ABSTRACT
Background: The collection of microorganisms, mainly bacteria, which live in the gastrointestinal (GI) tract are collectible known as the gut microbiota. GI bacteria play an active role in regulation of the host's immune system and metabolism, as well as certain pathophysiological processes. Diet is the main factor modulating GI microbiota composition and recent studies have shown that high fat (HF) diets induce detrimental changes, known as dysbiosis, in the GI bacterial makeup. HF diet induced microbiota dysbiosis has been associated with structural and functional changes in gut-brain vagally mediated signaling system, associated with overeating and obesity. Although HF-driven changes in microbiota composition are sufficient to alter vagal signaling, it is unknown if restoring normal microbiota in obesity can improve gut-brain signaling and metabolic outcomes. In this study, we evaluated the effect of lean gut microbiota transfer in obese, vagally compromised, rats on gut-brain communication, food intake, and body weight. Male Sprague-Dawley rats were maintained on regular chow, or 45% HF diet for nine weeks followed by three weeks of microbiota depletion using an antibiotic cocktail. The animals were then divided into four groups (n=10 each): LF - control group on regular chow, LF-LF - chow fed animals that received antibiotics and microbiota from chow fed animals, HF-LF - HF fed animals that received microbiota from chow fed animals, and HF-HF - HF fed animals that received microbiota from HF fed animals. Animals were gavaged with donor microbiota for three consecutive days on week one and once a week thereafter for three more weeks. HF-LF animals received inulin as a prebiotic to aid the establishment of the lean microbiome. Results: We found that transferring a LF microbiota to HF fed animals (HF-LF) reduced caloric intake during the light phase when compared with HF-HF rats and prevented additional excessive weight gain. We did not observe significant changes in the density of vagal afferents terminating in the brainstem among the groups, however, HF-LF animals displayed an increase in postprandial activation of both primary sensory neurons innervating the GI tract and brainstem secondary neurons. Conclusions: We concluded from these data that normalizing microbiota composition in obese rats improves gut-brain communication and restores normal feeding patterns which was associated with a reduction in weight gain.
ABSTRACT
Cardiovascular homeostasis is maintained, in part, by neural signals arising from arterial baroreceptors that apprise the brain of blood volume and pressure. Here, we test whether neurons within the nodose ganglia that express angiotensin type-1a receptors (referred to as NGAT1aR) serve as baroreceptors that differentially influence blood pressure (BP) in male and female mice. Using Agtr1a-Cre mice and Cre-dependent AAVs to direct tdTomato to NGAT1aR, neuroanatomical studies revealed that NGAT1aR receive input from the aortic arch, project to the caudal nucleus of the solitary tract (NTS), and synthesize mechanosensitive ion channels, Piezo1/2 To evaluate the functionality of NGAT1aR, we directed the fluorescent calcium indicator (GCaMP6s) or the light-sensitive channelrhodopsin-2 (ChR2) to Agtr1a-containing neurons. Two-photon intravital imaging in Agtr1a-GCaMP6s mice revealed that NGAT1aR couple their firing to elevated BP, induced by phenylephrine (i.v.). Furthermore, optical excitation of NGAT1aR at their soma or axon terminals within the caudal NTS of Agtr1a-ChR2 mice elicited robust frequency-dependent decreases in BP and heart rate, indicating that NGAT1aR are sufficient to elicit appropriate compensatory responses to vascular mechanosensation. Optical excitation also elicited hypotensive and bradycardic responses in ChR2-expressing mice that were subjected to deoxycorticosterone acetate (DOCA)-salt hypertension; however, the duration of these effects was altered, suggestive of hypertension-induced impairment of the baroreflex. Similarly, increased GCaMP6s fluorescence observed after administration of phenylephrine was delayed in mice subjected to DOCA-salt or chronic delivery of angiotensin II. Collectively, these results reveal the structure and function of NGAT1aR and suggest that such neurons may be exploited to discern and relieve hypertension.
