Dissociable hindbrain GLP1R circuits for satiety and aversion.

The most successful obesity therapeutics, glucagon-like peptide-1 receptor (GLP1R) agonists, cause aversive responses such as nausea and vomiting1,2, effects that may contribute to their efficacy. Here, we investigated the brain circuits that link satiety to aversion, and unexpectedly discovered that the neural circuits mediating these effects are functionally separable. Systematic investigation across drug-accessible GLP1R populations revealed that only hindbrain neurons are required for the efficacy of GLP1-based obesity drugs. In vivo two-photon imaging of hindbrain GLP1R neurons demonstrated that most neurons are tuned to either nutritive or aversive stimuli, but not both. Furthermore, simultaneous imaging of hindbrain subregions indicated that area postrema (AP) GLP1R neurons are broadly responsive, whereas nucleus of the solitary tract (NTS) GLP1R neurons are biased towards nutritive stimuli. Strikingly, separate manipulation of these populations demonstrated that activation of NTSGLP1R neurons triggers satiety in the absence of aversion, whereas activation of APGLP1R neurons triggers strong aversion with food intake reduction. Anatomical and behavioural analyses revealed that NTSGLP1R and APGLP1R neurons send projections to different downstream brain regions to drive satiety and aversion, respectively. Importantly, GLP1R agonists reduce food intake even when the aversion pathway is inhibited. Overall, these findings highlight NTSGLP1R neurons as a population that could be selectively targeted to promote weight loss while avoiding the adverse side effects that limit treatment adherence.

Reverse-translational identification of a cerebellar satiation network.

The brain is the seat of body weight homeostasis. However, our inability to control the increasing prevalence of obesity highlights a need to look beyond canonical feeding pathways to broaden our understanding of body weight control1-3. Here we used a reverse-translational approach to identify and anatomically, molecularly and functionally characterize a neural ensemble that promotes satiation. Unbiased, task-based functional magnetic resonance imaging revealed marked differences in cerebellar responses to food in people with a genetic disorder characterized by insatiable appetite. Transcriptomic analyses in mice revealed molecularly and topographically -distinct neurons in the anterior deep cerebellar nuclei (aDCN) that are activated by feeding or nutrient infusion in the gut. Selective activation of aDCN neurons substantially decreased food intake by reducing meal size without compensatory changes to metabolic rate. We found that aDCN activity terminates food intake by increasing striatal dopamine levels and attenuating the phasic dopamine response to subsequent food consumption. Our study defines a conserved satiation centre that may represent a novel therapeutic target for the management of excessive eating, and underscores the utility of a 'bedside-to-bench' approach for the identification of neural circuits that influence behaviour.

Chemosensory modulation of neural circuits for sodium appetite.

Sodium is the main cation in the extracellular fluid and it regulates various physiological functions. Depletion of sodium in the body increases the hedonic value of sodium taste, which drives animals towards sodium consumption1,2. By contrast, oral sodium detection rapidly quenches sodium appetite3,4, suggesting that taste signals have a central role in sodium appetite and its satiation. Nevertheless, the neural mechanisms of chemosensory-based appetite regulation remain poorly understood. Here we identify genetically defined neural circuits in mice that control sodium intake by integrating chemosensory and internal depletion signals. We show that a subset of excitatory neurons in the pre-locus coeruleus express prodynorphin, and that these neurons are a critical neural substrate for sodium-intake behaviour. Acute stimulation of this population triggered robust ingestion of sodium even from rock salt, while evoking aversive signals. Inhibition of the same neurons reduced sodium consumption selectively. We further demonstrate that the oral detection of sodium rapidly suppresses these sodium-appetite neurons. Simultaneous in vivo optical recording and gastric infusion revealed that sodium taste-but not sodium ingestion per se-is required for the acute modulation of neurons in the pre-locus coeruleus that express prodynorphin, and for satiation of sodium appetite. Moreover, retrograde-virus tracing showed that sensory modulation is in part mediated by specific GABA (γ-aminobutyric acid)-producing neurons in the bed nucleus of the stria terminalis. This inhibitory neural population is activated by sodium ingestion, and sends rapid inhibitory signals to sodium-appetite neurons. Together, this study reveals a neural architecture that integrates chemosensory signals and the internal need to maintain sodium balance.

