhile, the associations of total BCFAs and isovaleric acid with diabetes were partially mediated by triglycerides, insulin resistance, and β-cell function in mediation analysis. These findings, for the first time in a large prospective cohort, provide evidence for an association between circulating SCFAs and BCFAs with T2DM risk, and support the potential role of circulating propionate with gender disparities in the early pathogenesis of diabetes.

Platelet hyperreactivity contributes significantly to thrombosis in acute myocardial infarction and stroke. While antiplatelet drugs are used, residual ischemic risk remains. Intermittent fasting (IF), a dietary pattern characterized by alternating periods of eating and fasting, has shown cardiovascular benefits, but its effect on platelet activation is unclear. This study demonstrates that IF inhibits platelet activation and thrombosis in both patients with coronary artery disease and apolipoprotein E (ApoE) knockout (ApoE^−/−) mice, by enhancing intestinal flora production of indole-3-propionic acid (IPA). Mechanistically, elevated IPA in plasma directly attenuates platelet activation by binding to the platelet pregnane X receptor (PXR) and suppressing downstream signaling pathways, including Src/Lyn/Syk and LAT/PLCγ/PKC/Ca²⁺. Importantly, IF alleviates myocardial and cerebral ischemia/reperfusion injury in ApoE^−/− mice. These findings suggest that IF mitigates platelet activation and thrombosis risk in coronary atherosclerosis by enhancing intestinal flora production of IPA, which subsequently activates the platelet PXR-related signaling pathways.

Intestinal farnesoid X receptor (FXR) antagonists have been proven to be efficacious in ameliorating metabolic diseases, particularly for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). All the reported FXR antagonists target to the ligand-binding pocket (LBP) of the receptor, whereas antagonist acting on the non-LBP site of nuclear receptor (NR) is conceived as a promising strategy to discover novel FXR antagonist. Here, we have postulated the hypothesis of antagonizing FXR by disrupting the interaction between FXR and coactivators, and have successfully developed a series of macrocyclic peptides as FXR antagonists based on this premise. The cyclopeptide DC646 not only exhibits potent inhibitory activity of FXR, but also demonstrates a high degree of selectivity towards other NRs. Moreover, cyclopeptide DC646 has high potential therapeutic benefit for the treatment of MASH in an intestinal FXR-dependent manner, along with a commendable safety profile. Mechanistically, distinct from other known FXR antagonists, cyclopeptide DC646 specifically binds to the coactivator binding site of FXR, which can block the coactivator recruitment, reducing the circulation of intestine-derived ceramides to the liver, and promoting the release of glucagon-like peptide-1 (GLP-1). Overall, we identify a novel cyclopeptide that targets FXR-coactivator interaction, paving the way for a new approach to treating MASH with FXR antagonists.

The dietary intervention of calorie restriction (CR) is known to have the most profound effects on healthspan and lifespan across several species. In two recent back-to-back articles published in Nature, Qu et al. [1, 2] revealed that lithocholic acid (LCA), a singular secondary bile acid found to be elevated in the serum of calorie-restricted mice, is sufficient to mimic the effects of CR by delaying the onset of age-associated phenotypes in mice, and promoting lifespan extension in nematodes and flies. The authors showed that the anti-ageing effects of LCA are mediated through a conserved mechanism resulting in the activation of the lysosomal adenosine-monophosphate (AMP)-activated protein kinase (AMPK) pathway through the TUB-like protein 3 (TULP3)-sirtuin (SIRT)-vacuolar H⁺-ATPase (v-ATPase) axis to mediate the benefits of CR.

In the last decade, intermittent fasting (IF) has risen in popularity due to its ability to promote significant weight loss and improve overall cardiometabolic health. In a recent study published in Cell, Chen and colleagues found that fasting-induced lipolysis of dermal adipocytes triggers hair follicle stem cells (HFSCs) to undergo apoptosis, thus inhibiting hair follicle regeneration in both mice and humans (Fig. 1).

Serotonin is one of the most potent gastrointestinal, peripheral, and neuronal signaling molecules and plays a key role in regulating energy metabolism. Accumulating evidence has shown the complex interplay between gut microbiota and host energy metabolism. In this review, we summarize recent findings on the role of gut microbiota in serotonin metabolism and discuss the complicated mechanisms by which serotonin, working in conjunction with the gut microbiota, affects total body energy metabolism in the host. Gut microbiota affects serotonin synthesis, storage, release, transport, and catabolism. In addition, serotonin plays an indispensable role in regulating host energy homeostasis through organ crosstalk and microbe–host communication, particularly with a wide array of serotonergic effects mediated by diverse serotonin receptors with unique tissue specificity. This fresh perspective will help broaden the understanding of serotonergic signaling in modulating energy metabolism, thus shedding light on the design of innovative serotonin-targeting strategies to treat metabolic diseases.