Effect of Sustainably Sourced Protein Consumption on Nutrient Intake and Gut Health in Older Adults: A Systematic Review.

Diet is integral to the healthy ageing process and certain diets can mitigate prolonged and deleterious inflammation. This review aims to assess the impact of diets high in sustainably sourced proteins on nutrient intake, gut, and age-related health in older adults. A systematic search of the literature was conducted on 5 September 2023 across multiple databases and sources. Studies assessing sustainably sourced protein consumption in community dwelling older adults (≥65 years) were included. Risk of bias (RoB) was assessed using 'RoB 2.0' and 'ROBINS-E'. Narrative synthesis was performed due to heterogeneity of studies. Twelve studies involving 12,166 older adults were included. Nine studies (n = 10,391) assessed habitual dietary intake and had some RoB concerns, whilst three studies (n = 1812), two with low and one with high RoB, conducted plant-based dietary interventions. Increased adherence to sustainably sourced diets was associated with improved gut microbial factors (n = 4640), healthier food group intake (n = 2142), and increased fibre and vegetable protein intake (n = 1078). Sustainably sourced diets positively impacted on gut microbiota and healthier intake of food groups, although effects on inflammatory outcomes and health status were inconclusive. Future research should focus on dietary interventions combining sustainable proteins and fibre to evaluate gut barrier function and consider inflammatory and body composition outcomes in older adults.

Robust Responses of Female Caribou to Changes in Food Supply.

AbstractUngulates can respond to changes in food supply by altering foraging behavior, digestive function, and metabolism. A multifaceted response to an environmental change is considered robust. Short seasons of plant growth make herbivores sensitive to changes in food supply because maintenance and production must be accomplished in less time with fewer options in a more fragile response. Caribou live at high latitudes where short summers constrain their response to changes in food supply. We measured the ability of female caribou to resist and tolerate changes in the quality and quantity of their food supply during winter and summer. Caribou resisted changes in food abundance and quality by changing food intake and physical activity with changes in daily temperature within each season. Peak food intake rose by 134% from winter pregnancy to summer lactation (98 vs. 229 g kg-0.75 d-1), as digestible requirements to maintain the body increased by 85% for energy (1,164 vs. 2,155 kJ kg-0.75 d-1) and by 266% for N (0.79 vs. 2.89 g N kg-0.75 d-1). Caribou required a diet with a digestible content of 12 kJ g-1 and 0.8% N in pregnancy, 18 kJ g-1 and 1.9% N in early lactation, and 11 kJ g-1 and 1.2% N in late lactation, which corresponds with the phenology of the wild diet. Female caribou tolerated restriction of ad lib. food intake to 58% of their energy requirement (680 vs. 1,164 kJ kg-0.75 d-1) during winter pregnancy and to 84% of their energy requirement (1,814 vs. 2,155 kJ kg-0.75 d-1) during summer lactation without a change in stress level, as indicated by fecal corticosterone concentration. Conversely, caribou can respond to increased availability of food with a spare capacity to process digestible energy and N at 123% (2,642 vs. 2,155 kJ kg-0.75 d-1) and 145% (4.20 vs. 2.89 g N kg-0.75 d-1) of those respective requirements during lactation. Robust responses to changes in food supply allow caribou to sustain reproduction, which would buffer demographic response. However, herds may decline when thresholds of behavioral resistance and physiological tolerance are frequently exceeded. Therefore, the challenge for managing declining populations of caribou and other robust species is to identify declines in robustness before their response becomes fragile.

Impact of parity on prepartum activities and behaviour in dromedary camels under farm conditions.