Phototaxis is a satiety-dependent behavioral sequence in Hydra vulgaris.

Understanding how internal states such as satiety are connected to animal behavior is a fundamental question in neuroscience. Hydra vulgaris, a freshwater cnidarian with only 12 neuronal cell types, serves as a tractable model system for studying state-dependent behaviors. We found that starved hydras consistently move towards light, while fed hydras do not. By modeling this behavior as a set of three sequences of head orientation, jump distance and jump rate, we demonstrate that the satiety state only affects the rate of the animal jumping to a new position, while the orientation and jump distance are unaffected. These findings yield insights into how internal states in a simple organism, Hydra, affect specific elements of a behavior, and offer general principles for studying the relationship between state-dependent behaviors and their underlying molecular mechanisms.

Encoding of danger by parabrachial CGRP neurons.

Animals must respond to various threats to survive. Neurons that express calcitonin gene-related peptide in the parabrachial nucleus (CGRPPBN neurons) relay sensory signals that contribute to satiation and pain-induced fear behaviour, but it is unclear how they encode these distinct processes. Here, by recording calcium transients in vivo from individual neurons in mice, we show that most CGRPPBN neurons are activated by noxious cutaneous (shock, heat, itch) and visceral stimuli (lipopolysaccharide). The same neurons are inhibited during feeding, but become activated during satiation, consistent with evidence that CGRPPBN neurons prevent overeating. CGRPPBN neurons are also activated during consumption of novel foods or by an auditory cue that has previously been paired with electrical footshocks. Correspondingly, silencing of CGRPPBN neurons attenuates the expression of food neophobia and conditioned fear responses. Therefore, in addition to transducing primary sensory danger signals, CGRPPBN neurons promote affective-behavioural states that limit harm in response to potential threats.

Hierarchical neural architecture underlying thirst regulation.

Neural circuits for appetites are regulated by both homeostatic perturbations and ingestive behaviour. However, the circuit organization that integrates these internal and external stimuli is unclear. Here we show in mice that excitatory neural populations in the lamina terminalis form a hierarchical circuit architecture to regulate thirst. Among them, nitric oxide synthase-expressing neurons in the median preoptic nucleus (MnPO) are essential for the integration of signals from the thirst-driving neurons of the subfornical organ (SFO). Conversely, a distinct inhibitory circuit, involving MnPO GABAergic neurons that express glucagon-like peptide 1 receptor (GLP1R), is activated immediately upon drinking and monosynaptically inhibits SFO thirst neurons. These responses are induced by the ingestion of fluids but not solids, and are time-locked to the onset and offset of drinking. Furthermore, loss-of-function manipulations of GLP1R-expressing MnPO neurons lead to a polydipsic, overdrinking phenotype. These neurons therefore facilitate rapid satiety of thirst by monitoring real-time fluid ingestion. Our study reveals dynamic thirst circuits that integrate the homeostatic-instinctive requirement for fluids and the consequent drinking behaviour to maintain internal water balance.

Reward-specific satiety affects subjective value signals in orbitofrontal cortex during multicomponent economic choice.