Subject(s)
Desoxycorticosterone Acetate , Hypertension , Red Fluorescent Protein , Mice , Male , Female , Animals , Desoxycorticosterone Acetate/pharmacology , Solitary Nucleus/physiology , Sensory Receptor Cells , Blood Pressure/physiology , Phenylephrine/pharmacology , Ion ChannelsABSTRACT
Food is a powerful natural reinforcer that guides feeding decisions. The vagus nerve conveys internal sensory information from the gut to the brain about nutritional value; however, the cellular and molecular basis of macronutrient-specific reward circuits is poorly understood. Here, we monitor in vivo calcium dynamics to provide direct evidence of independent vagal sensing pathways for the detection of dietary fats and sugars. Using activity-dependent genetic capture of vagal neurons activated in response to gut infusions of nutrients, we demonstrate the existence of separate gut-brain circuits for fat and sugar sensing that are necessary and sufficient for nutrient-specific reinforcement. Even when controlling for calories, combined activation of fat and sugar circuits increases nigrostriatal dopamine release and overeating compared with fat or sugar alone. This work provides new insights into the complex sensory circuitry that mediates motivated behavior and suggests that a subconscious internal drive to consume obesogenic diets (e.g., those high in both fat and sugar) may impede conscious dieting efforts.
Subject(s)
Carbohydrates , Sugars , Humans , Sugars/metabolism , Brain/metabolism , Diet , Hyperphagia/metabolismABSTRACT
Circadian desynchrony induced by shiftwork or jetlag is detrimental to metabolic health, but how synchronous/desynchronous signals are transmitted among tissues is unknown. Here we report that liver molecular clock dysfunction is signaled to the brain via the hepatic vagal afferent nerve (HVAN), leading to altered food intake patterns that are corrected by ablation of the HVAN. Hepatic branch vagotomy also prevents food intake disruptions induced by high-fat diet feeding and reduces body weight gain. Our findings reveal a previously unrecognized homeostatic feedback signal that relies on synchrony between the liver and the brain to control circadian food intake patterns. This identifies the hepatic vagus nerve as a therapeutic target for obesity in the setting of chrono-disruption. One Sentence Summary: The hepatic vagal afferent nerve signals internal circadian desynchrony between the brain and liver to induce maladaptive food intake patterns.
ABSTRACT
The hippocampus (HPC), traditionally known for its role in learning and memory, has emerged as a controller of food intake. While prior studies primarily associated the HPC with food intake inhibition, recent research suggests a critical role in appetitive processes. We hypothesized that orexigenic HPC neurons differentially respond to fats and/or sugars, potent natural reinforcers that contribute to obesity development. Results uncover previously-unrecognized, spatially-distinct neuronal ensembles within the dorsal HPC (dHPC) that are responsive to separate nutrient signals originating from the gut. Using activity-dependent genetic capture of nutrient-responsive HPC neurons, we demonstrate a causal role of both populations in promoting nutrient-specific preference through different mechanisms. Sugar-responsive neurons encode an appetitive spatial memory engram for meal location, whereas fat-responsive neurons selectively enhance the preference and motivation for fat intake. Collectively, these findings uncover a neural basis for the exquisite specificity in processing macronutrient signals from a meal that shape dietary choices.
ABSTRACT
The ability to encode and retrieve meal-related information is critical to efficiently guide energy acquisition and consumption, yet the underlying neural processes remain elusive. Here we reveal that ventral hippocampus (HPCv) neuronal activity dynamically elevates during meal consumption and this response is highly predictive of subsequent performance in a foraging-related spatial memory task. Targeted recombination-mediated ablation of HPCv meal-responsive neurons impairs foraging-related spatial memory without influencing food motivation, anxiety-like behavior, or escape-mediated spatial memory. These HPCv meal-responsive neurons project to the lateral hypothalamic area (LHA) and single-nucleus RNA sequencing and in situ hybridization analyses indicate they are enriched in serotonin 2a receptors (5HT2aR). Either chemogenetic silencing of HPCv-to-LHA projections or intra-HPCv 5HT2aR antagonist yielded foraging-related spatial memory deficits, as well as alterations in caloric intake and the temporal sequence of spontaneous meal consumption. Collective results identify a population of HPCv neurons that dynamically respond to eating to encode meal-related memories.