This study was conducted to assess the disparities in camel activities such as eating, drinking, sitting, standing, and sleeping between primiparous and multiparous females before parturition using computer vision. Also, any extraordinary behaviours during the final 2 h before parturition and the necessary manual interventions were meticulously recorded. Five primiparous (age: 4.5-7 years) and 7 multiparous (age: 8-14 years; parity: 2.1 ± 1.5) dromedary camels, were included in this study. Pre-partum females were housed double in a parturition pen provided with two Reolink RLC-810A cameras and the data were collected and recorded for each female. Two primiparous and 1 multiparous female required assistance in pulling the calf from both forelimbs to complete their parturition (27.3%). The drinking and sleeping activities were similar in primiparous and multiparous females during the recorded 32 h leading up to calving. Only eating activity exhibited a longer period in primiparous females compared to multiparous females specifically during the 12-h before calving. Sitting activity was longer, and standing activity was shorter in multiparous than in primiparous females during the 24, 12, and 6 h before calving. All parturient camels, whether primiparous or multiparous, exhibited signs of distress. Some extraordinary behaviours were observed, such as two multiparous females attempting to deter their primiparous counterparts from eating. Additionally, three females displayed a distinctive standing position on their knees while their hind limbs were in a complete standing position for 3-5 min before transitioning to sitting or standing positions. Furthermore, one primiparous female stood while the head and forelimbs of the calf partially protruded from her vulva. In conclusion, the application of computer vision and deep learning technology proves valuable for observing prepartum camels under farm conditions, potentially reducing economic losses stemming from delayed human intervention in dystocia cases.

Dopamine, activation of ingestion and evaluation of response efficacy: a focus on the within-session time-course of licking burst number.

RATIONALE: Evidence on the effect of dopamine D1-like and D2-like receptor antagonists on licking microstructure and the forced swimming response led us to suggest that (i) dopamine on D1-like receptors plays a role in activating reward-directed responses and (ii) the level of response activation is reboosted based on a process of evaluation of response efficacy requiring dopamine on D2-like receptors. A main piece of evidence in support of this hypothesis is the observation that the dopamine D2-like receptor antagonist raclopride induces a within-session decrement of burst number occurring after the contact with the reward. The few published studies with a detailed analysis of the time-course of this measure were conducted in our laboratory. OBJECTIVES: The aim of this review is to recapitulate and discuss the evidence in support of the analysis of the within-session burst number as a behavioural substrate for the study of the mechanisms governing ingestion, behavioural activation and the related evaluation processes, and its relevance in the analysis of drug effects on ingestion. CONCLUSIONS: The evidence gathered so far suggests that the analysis of the within-session time-course of burst number provides an important behavioural substrate for the study of the mechanisms governing ingestion, behavioural activation and the related evaluation processes, and might provide decisive evidence in the analysis of the effects of drugs on ingestion. However, further evidence from independent sources is necessary to validate the use and the proposed interpretation of this measure.

Compilations and updates on residual feed intake in sheep.

The increasing global demand for food and the strong effect of climate change have forced animal science to advance regarding new methods of selection in search of more efficient animals in production systems. Feed consumption represents more than 70% of the costs of sheep farms, and more efficient animals can increase the farmers' profitability. One of the main measures of feed efficiency is estimated residual feed intake (RFI), created in 1963 by Robert Koch for estimation in cattle and later adapted for sheep. Animals with negative RFI values (RFI-) are more efficient than animals with positive values (RFI+), with influence on the variables of performance, carcass quality and production of enteric gases. The RFI is the most common and accepted metric of the feed efficiency trait for genetic selection, since it is independent of growth traits, unlike the feed conversion ratio. The purpose of this review article was to present updated literature information on the relationship of RFI estimates with performance measures, molecular markers, greenhouse gas production and feed efficiency, the technical aspects and physiological basis of metabolic in sheep.

Effects of ingesting large prey on the kinematics of rectilinear locomotion in Boa constrictor.

Large and stout snakes commonly consume large prey and use rectilinear crawling; yet, whether body wall distention after feeding impairs rectilinear locomotion is poorly understood. After eating large prey (30-37% body mass), all Boa constrictor tested could perform rectilinear locomotion in the region with the food bolus despite a greatly increased distance between the ribs and the ventral skin that likely lengthens muscles relevant to propulsion. Unexpectedly, out of 11 kinematic variables, only two changed significantly (P<0.05) after feeding: cyclic changes in snake height increased by more than 1.5 times and the longitudinal movements of the ventral skin relative to the skeleton decreased by more than 25%. Additionally, cyclic changes in snake width suggest that the ribs are active and mobile during rectilinear locomotion, particularly in fed snakes, but also in unfed snakes. These kinematic changes suggest that rectilinear actuators reorient more vertically and undergo smaller longitudinal excursions following large prey ingestion, both of which likely act to reduce elongation of these muscles that may otherwise experience substantial strain.

Dietary L-Glu sensing by enteroendocrine cells adjusts food intake via modulating gut PYY/NPF secretion.

Amino acid availability is monitored by animals to adapt to their nutritional environment. Beyond gustatory receptors and systemic amino acid sensors, enteroendocrine cells (EECs) are believed to directly percept dietary amino acids and secrete regulatory peptides. However, the cellular machinery underlying amino acid-sensing by EECs and how EEC-derived hormones modulate feeding behavior remain elusive. Here, by developing tools to specifically manipulate EECs, we find that Drosophila neuropeptide F (NPF) from mated female EECs inhibits feeding, similar to human PYY. Mechanistically, dietary L-Glutamate acts through the metabotropic glutamate receptor mGluR to decelerate calcium oscillations in EECs, thereby causing reduced NPF secretion via dense-core vesicles. Furthermore, two dopaminergic enteric neurons expressing NPFR perceive EEC-derived NPF and relay an anorexigenic signal to the brain. Thus, our findings provide mechanistic insights into how EECs assess food quality and identify a conserved mode of action that explains how gut NPF/PYY modulates food intake.

Association between time-of-day for eating, exercise, and sleep with blood pressure in adults with elevated blood pressure or hypertension: a systematic review.

The purpose of this review is to synthesize results from studies examining the association between time-of-day for eating, exercise, and sleep with blood pressure (BP) in adults with elevated BP or hypertension. Six databases were searched for relevant publications from which 789 were identified. Ten studies met inclusion criteria. Four studies examined time-of-day for eating, five examined time-of-day for exercise, and one examined time-of-day for sleep and their associations with BP. Results suggested that later time-of-day for eating ( n  = 2/4) and later sleep mid-point ( n  = 1/1) were significantly related to higher BP in multivariable models, whereas morning ( n  = 3/5) and evening ( n  = 4/5) exercise were associated with significantly lower BP. Although this small body of work is limited by a lack of prospective, randomized controlled study designs and underutilization of 24 h ambulatory BP assessment, these results provide preliminary, hypothesis-generating support for the independent role of time-of-day for eating, exercise, and sleep with lower BP.

Time matters: an insight into the relationship between chrononutrition and diabetes.

Chrononutrition is a branch of chronobiology that evaluates nutrients and the pathways implicated in their regulation in accordance with circadian rhythms. Sleep deprivation and disturbances have been strongly associated with the progression of different metabolic alterations, and the time of food intake plays a fundamental role in maintaining metabolic homeostasis. It has been demonstrated that not only the components of food are important, but quantity and quality are also crucial elements of a healthy eating pattern. Chrononutrition is an emerging tool that could help improve dietary interventions beyond those derived from consuming an adequate amount of each nutrient. Diabetes is a complex endocrine pathology characterized by sustained hyperglycemia. Dietary changes are a key component in obtaining adequate control and preventing long-term complications. Recent studies emphasize the use of chrononutrition and its components as a novel dietary intervention that could improve metabolic control. The use of chrononutrition as a dietary intervention is faced with challenges such as the presence of gaps in the literature that limit its implementation. This emphasizes the imperative need for additional research that can lead to an evidence-based use of this intervention.

Decoding the influence of central LEAP2 on food intake and its effect on accumbal dopamine release.

The gut-brain peptide ghrelin and its receptor are established as a regulator of hunger and reward-processing. However, the recently recognized ghrelin receptor inverse agonist, liver-expressed antimicrobial peptide 2 (LEAP2), is less characterized. The present study aimed to elucidate LEAP2s central effect on reward-related behaviors through feeding and its mechanism. LEAP2 was administrated centrally in mice and effectively reduced feeding and intake of palatable foods. Strikingly, LEAP2s effect on feeding was correlated to the preference of the palatable food. Further, LEAP2 reduced the rewarding memory of high preference foods, and attenuated the accumbal dopamine release associated with palatable food exposure and eating. Interestingly, LEAP2 was widely expressed in the brain, and particularly in reward-related brain areas such as the laterodorsal tegmental area (LDTg). This expression was markedly altered when allowed free access to palatable foods. Accordingly, infusion of LEAP2 into LDTg was sufficient to transiently reduce acute palatable food intake. Taken together, the present results show that central LEAP2 has a profound effect on dopaminergic reward signaling associated with food and affects several aspects of feeding. The present study highlights LEAP2s effect on reward, which may have applications for obesity and other reward-related psychiatric and neurological disorders.

Examining the evidence between screen time and night eating behaviour with dietary intake related to metabolic syndrome: A narrative review.

Screen time (ST) on digital devices has increased in recent decades due to digital development. Furthermore, constant engagement with digital devices alters sleep patterns, leading to nocturnal eating behaviour among users. These phenomena are therefore of great concern, as digital device addiction and night eating are associated with unhealthy food intake, increasing the metabolic syndrome (MetS) risks. The purpose of this review was to examine the evidence of the influence of ST and night eating behaviour (NEB) on dietary intake and its association with MetS based on previous literature. Prolonged ST and NEB have an association with excessive intake of energy from overconsumption of high-sugar and high-fat foods. However, the relationship between digital content and its influence on food intake is inconsistent. A higher MetS risk was found in individuals with longer ST due to a sedentary lifestyle, while positive energy balance and a shift in circadian rhythm contributed to night eaters. ST and NEB presented with a significant influence on food intake in adults. Additionally, unhealthy food intake due to excessive consumption of empty-calorie foods such as sweet and fatty foods due to addiction to electronic devices and eating at night has a detrimental effect on metabolic function. Therefore, improving food intake by reducing ST and night binges is essential to reduce the risk of MetS.

Cholinergic Neurotransmission Controls Orexigenic Endocannabinoid Signaling in the Gut in Diet-Induced Obesity.

The brain bidirectionally communicates with the gut to control food intake and energy balance, which becomes dysregulated in obesity. For example, endocannabinoid (eCB) signaling in the small-intestinal (SI) epithelium is upregulated in diet-induced obese (DIO) mice and promotes overeating by a mechanism that includes inhibiting gut-brain satiation signaling. Upstream neural and molecular mechanism(s) involved in overproduction of orexigenic gut eCBs in DIO, however, are unknown. We tested the hypothesis that overactive parasympathetic signaling at the muscarinic acetylcholine receptors (mAChRs) in the SI increases biosynthesis of the eCB, 2-arachidonoyl-sn-glycerol (2-AG), which drives hyperphagia via local CB1Rs in DIO. Male mice were maintained on a high-fat/high-sucrose Western-style diet for 60 d, then administered several mAChR antagonists 30 min prior to tissue harvest or a food intake test. Levels of 2-AG and the activity of its metabolic enzymes in the SI were quantitated. DIO mice, when compared to those fed a low-fat/no-sucrose diet, displayed increased expression of cFos protein in the dorsal motor nucleus of the vagus, which suggests an increased activity of efferent cholinergic neurotransmission. These mice exhibited elevated levels of 2-AG biosynthesis in the SI, that was reduced to control levels by mAChR antagonists. Moreover, the peripherally restricted mAChR antagonist, methylhomatropine bromide, and the peripherally restricted CB1R antagonist, AM6545, reduced food intake in DIO mice for up to 24 h but had no effect in mice conditionally deficient in SI CB1Rs. These results suggest that hyperactivity at mAChRs in the periphery increases formation of 2-AG in the SI and activates local CB1Rs, which drives hyperphagia in DIO.

Acute nicotine activates orectic and inhibits anorectic brain regions in rats exposed to chronic nicotine.

Nicotine use produces psychoactive effects, and chronic use is associated with physiological and psychological symptoms of addiction. However, chronic nicotine use is known to decrease food intake and body weight gain, suggesting that nicotine also affects central metabolic and appetite regulation. We recently showed that acute nicotine self-administration in nicotine-dependent animals produces a short-term increase in food intake, contrary to its long-term decrease of feeding behavior. As feeding behavior is regulated by complex neural signaling mechanisms, this study aimed to test the hypothesis that nicotine intake in animals exposed to chronic nicotine may increase activation of pro-feeding regions and decrease activation of pro-satiety regions to produce the acute increase in feeding behavior. FOS immunohistochemistry revealed that acute nicotine intake in nicotine self-administering animals increased activation of the pro-feeding arcuate and lateral hypothalamic nuclei and decreased activation of the pro-satiety parabrachial nucleus. Regional correlational analysis also showed that acute nicotine changes the functional connectivity of the hunger/satiety network. Further dissection of the role of the arcuate nucleus using electrophysiology found that putative POMC neurons in animals given chronic nicotine exhibited decreased firing following acute nicotine application. These brain-wide central signaling changes may contribute to the acute increase in feeding behavior we see in rats after acute nicotine and provide new areas of focus for studying both nicotine addiction and metabolic regulation.

Exploring the association between number of teeth, food intake, and cognitive function: A 9-year longitudinal study.

OBJECTIVES: This study aimed to investigate the association between the number of teeth, food intake, and cognitive function in Japanese community-dwelling older adults. METHODS: This 9-year longitudinal study included a total of 293 analyzable participants who participated in baseline and follow-up surveys. Dental status (number of teeth and periodontal pocket depth), dietary assessment using the brief-type self-administered diet history questionnaire, cognitive function, and the following confounding factors were evaluated: educational level, financial satisfaction, living situation, smoking and drinking habits, history of chronic diseases, apolipoprotein E-ε4 carrier, body mass index, handgrip strength, instrumental activities of daily living, and depressive symptomatology. The Japanese version of the Montreal Cognitive Assessment was used to evaluate cognitive function. A multinomial logistic regression analysis for the intake level of each food categorized into three groups (low, moderate, high), and a generalized estimating equation (GEE) for cognitive function over nine years were performed. RESULTS: After controlling for confounding factors, the number of teeth was shown to be associated with the intake of green-yellow vegetables and meat. Furthermore, the GEE indicated that the lowest quartile of intake of green-yellow vegetables significantly associated with lower cognitive function (unstandardized regression coefficient [B] = -0.96, 95 % confidence interval [CI]: -1.72 to -0.20), and the lowest quartile of intake of meat significantly associated with lower cognitive function (B = -1.42, 95 % CI: -2.27 to -0.58). CONCLUSIONS: The intake of green and yellow vegetables and meat, which is influenced by the number of teeth, was associated with cognitive function in Japanese community-dwelling older adults. CLINICAL SIGNIFICANCE: There are few studies that have examined the association between oral health, food intake, and cognitive function. This 9-year longitudinal study suggests that it is important to maintain natural teeth to enable the functional means to consume green-yellow vegetables and meat, and thereby help maintain cognitive function.

A mammalian tripartite enhancer cluster controls hypothalamic Pomc expression, food intake, and body weight.

Food intake and energy balance are tightly regulated by a group of hypothalamic arcuate neurons expressing the proopiomelanocortin (POMC) gene. In mammals, arcuate-specific POMC expression is driven by two cis-acting transcriptional enhancers known as nPE1 and nPE2. Because mutant mice lacking these two enhancers still showed hypothalamic Pomc mRNA, we searched for additional elements contributing to arcuate Pomc expression. By combining molecular evolution with reporter gene expression in transgenic zebrafish and mice, here, we identified a mammalian arcuate-specific Pomc enhancer that we named nPE3, carrying several binding sites also present in nPE1 and nPE2 for transcription factors known to activate neuronal Pomc expression, such as ISL1, NKX2.1, and ERα. We found that nPE3 originated in the lineage leading to placental mammals and remained under purifying selection in all mammalian orders, although it was lost in Simiiformes (monkeys, apes, and humans) following a unique segmental deletion event. Interestingly, ablation of nPE3 from the mouse genome led to a drastic reduction (>70%) in hypothalamic Pomc mRNA during development and only moderate (<33%) in adult mice. Comparison between double (nPE1 and nPE2) and triple (nPE1, nPE2, and nPE3) enhancer mutants revealed the relative contribution of nPE3 to hypothalamic Pomc expression and its importance in the control of food intake and adiposity in male and female mice. Altogether, these results demonstrate that nPE3 integrates a tripartite cluster of partially redundant enhancers that originated upon a triple convergent evolutionary process in mammals and that is critical for hypothalamic Pomc expression and body weight homeostasis.

Octopamine integrates the status of internal energy supply into the formation of food-related memories.

The brain regulates food intake in response to internal energy demands and food availability. However, can internal energy storage influence the type of memory that is formed? We show that the duration of starvation determines whether Drosophila melanogaster forms appetitive short-term or longer-lasting intermediate memories. The internal glycogen storage in the muscles and adipose tissue influences how intensely sucrose-associated information is stored. Insulin-like signaling in octopaminergic reward neurons integrates internal energy storage into memory formation. Octopamine, in turn, suppresses the formation of long-term memory. Octopamine is not required for short-term memory because octopamine-deficient mutants can form appetitive short-term memory for sucrose and to other nutrients depending on the internal energy status. The reduced positive reinforcing effect of sucrose at high internal glycogen levels, combined with the increased stability of food-related memories due to prolonged periods of starvation, could lead to increased food intake.

Deciding what and how much to eat is a complex biological process which involves balancing many types of information such as the levels of internal energy storage, the amount of food previously available in the environment, the perceived value of certain food items, and how these are remembered. At the molecular level, food contains carbohydrates that are broken down to produce glucose, which is then delivered to cells under the control of a hormone called insulin. There, glucose molecules are either immediately used or stored as glycogen until needed. Insulin signalling is also known to interact with the brain's decision-making systems that control eating behaviors; however, how our brains balance food intake with energy storage is poorly understood. Berger et al. set out to investigate this question using fruit flies as an experimental model. These insects also produce insulin-like molecules which help to relay information about glycogen levels to the brain's decision-making system. In particular, these signals reach a population of neurons that produce a messenger known as octopamine similar to the human noradrenaline, which helps regulate how much the flies find consuming certain types of foods rewarding. Berger et al. were able to investigate the role of octopamine in helping to integrate information about internal and external resource levels, memory formation and the evaluation of different food types. When the insects were fed normally, increased glycogen levels led to foods rich in carbohydrates being rated as less rewarding by the decision-making cells, and therefore being consumed less. Memories related to food intake were also short-lived ­ in other words, long-term 'food memory' was suppressed, re-setting the whole system after every meal. In contrast, long periods of starvation in insects with high carbohydrates resources produced a stable, long-term memory of food and hunger which persisted even after the flies had fed again. This experience also changed their food rating system, with highly nutritious foods no longer being perceived as sufficiently rewarding. As a result, the flies overate. This study sheds new light on the mechanisms our bodies may use to maintain energy reserves when food is limited. The persistence of 'food memory' after long periods of starvation may also explain why losing weight is difficult, especially during restrictive diets. In the future, Berger et al. hope that this knowledge will contribute to better strategies for weight management.

Impaired metabolic flexibility to fasting is associated with increased ad libitum energy intake in healthy adults.

OBJECTIVE: We investigated how changes in 24-h respiratory exchange ratio (RER) and substrate oxidation during fasting versus an energy balance condition influence subsequent ad libitum food intake. METHODS: Forty-four healthy, weight-stable volunteers (30 male and 14 female; mean [SD], age 39.3 [11.0] years; BMI 31.7 [8.3] kg/m2) underwent 24-h energy expenditure measurements in a respiratory chamber during energy balance (50% carbohydrate, 30% fat, and 20% protein) and 24-h fasting. Immediately after each chamber stay, participants were allowed 24-h ad libitum food intake from computerized vending machines. RESULTS: Twenty-four-hour RER decreased by 9.4% (95% CI: -10.4% to -8.5%; p < 0.0001) during fasting compared to energy balance, reflecting a decrease in carbohydrate oxidation (mean [SD], -2.6 [0.8] MJ/day; p < 0.0001) and an increase in lipid oxidation (2.3 [0.9] MJ/day; p < 0.0001). Changes in 24-h RER and carbohydrate oxidation in response to fasting were correlated with the subsequent energy intake such that smaller decreases in fasting 24-h RER and carbohydrate oxidation, but not lipid oxidation, were associated with greater energy intake after fasting (r = 0.31, p = 0.04; r = 0.40, p = 0.007; and r = -0.27, p = 0.07, respectively). CONCLUSIONS: Impaired metabolic flexibility to fasting, reflected by an inability to transition away from carbohydrate oxidation, is linked with increased energy intake.

A brainstem to hypothalamic arcuate nucleus GABAergic circuit drives feeding.

The obesity epidemic is principally driven by the consumption of more calories than the body requires. It is therefore essential that the mechanisms underpinning feeding behavior are defined. Neurons within the brainstem dorsal vagal complex (DVC) receive direct information from the digestive system and project to second-order regions in the brain to regulate food intake. Although γ-aminobutyric acid is expressed in the DVC (GABADVC), its function in this region has not been defined. In order to discover the unique gene expression signature of GABADVC cells, we used single-nucleus RNA sequencing (Nuc-seq), and this revealed 19 separate clusters. We next probed the function of GABADVC cells and discovered that the selective activation of GABADVC neurons significantly controls food intake and body weight. Optogenetic interrogation of GABADVC circuitry identified GABADVC → hypothalamic arcuate nucleus (ARC) projections as appetite suppressive without creating aversion. Electrophysiological analysis revealed that GABADVC → ARC stimulation inhibits hunger-promoting neuropeptide Y (NPY) neurons via GABA release. Adopting an intersectional genetics strategy, we clarify that the GABADVC → ARC circuit curbs food intake. These data identify GABADVC as a new modulator of feeding behavior and body weight and a controller of orexigenic NPY neuron activity, thereby providing insight into the neural underpinnings of obesity.

A brainstem-hypothalamus neuronal circuit reduces feeding upon heat exposure.

Empirical evidence suggests that heat exposure reduces food intake. However, the neurocircuit architecture and the signalling mechanisms that form an associative interface between sensory and metabolic modalities remain unknown, despite primary thermoceptive neurons in the pontine parabrachial nucleus becoming well characterized1. Tanycytes are a specialized cell type along the wall of the third ventricle2 that bidirectionally transport hormones and signalling molecules between the brain's parenchyma and ventricular system3-8. Here we show that tanycytes are activated upon acute thermal challenge and are necessary to reduce food intake afterwards. Virus-mediated gene manipulation and circuit mapping showed that thermosensing glutamatergic neurons of the parabrachial nucleus innervate tanycytes either directly or through second-order hypothalamic neurons. Heat-dependent Fos expression in tanycytes suggested their ability to produce signalling molecules, including vascular endothelial growth factor A (VEGFA). Instead of discharging VEGFA into the cerebrospinal fluid for a systemic effect, VEGFA was released along the parenchymal processes of tanycytes in the arcuate nucleus. VEGFA then increased the spike threshold of Flt1-expressing dopamine and agouti-related peptide (Agrp)-containing neurons, thus priming net anorexigenic output. Indeed, both acute heat and the chemogenetic activation of glutamatergic parabrachial neurons at thermoneutrality reduced food intake for hours, in a manner that is sensitive to both Vegfa loss-of-function and blockage of vesicle-associated membrane protein 2 (VAMP2)-dependent exocytosis from tanycytes. Overall, we define a multimodal neurocircuit in which tanycytes link parabrachial sensory relay to the long-term enforcement of a metabolic code.