Sensitivity to satiety constitutes a basic requirement for neuronal coding of subjective reward value. Satiety from natural ongoing consumption affects reward functions in learning and approach behavior. More specifically, satiety reduces the subjective economic value of individual rewards during choice between options that typically contain multiple reward components. The unconfounded assessment of economic reward value requires tests at choice indifference between two options, which is difficult to achieve with sated rewards. By conceptualizing choices between options with multiple reward components ("bundles"), Revealed Preference Theory may offer a solution. Despite satiety, choices against an unaltered reference bundle may remain indifferent when the reduced value of a sated bundle reward is compensated by larger amounts of an unsated reward of the same bundle, and then the value loss of the sated reward is indicated by the amount of the added unsated reward. Here, we show psychophysically titrated choice indifference in monkeys between bundles of differently sated rewards. Neuronal chosen value signals in the orbitofrontal cortex (OFC) followed closely the subjective value change within recording periods of individual neurons. A neuronal classifier distinguishing the bundles and predicting choice substantiated the subjective value change. The choice between conventional single rewards confirmed the neuronal changes seen with two-reward bundles. Thus, reward-specific satiety reduces subjective reward value signals in OFC. With satiety being an important factor of subjective reward value, these results extend the notion of subjective economic reward value coding in OFC neurons.

Secretin modulates appetite via brown adipose tissue-brain axis.

PURPOSE: Secretin activates brown adipose tissue (BAT) and induces satiation in both mice and humans. However, the exact brain mechanism of this satiety inducing, secretin-mediated gut-BAT-brain axis is largely unknown. METHODS AND RESULTS: In this placebo-controlled, single-blinded neuroimaging study, firstly using [18F]-fluorodeoxyglucose (FDG) PET measures (n = 15), we established that secretin modulated brain glucose consumption through the BAT-brain axis. Predominantly, we found that BAT and caudate glucose uptake levels were negatively correlated (r = -0.54, p = 0.037) during secretin but not placebo condition. Then, using functional magnetic resonance imaging (fMRI; n = 14), we found that secretin improved inhibitory control and downregulated the brain response to appetizing food images. Finally, in a PET-fMRI fusion analysis (n = 10), we disclosed the patterned correspondence between caudate glucose uptake and neuroactivity to reward and inhibition, showing that the secretin-induced neurometabolic coupling patterns promoted satiation. CONCLUSION: These findings suggest that secretin may modulate the BAT-brain metabolic crosstalk and subsequently the neurometabolic coupling to induce satiation. The study advances our understanding of the secretin signaling in motivated eating behavior and highlights the potential role of secretin in treating eating disorders and obesity. TRIAL REGISTRATION: EudraCT no. 2016-002373-35, registered 2 June 2016; Clinical Trials no. NCT03290846, registered 25 September 2017.

Homeostatic circuits selectively gate food cue responses in insular cortex.

Physiological needs bias perception and attention to relevant sensory cues. This process is 'hijacked' by drug addiction, causing cue-induced cravings and relapse. Similarly, its dysregulation contributes to failed diets, obesity, and eating disorders. Neuroimaging studies in humans have implicated insular cortex in these phenomena. However, it remains unclear how 'cognitive' cortical representations of motivationally relevant cues are biased by subcortical circuits that drive specific motivational states. Here we develop a microprism-based cellular imaging approach to monitor visual cue responses in the insular cortex of behaving mice across hunger states. Insular cortex neurons demonstrate food-cue-biased responses that are abolished during satiety. Unexpectedly, while multiple satiety-related visceral signals converge in insular cortex, chemogenetic activation of hypothalamic 'hunger neurons' (expressing agouti-related peptide (AgRP)) bypasses these signals to restore hunger-like response patterns in insular cortex. Circuit mapping and pathway-specific manipulations uncover a pathway from AgRP neurons to insular cortex via the paraventricular thalamus and basolateral amygdala. These results reveal a neural basis for state-specific biased processing of motivationally relevant cues.

A cholinergic basal forebrain feeding circuit modulates appetite suppression.

Atypical food intake is a primary cause of obesity and other eating and metabolic disorders. Insight into the neural control of feeding has previously focused mainly on signalling mechanisms associated with the hypothalamus, the major centre in the brain that regulates body weight homeostasis. However, roles of non-canonical central nervous system signalling mechanisms in regulating feeding behaviour have been largely uncharacterized. Acetylcholine has long been proposed to influence feeding owing in part to the functional similarity between acetylcholine and nicotine, a known appetite suppressant. Nicotine is an exogenous agonist for acetylcholine receptors, suggesting that endogenous cholinergic signalling may play a part in normal physiological regulation of feeding. However, it remains unclear how cholinergic neurons in the brain regulate food intake. Here we report that cholinergic neurons of the mouse basal forebrain potently influence food intake and body weight. Impairment of cholinergic signalling increases food intake and results in severe obesity, whereas enhanced cholinergic signalling decreases food consumption. We found that cholinergic circuits modulate appetite suppression on downstream targets in the hypothalamus. Together our data reveal the cholinergic basal forebrain as a major modulatory centre underlying feeding behaviour.

