1. The short-chain fatty acid acetate modulates orexin/hypocretin neurons: A novel mechanism in gut-brain axis regulation of energy homeostasis and feeding.
- Author
-
Forte N, Marfella B, Nicois A, Palomba L, Paris D, Motta A, Pina Mollica M, Di Marzo V, and Cristino L
- Subjects
- Animals, Mice, Male, Mice, Inbred C57BL, Mice, Knockout, Fatty Acids, Volatile metabolism, Fatty Acids, Volatile pharmacology, Eating drug effects, Eating physiology, Hypothalamus metabolism, Hypothalamus drug effects, Feeding Behavior drug effects, Feeding Behavior physiology, Orexins metabolism, Neurons metabolism, Neurons drug effects, Homeostasis drug effects, Homeostasis physiology, Energy Metabolism drug effects, Energy Metabolism physiology, Acetates pharmacology, Acetates metabolism, Brain-Gut Axis drug effects, Brain-Gut Axis physiology
- Abstract
The short-chain fatty acids (SCFAs) acetate, propionate and butyrate, the major products of intestinal microbial fermentation of dietary fibres, are involved in fine-tuning brain functions via the gut-brain axis. However, the effects of SCFAs in the hypothalamic neuronal network regulating several autonomic-brain functions are still unknown. Using NMR spectroscopy, we detected a reduction in brain acetate concentrations in the hypothalamus of obese leptin knockout ob/ob mice compared to lean wild-type littermates. Therefore, we investigated the effect of acetate on orexin/hypocretin neurons (hereafter referred as OX or OX-A neurons), a subset of hypothalamic neurons regulating energy homeostasis, which we have characterized in previous studies to be over-activated by the lack of leptin and enhancement of endocannabinoid tone in the hypothalamus of ob/ob mice. We found that acetate reduces food-intake in concomitance with a reduction of orexin neuronal activity in ob/ob mice. This was demonstrated by evaluating food-intake behaviour and orexin-A/c-FOS immunoreactivity coupled with patch-clamp recordings in Hcrt-eGFP neurons, quantification of prepro-orexin mRNA, and immunolabeling of GPR-43, the main acetate receptor. Our data provide new insights into the mechanisms of the effects of chronic dietary supplementation with acetate, or complex carbohydrates, on energy intake and body weight, which may be partly mediated by inhibition of orexinergic neuron activity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF