Gut–brain circuits for fat preference

Nature, Год журнала: 2022, Номер 610(7933), С. 722 - 730

Опубликована: Сен. 7, 2022

Abstract The perception of fat evokes strong appetitive and consummatory responses 1 . Here we show that stimuli can induce behavioural attraction even in the absence a functional taste system 2,3 We demonstrate acts after ingestion via gut–brain axis to drive preference for fat. Using single-cell data, identified vagal neurons responding intestinal delivery fat, showed genetic silencing this gut-to-brain circuit abolished development preference. Next, compared pathways driving versus sugar 4 , uncovered two parallel systems, one functioning as general sensor essential nutrients, stimulation with sugar, amino acids, whereas other is activated only by stimuli. Finally, engineered mice lacking candidate receptors detect presence validated their role mediators fat-evoked responses. Together, these findings reveal distinct cells use fundamental conduit

Язык: Английский

---

Integrative neurocircuits that control metabolism and food intake

Science, Год журнала: 2023, Номер 381(6665)

Опубликована: Сен. 28, 2023

Systemic metabolism has to be constantly adjusted the variance of food intake and even prepared for anticipated changes in nutrient availability. Therefore, brain integrates multiple homeostatic signals with numerous cues that predict future deviations energy supply. Recently, our understanding neural pathways underlying these regulatory principles-as well as their convergence hypothalamus key coordinator intake, expenditure, glucose metabolism-have been revealed. These advances have changed view brain-dependent control metabolic physiology. In this Review, we discuss new concepts about how alterations contribute development prevalent diseases such obesity type 2 diabetes mellitus emerging knowledge may provide targets treatment.

Язык: Английский

---

Multifunctional microelectronic fibers enable wireless modulation of gut and brain neural circuits

Nature Biotechnology, Год журнала: 2023, Номер 42(6), С. 892 - 904

Опубликована: Июнь 22, 2023

Abstract Progress in understanding brain–viscera interoceptive signaling is hindered by a dearth of implantable devices suitable for probing both brain and peripheral organ neurophysiology during behavior. Here we describe multifunctional neural interfaces that combine the scalability mechanical versatility thermally drawn polymer-based fibers with sophistication microelectronic chips organs as diverse gut. Our approach uses meters-long continuous can integrate light sources, electrodes, thermal sensors microfluidic channels miniature footprint. Paired custom-fabricated control modules, wirelessly deliver optogenetics transfer data physiological recording. We validate this technology modulating mesolimbic reward pathway mouse brain. then apply anatomically challenging intestinal lumen demonstrate wireless sensory epithelial cells guide feeding behaviors. Finally, show optogenetic stimulation vagal afferents from sufficient to evoke phenotype untethered mice.

Язык: Английский

---

The intestine as an endocrine organ and the role of gut hormones in metabolic regulation

Nature Reviews Gastroenterology & Hepatology, Год журнала: 2023, Номер 20(12), С. 784 - 796

Опубликована: Авг. 25, 2023

Язык: Английский

---

Cellular mechanisms of incretin hormone secretion

Journal of Molecular Endocrinology, Год журнала: 2024, Номер 72(4)

Опубликована: Янв. 19, 2024

Enteroendocrine cells located along the gastrointestinal epithelium sense different nutrients/luminal contents that trigger secretion of a variety gut hormones with roles in glucose homeostasis and appetite regulation. The incretin glucagon-like peptide-1 (GLP-1) glucose-dependent insulinotropic polypeptide (GIP) are involved regulation insulin secretion, appetite, food intake body weight after their nutrient-induced from gut. GLP-1 mimetics have been developed used treatment type 2 diabetes mellitus obesity. Modulating release endogenous intestinal may be promising approach for obesity without surgery. For reason, current understanding cellular mechanisms underlying hormone will focus this review. controlling depend on nature stimulus, involving signalling pathways including ion channels, nutrient transporters G-protein-coupled receptors.

Язык: Английский

---

Enteroendocrine cell types that drive food reward and aversion

eLife, Год журнала: 2022, Номер 11

Опубликована: Авг. 1, 2022

Animals must learn through experience which foods are nutritious and should be consumed, toxic avoided. Enteroendocrine cells (EECs) the principal chemosensors in GI tract, but investigation of their role behavior has been limited by difficulty selectively targeting these vivo. Here, we describe an intersectional genetic approach for manipulating EEC subtypes behaving mice. We show that multiple inhibit food intake have different effects on learning. Conditioned flavor preference is driven release cholecystokinin whereas conditioned taste aversion mediated serotonin substance P. These positive negative valence signals transmitted vagal spinal afferents, respectively. findings establish a cellular basis how chemosensing gut drives learning about food.