Influence of exclusive breastfeeding on hippocampal structure, satiety responsiveness, and weight status.

Longer exclusive breastfeeding duration has been associated with differences in neural development, better satiety responsiveness, and decreased risk for childhood obesity. Given hippocampus sensitivity to diet and potential role in the integration of satiety signals, hippocampus may play a role in these relationships. We conducted a secondary analysis of 149, 7-11-year-olds (73 males) who participated in one of five studies that assessed neural responses to food cues. Hippocampal grey matter volume was extracted from structural scans using CAT12, weight status was assessed using age- and sex-adjusted body mass index (%BMIp85 ), and parents reported exclusive breastfeeding duration and satiety responsiveness (Children's Eating Behaviour Questionnaire). Separate path models for left and right hippocampus tested: (1) the direct effect of exclusive breastfeeding on satiety responsiveness and its indirect effect through hippocampal grey matter volume; (2) the direct effect of hippocampal grey matter volume on %BMIp85 and its indirect effect through satiety responsiveness. %BMIp85 was adjusted for maternal education, yearly income, and premature birth while hippocampal grey matter volume was adjusted for total intercranial volume, age, and study from which data were extracted. Longer exclusive breastfeeding duration was associated with greater bilateral hippocampal grey matter volumes. In addition, better satiety responsiveness and greater left hippocampal grey matter volume were both associated with lower %BMIp85 . However, hippocampal grey matter volumes were not associated with satiety responsiveness. Although no relationship was found between breastfeeding and child weight status, these results highlight the potential impact of exclusive breastfeeding duration on the hippocampal structure.

Associations between ghrelin and leptin and neural food cue reactivity in a fasted and sated state.

Food cue exposure can trigger eating. Food cue reactivity (FCR) is a conditioned response to food cues and includes physiological responses and activation of reward-related brain areas. FCR can be affected by hunger and weight status. The appetite-regulating hormones ghrelin and leptin play a pivotal role in homeostatic as well as hedonic eating. We examined the association between ghrelin and leptin levels and neural FCR in the fasted and sated state and the association between meal-induced changes in ghrelin and neural FCR, and in how far these associations are related to BMI and HOMA-IR. Data from 109 participants from three European centers (age 50±18 y, BMI 27±5 kg/m2) who performed a food viewing task during fMRI after an overnight fast and after a standardized meal were analyzed. Blood samples were drawn prior to the viewing task in which high-caloric, low-caloric and non-food images were shown. Fasting ghrelin was positively associated with neural FCR in the inferior and superior occipital gyrus in the fasted state. This was partly attributable to BMI and HOMA-IR. These brain regions are involved in visual attention, suggesting that individuals with higher fasting ghrelin have heightened attention to food cues. Leptin was positively associated with high calorie FCR in the medial prefrontal cortex (PFC) in the fasted state and to neural FCR in the left supramarginal gyrus in the fasted versus sated state, when correcting for BMI and HOMA-IR, respectively. This PFC region is involved in assessing anticipated reward value, suggesting that for individuals with higher leptin levels high-caloric foods are more salient than low-caloric foods, but foods in general are not more salient than non-foods. There were no associations between ghrelin and leptin and neural FCR in the sated state, nor between meal-induced changes in ghrelin and neural FCR. In conclusion, we show modest associations between ghrelin and leptin and neural FCR in a relatively large sample of European adults with a broad age and BMI range. Our findings indicate that people with higher leptin levels for their weight status and people with higher ghrelin levels may be more attracted to high caloric foods when hungry. The results of the present study form a foundation for future studies to test whether food intake and (changes in) weight status can be predicted by the association between (mainly fasting) ghrelin and leptin levels and neural FCR.

