期刊
NATURE METABOLISM
卷 3, 期 5, 页码 595-+出版社
NATURE RESEARCH
DOI: 10.1038/s42255-021-00398-4
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资金
- NIDDK NIH HHS [R01 DK097566] Funding Source: Medline
- Swiss National Science Foundation [189178, 180317] Funding Source: Medline
Bile acids can reach the brain and activate a negative-feedback loop through TGR5, controlling satiety in response to physiological feeding.
Bile acids (BAs) are signalling molecules that mediate various cellular responses in both physiological and pathological processes. Several studies report that BAs can be detected in the brain(1), yet their physiological role in the central nervous system is still largely unknown. Here we show that postprandial BAs can reach the brain and activate a negative-feedback loop controlling satiety in response to physiological feeding via TGR5, a G-protein-coupled receptor activated by multiple conjugated and unconjugated BAs2 and an established regulator of peripheral metabolism(3-8). Notably, peripheral or central administration of a BA mix or a TGR5-specific BA mimetic (INT-777) exerted an anorexigenic effect in wild-type mice, while whole-body, neuron-specific or agouti-related peptide neuronal TGR5 deletion caused a significant increase in food intake. Accordingly, orexigenic peptide expression and secretion were reduced after short-term TGR5 activation. In vitro studies demonstrated that activation of the Rho-ROCK-actin-remodelling pathway decreases orexigenic agouti-related peptide/neuropeptide Y (AgRP/NPY) release in a TGR5-dependent manner. Taken together, these data identify a signalling cascade by which BAs exert acute effects at the transition between fasting and feeding and prime the switch towards satiety, unveiling a previously unrecognized role of physiological feedback mediated by BAs in the central nervous system. Bile acids are shown to enter the brain and regulate short-term reductions in food intake after a meal by inhibiting neuropeptide release from agouti-related peptide/neuropeptide Y neurons.
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