Язык: Английский

---

Sequential appetite suppression by oral and visceral feedback to the brainstem

Nature, Год журнала: 2023, Номер 624(7990), С. 130 - 137

Опубликована: Ноя. 22, 2023

Abstract The termination of a meal is controlled by dedicated neural circuits in the caudal brainstem. A key challenge to understand how these transform sensory signals generated during feeding into dynamic control behaviour. nucleus solitary tract (cNTS) first site brain where many meal-related are sensed and integrated 1–4 , but cNTS processes ingestive feedback behaviour unknown. Here we describe prolactin-releasing hormone (PRLH) GCG neurons, two principal cell types that promote non-aversive satiety, regulated ingestion. PRLH neurons showed sustained activation visceral when nutrients were infused stomach, responses substantially reduced oral consumption. Instead, shifted phasic activity pattern was time-locked ingestion linked taste food. Optogenetic manipulations revealed duration seconds-timescale bursts, revealing mechanism which orosensory feed back restrain pace By contrast, activated mechanical from gut, tracked amount food consumed promoted satiety lasted for tens minutes. These findings reveal sequential negative mouth gut engage distinct brainstem, turn elements operating on short long timescales.

Язык: Английский

---

NK2R control of energy expenditure and feeding to treat metabolic diseases

Nature, Год журнала: 2024, Номер 635(8040), С. 987 - 1000

Опубликована: Ноя. 13, 2024

The combination of decreasing food intake and increasing energy expenditure represents a powerful strategy for counteracting cardiometabolic diseases such as obesity type 2 diabetes1. Yet current pharmacological approaches require conjugation multiple receptor agonists to achieve both effects2–4, so far, no safe energy-expending option has reached the clinic. Here we show that activation neurokinin (NK2R) is sufficient suppress appetite centrally increase peripherally. We focused on NK2R after revealing its genetic links glucose control. However, therapeutically exploiting signalling previously been unattainable because endogenous ligand, A, short-lived lacks specificity5,6. Therefore, developed selective, long-acting with potential once-weekly administration in humans. In mice, these elicit weight loss by inducing non-aversive suppression circumvents canonical leptin signalling. Additionally, hyperinsulinaemic–euglycaemic clamp reveals agonism acutely enhances insulin sensitization. diabetic, obese macaques, significantly decreases body weight, blood glucose, triglycerides cholesterol, ameliorates resistance. These findings identify single target leverages appetite-suppressing programmes improve homeostasis reverse dysfunction across species. mouse nonhuman primate models, treatment aids suppressing expenditure, well sensitivity.

Язык: Английский

---

Stimulating intestinal GIP release reduces food intake and body weight in mice

Molecular Metabolism, Год журнала: 2024, Номер 84, С. 101945 - 101945

Опубликована: Апрель 21, 2024

Glucose dependent insulinotropic polypeptide (GIP) is well established as an incretin hormone, boosting glucose-dependent insulin secretion. However, whilst anorectic actions of its sister-incretin glucagon-like peptide-1 (GLP-1) are established, a physiological role for GIP in appetite regulation controversial, despite the superior weight loss seen preclinical models and humans with GLP-1/GIP dual receptor agonists compared GLP-1R agonism alone. We generated mouse model which expressing K-cells can be activated through hM3Dq Designer Receptor Activated by Drugs (DREADD, GIP-Dq) to explore intestinally-released GIP. In lean mice, Dq-stimulation cells increased plasma levels similar those found postprandially. The increase was associated improved glucose tolerance, expected, but also triggered unexpected robust inhibition food intake. Validating that this represented response GIP, suppression intake prevented injecting mice peripherally or centrally antagonistic GIPR-antibodies, reproduced intersectional utilising Gip-Cre / Villin-Flp limit Dq transgene expression intestinal epithelium. effects cell activation were maintained diet induced obese chronic K-cell reduced attenuated body gain. These studies establish gut-brain GIP-axis regulating adding multi-faceted metabolic need taken into account when developing GIPR-targeted therapies obesity diabetes.

Язык: Английский

---

Microbiota–neuroepithelial signalling across the gut–brain axis

Nature Reviews Microbiology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 2, 2025

Язык: Английский

---