ABSTRACT
Interoception broadly refers to awareness of one's internal milieu. Vagal sensory afferents monitor the internal milieu and maintain homeostasis by engaging brain circuits that alter physiology and behavior. While the importance of the body-to-brain communication that underlies interoception is implicit, the vagal afferents and corresponding brain circuits that shape perception of the viscera are largely unknown. Here, we use mice to parse neural circuits subserving interoception of the heart and gut. We determine vagal sensory afferents expressing the oxytocin receptor, hereafter referred to as NDGOxtr, send projections to the aortic arch or stomach and duodenum with molecular and structural features indicative of mechanosensation. Chemogenetic excitation of NDGOxtr significantly decreases food and water consumption, and remarkably, produces a torpor-like phenotype characterized by reductions in cardiac output, body temperature, and energy expenditure. Chemogenetic excitation of NDGOxtr also creates patterns of brain activity associated with augmented hypothalamic-pituitary-adrenal axis activity and behavioral indices of vigilance. Recurrent excitation of NDGOxtr suppresses food intake and lowers body mass, indicating that mechanosensation of the heart and gut can exert enduring effects on energy balance. These findings suggest that the sensation of vascular stretch and gastrointestinal distention may have profound effects on whole body metabolism and mental health.
ABSTRACT
OBJECTIVE: Our goal is to investigate if microbiota composition modulates reward signaling and assess the role of the vagus in mediating microbiota to brain communication. METHODS: Male germ-free Fisher rats were colonized with gastrointestinal contents from chow (low fat (LF) ConvLF) or HF (ConvHF) fed rats. RESULTS: Following colonization, ConvHF rats consumed significantly more food than ConvLF animals. ConvHF rats displayed lower feeding-induced extracellular DOPAC levels (a metabolite of dopamine) in the Nucleus Accumbens (NAc) as well as reduced motivation for HF foods compared to ConvLF rats. Dopamine receptor 2 (DDR2) expression levels in the NAc were also significantly lower in ConvHF animals. Similar deficits were observed in conventionally raised HF fed rats, showing that diet-driven alteration in reward can be initiated via microbiota. Selective gut to brain deafferentation restored DOPAC levels, DRD2 expression, and motivational drive in ConvHF rats. CONCLUSIONS: We concluded from these data that a HF-type microbiota is sufficient to alter appetitive feeding behavior and that bacteria to reward communication is mediated by the vagus nerve.
Subject(s)
Brain-Gut Axis , Feeding Behavior , Rats , Male , Animals , 3,4-Dihydroxyphenylacetic Acid , Feeding Behavior/physiology , Reward , BacteriaABSTRACT
Metformin, a frontline therapy for type 2 diabetes and related metabolic diseases, results in variable outcomes. This study aimed to investigate whether sweetened beverages (caloric or non-caloric) affect the therapeutic benefits of metformin on glucose, food intake, and weight loss in diet-induced obesity. Mice were given a high-fat diet and sweetened water for 8 weeks to induce obesity and glucose intolerance. Then, mice were randomized to receive metformin in either water, high-fructose corn syrup (HFCS), or the non-nutritive sweetener saccharin for 6 weeks. After 6 weeks of metformin treatment, all groups had improved glucose tolerance compared to pretreatment. However, saccharin resulted in worse glucose tolerance and weight gain outcomes than the water or HFCS groups and correlated with lower plasma growth differentiation factor 15 levels. In conclusion, reducing non-nutritive sweetener consumption during metformin therapy is recommended to avoid impairing the therapeutic effects of metformin on body weight and glucose homeostasis.
Subject(s)
Diabetes Mellitus, Type 2 , High Fructose Corn Syrup , Metformin , Non-Nutritive Sweeteners , Prediabetic State , Sugar-Sweetened Beverages , Animals , Mice , Diabetes Mellitus, Type 2/drug therapy , Diet, High-Fat/adverse effects , High Fructose Corn Syrup/adverse effects , Metformin/pharmacology , Metformin/therapeutic use , Mice, Obese , Non-Nutritive Sweeteners/adverse effects , Obesity/drug therapy , Obesity/etiology , Saccharin , Glucose IntoleranceABSTRACT
We investigated the lateralization of gut-innervating vagal sensory neurons and their roles in feeding behavior. Using genetic, anatomical, and behavioral analyses, we discovered a subset of highly lateralized vagal sensory neurons with distinct sensory responses to intestinal stimuli. Our results demonstrated that left vagal sensory neurons (LNG) are crucial for distension-induced satiety, while right vagal sensory neurons (RNG) mediate preference for nutritive foods. Furthermore, these lateralized neurons engage different central circuits, with LNG neurons recruiting brain regions associated with energy balance and RNG neurons activating areas related to salience, memory, and reward. Altogether, our findings unveil the diverse roles of asymmetrical gut-vagal-brain circuits in feeding behavior, offering new insights for potential therapeutic interventions targeting vagal nerve stimulation in metabolic and neuropsychiatric diseases.
ABSTRACT
MPYS/STING (stimulator of IFN genes) senses cyclic dinucleotides (CDNs), generates type I IFNs, and plays a critical role in infection, inflammation, and cancer. In this study, analyzing genotype and haplotype data from the 1000 Genomes Project, we found that the R71H-G230A-R293Q (HAQ) MPYS allele frequency increased 57-fold in East Asians compared with sub-Saharan Africans. Meanwhile, the G230A-R293Q (AQ) allele frequency decreased by 98% in East Asians compared with sub-Saharan Africans. We propose that the HAQ and AQ alleles underwent a natural selection during the out-of-Africa migration. We used mouse models of HAQ and AQ to investigate the underlying mechanism. We found that the mice carrying the AQ allele, which disappeared in East Asians, had normal CDN-type I IFN responses. Adult AQ mice, however, had less fat mass than did HAQ or wild-type mice on a chow diet. AQ epididymal adipose tissue had increased regulatory T cells and M2 macrophages with protein expression associated with enhanced fatty acid oxidation. Conditional knockout mice and adoptive cell transfer indicate a macrophage and regulatory T cell-intrinsic role of MPYS in fatty acid metabolism. Mechanistically, AQ/IFNAR1-/- mice had a similar lean phenotype as for the AQ mice. MPYS intrinsic tryptophan fluorescence revealed that the R71H change increased MPYS hydrophilicity. Lastly, we found that the second transmembrane (TM) and the TM2-TM3 linker region of MPYS interact with activated fatty acid, fatty acyl-CoA. In summary, studying the evolution of the human MPYS gene revealed an MPYS function in modulating fatty acid metabolism that may be critical during the out-of-Africa migration.
Subject(s)
Fatty Acids , Immune Tolerance , Membrane Proteins , Adult , Animals , Humans , Mice , Fatty Acids/metabolism , Homeostasis , Membrane Proteins/metabolism , Mice, Knockout , Interferon Type IABSTRACT
BACKGROUND: Anxiety disorders are associated with an altered perception of the body's internal state. Therefore, understanding the neuronal basis of interoception can foster novel anxiety therapies. In rodents, the feeding status bidirectionally modulates anxiety-like behavior but how the sensing of gastrointestinal state affects anxiety remains unclear. METHODS: We combined chemogenetics, neuropharmacology, and behavioral approaches in male and female rats to test whether vagal afferents terminating in the gastrointestinal tract mediate feeding-induced tuning of anxiety. Using saporin-based lesions and transcriptomics, we investigated the chronic impact of this gut-brain circuit on anxiety-like behavior. RESULTS: Both feeding and selective chemogenetic activation of gut-innervating vagal afferents increased anxiety-like behavior. Conversely, chemogenetic inhibition blocked the increase in anxiety-like behavior induced by feeding. Using a selective saporin-based lesion, we demonstrate that the loss of gut-innervating vagal afferent signaling chronically reduces anxiety-like behavior in male rats but not in female rats. We next identify a vagal circuit that connects the gut to the central nucleus of the amygdala, using anterograde transsynaptic tracing from the nodose ganglia. Lesion of this gut-brain vagal circuit modulated the central amygdala transcriptome in both sexes but selectively affected a network of GABA (gamma-aminobutyric acid)-related genes only in males, suggesting a potentiation of inhibitory control. Blocking GABAergic signaling in the central amygdala re-established normal anxiety levels in male rats. CONCLUSIONS: Vagal sensory signals from the gastrointestinal tract are critical for baseline and feeding-induced tuning of anxiety via the central amygdala in rats. Our results suggest vagal gut-brain signaling as a target to normalize interoception in anxiety disorders.
Subject(s)
Anxiety , Vagus Nerve , Animals , Feedback , Female , Gastrointestinal Tract , Male , Neural Pathways/physiology , Rats , Saporins/metabolism , Vagus Nerve/metabolism , gamma-Aminobutyric Acid/metabolismABSTRACT
Maintaining homeostasis while navigating one's environment involves accurately assessing and interacting with external stimuli while remaining consciously in tune with internal signals such as hunger and thirst. Both atypical social interactions and unhealthy eating patterns emerge as a result of dysregulation in factors that mediate the prioritization and attention to salient stimuli. Oxytocin is an evolutionarily conserved peptide that regulates attention to exteroceptive and interoceptive stimuli in a social environment by functioning in the brain as a modulatory neuropeptide to control social behavior, but also in the periphery as a hormone acting at oxytocin receptors (Oxtr) expressed in the heart, gut, and peripheral ganglia. Specialized sensory afferent nerve endings of Oxtr-expressing nodose ganglia cells transmit cardiometabolic signals via the Vagus nerve to integrative regions in the brain that also express Oxtr(s). These brain regions are influenced by vagal sensory pathways and coordinate with external events such as those demanding attention to social stimuli, thus the sensations related to cardiometabolic function and social interactions are influenced by oxytocin signaling. This review investigates the literature supporting the idea that oxytocin mediates the interoception of cardiovascular and gastrointestinal systems, and that the modulation of this awareness likewise influences social cognition. These concepts are then considered in relation to Autism Spectrum Disorder, exploring how atypical social behavior is comorbid with cardiometabolic dysfunction.
ABSTRACT
Here, we provide a focused review of the evidence for the roles of the vagus nerve in mediating the regulatory effects of peripherally and centrally produced GLP-1 on eating behaviour and energy balance. We particularly focus on recent studies which have used selective genetic, viral, and transcriptomic approaches to provide important insights into the anatomical and functional organisation of GLP-1-mediated gut-brain signalling pathways. A number of these studies have challenged canonical ideas of how GLP-1 acts in the periphery and the brain to regulate eating behaviour, with important implications for the development of pharmacological treatments for obesity. LINKED ARTICLES: This article is part of a themed issue on GLP1 receptor ligands (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.4/issuetoc.
Subject(s)
Glucagon-Like Peptide 1 , Glucagon-Like Peptide-1 Receptor , Glucagon-Like Peptide-1 Receptor/metabolism , Humans , Obesity/drug therapy , Signal Transduction , Vagus Nerve/metabolismABSTRACT
Cocaine- and amphetamine-related transcript (CART) is a neuropeptide first discovered in the striatum of the rat brain. Later, the genetic sequence and function of CART peptide (CARTp) was found to be conserved among multiple mammalian species. Over the 25 years, since its discovery, CART mRNA (Cartpt) expression has been reported widely throughout the central and peripheral nervous systems underscoring its role in diverse physiological functions. Here, we review the localization and function of CARTp as it relates to energy homeostasis. We summarize the expression changes of central and peripheral Cartpt in response to metabolic states and make use of available large data sets to gain additional insights into the anatomy of the Cartpt expressing vagal neurons and their expression patterns in the gut. Furthermore, we provide an overview of the role of CARTp as an anorexigenic signal and its effect on energy expenditure and body weight control with insights from both pharmacological and transgenic animal studies. Subsequently, we discuss the role of CARTp in the pathophysiology of obesity and review important new developments towards identifying a candidate receptor for CARTp signalling. Altogether, the field of CARTp research has made rapid and substantial progress recently, and we review the case for considering CARTp as a potential therapeutic target for stemming the obesity epidemic.
Subject(s)
Nerve Tissue Proteins/metabolism , Neurons/metabolism , Peptides/metabolism , Vagus Nerve/metabolism , Animals , Energy Metabolism , Homeostasis , HumansABSTRACT
The anorexigenic peptide glucagon-like peptide-1 (GLP-1) is secreted from gut enteroendocrine cells and brain preproglucagon (PPG) neurons, which, respectively, define the peripheral and central GLP-1 systems. PPG neurons in the nucleus tractus solitarii (NTS) are widely assumed to link the peripheral and central GLP-1 systems in a unified gut-brain satiation circuit. However, direct evidence for this hypothesis is lacking, and the necessary circuitry remains to be demonstrated. Here we show that PPGNTS neurons encode satiation in mice, consistent with vagal signalling of gastrointestinal distension. However, PPGNTS neurons predominantly receive vagal input from oxytocin-receptor-expressing vagal neurons, rather than those expressing GLP-1 receptors. PPGNTS neurons are not necessary for eating suppression by GLP-1 receptor agonists, and concurrent PPGNTS neuron activation suppresses eating more potently than semaglutide alone. We conclude that central and peripheral GLP-1 systems suppress eating via independent gut-brain circuits, providing a rationale for pharmacological activation of PPGNTS neurons in combination with GLP-1 receptor agonists as an obesity treatment strategy.
Subject(s)
Central Nervous System/physiology , Glucagon-Like Peptide 1/physiology , Peripheral Nervous System/physiology , Satiety Response/physiology , Animals , Eating , Female , Gastrointestinal Tract/innervation , Gastrointestinal Tract/physiology , Glucagon-Like Peptide-1 Receptor/agonists , Glucagon-Like Peptides/pharmacology , Male , Mice , Mice, Inbred C57BL , Neurons/metabolism , Proglucagon/metabolism , Receptors, Oxytocin/metabolism , Vagus Nerve/physiologyABSTRACT
Vagal and spinal sensory endings in the wall of the hepatic portal and superior mesenteric veins (PMV) provide the brain with chemosensory information important for energy balance and other functions. To determine their medullary neuronal targets, we injected the transsynaptic anterograde viral tracer HSV-1 H129-772 (H129) into the PMV wall or left nodose ganglion (LNG) of male rats, followed by immunohistochemistry (IHC) and high-resolution imaging. We also determined the chemical phenotype of H129-infected neurons, and potential vagal and spinal axon terminal appositions in the dorsal motor nucleus of the vagus (DMX) and the nucleus of the solitary tract (NTS). PMV wall injections generated H129-infected neurons in both nodose ganglia and in thoracic dorsal root ganglia (DRGs). In the medulla, cholinergic preganglionic parasympathetic neurons in the DMX were virtually the only targets of chemosensory information from the PMV wall. H129-infected terminal appositions were identified on H129-infected somata and dendrites in the DMX, and on H129-infected DMX dendrites that extend into the NTS. Sensory transmission via vagal and possibly spinal routes from the PMV wall therefore reaches DMX neurons via axo-somatic appositions in the DMX and axo-dendritic appositions in the NTS. However, the dearth of H129-infected NTS neurons indicates that sensory information from the PMV wall terminates on DMX neurons without engaging NTS neurons. These previously underappreciated direct sensory routes into the DMX enable a vago-vagal and possibly spino-vagal reflexes that can directly influence visceral function.
Subject(s)
Mesenteric Veins , Nodose Ganglion , Animals , Male , Neurons , Rats , Solitary Nucleus , Vagus NerveABSTRACT
AIM: The tools that have been used to assess the function of the vagus nerve lack specificity. This could explain discrepancies about the role of vagal gut-brain signalling in long-term control of energy balance. Here we use a validated approach to selectively ablate sensory vagal neurones that innervate the gut to determine the role of vagal gut-brain signalling in the control of food intake, energy expenditure and glucose homoeostasis in response to different diets. METHODS: Rat nodose ganglia were injected bilaterally with either the neurotoxin saporin conjugated to the gastrointestinal hormone cholecystokinin (CCK), or unconjugated saporin as a control. Food intake, body weight, glucose tolerance and energy expenditure were measured in both groups in response to chow or high-fat high-sugar (HFHS) diet. Willingness to work for fat or sugar was assessed by progressive ratio for orally administered solutions, while post-ingestive feedback was tested by measuring food intake after an isocaloric lipid or sucrose pre-load. RESULTS: Vagal deafferentation of the gut increases meal number in lean chow-fed rats. Switching to a HFHS diet exacerbates overeating and body weight gain. The breakpoint for sugar or fat solution did not differ between groups, suggesting that increased palatability may not drive HFHS-induced hyperphagia. Instead, decreased satiation in response to intra-gastric infusion of fat, but not sugar, promotes hyperphagia in CCK-Saporin-treated rats fed with HFHS diet. CONCLUSIONS: We conclude that intact sensory vagal neurones prevent hyperphagia and exacerbation of weight gain in response to a HFHS diet by promoting lipid-mediated satiation.