Neurotrophic factor control of satiety and body weight.

Energy balance--that is, the relationship between energy intake and energy expenditure--is regulated by a complex interplay of hormones, brain circuits and peripheral tissues. Leptin is an adipocyte-derived cytokine that suppresses appetite and increases energy expenditure. Ironically, obese individuals have high levels of plasma leptin and are resistant to leptin treatment. Neurotrophic factors, particularly ciliary neurotrophic factor (CNTF) and brain-derived neurotrophic factor (BDNF), are also important for the control of body weight. CNTF can overcome leptin resistance in order to reduce body weight, although CNTF and leptin activate similar signalling cascades. Mutations in the gene encoding BDNF lead to insatiable appetite and severe obesity.

Hypothalamic POMC neurons promote cannabinoid-induced feeding.

Hypothalamic pro-opiomelanocortin (POMC) neurons promote satiety. Cannabinoid receptor 1 (CB1R) is critical for the central regulation of food intake. Here we test whether CB1R-controlled feeding in sated mice is paralleled by decreased activity of POMC neurons. We show that chemical promotion of CB1R activity increases feeding, and notably, CB1R activation also promotes neuronal activity of POMC cells. This paradoxical increase in POMC activity was crucial for CB1R-induced feeding, because designer-receptors-exclusively-activated-by-designer-drugs (DREADD)-mediated inhibition of POMC neurons diminishes, whereas DREADD-mediated activation of POMC neurons enhances CB1R-driven feeding. The Pomc gene encodes both the anorexigenic peptide α-melanocyte-stimulating hormone, and the opioid peptide ß-endorphin. CB1R activation selectively increases ß-endorphin but not α-melanocyte-stimulating hormone release in the hypothalamus, and systemic or hypothalamic administration of the opioid receptor antagonist naloxone blocks acute CB1R-induced feeding. These processes involve mitochondrial adaptations that, when blocked, abolish CB1R-induced cellular responses and feeding. Together, these results uncover a previously unsuspected role of POMC neurons in the promotion of feeding by cannabinoids.

Impact of a prenatal education intervention in pregnant women to prevent overweight in infants.

INTRODUCTION: During the first 1000 days of life is the basis for a child's future health established. OBJECTIVE: To evaluate the impact of a prenatal educational intervention in pregnant women on the nutritional status of the child from birth to 4 months of age. METHODS: Quasi-experimental intervention design in women with at least 12 weeks of gestation, who were randomly assigned to an intervention group (IG) to participate in five group and three individual sessions on feeding practices and maternal perception of the child's weight and signals of hunger-satiety; the control group (CG) received routine care that included at least three prenatal consultations. RESULTS: Thirty women were included in each group. After the intervention, women in the CG practiced less exclusive breastfeeding, were more likely to underestimate or overestimate the children's weight, and perceived hunger-satiety signals with less intensity (p < 0.05). 80 % of the infants in the IG had normal weight, whereas 63 % of those in the CG had a combination of overweight and obesity (p < 0.05). CONCLUSIONS: The prenatal education program in pregnant women showed a significant effect on postnatal nutritional status of infants four months after birth.

INTRODUCCIÓN: Durante los primeros 1000 días de vida se establece la base para la salud futura de un niño. OBJETIVO: Evaluar el impacto de una intervención educativa prenatal en mujeres embarazadas sobre el estado nutricional del hijo desde el nacimiento hasta los cuatro meses de edad. MÉTODOS: Diseño cuasiexperimental de intervención con mujeres a partir de la semana 12 de gestación, asignadas aleatoriamente a un grupo de intervención (GI) para recibir cinco sesiones grupales y tres individuales sobre prácticas de alimentación y percepción materna del peso del hijo y de señales de hambre-saciedad; el grupo control (GC) recibió atención de rutina que incluía al menos tres consultas prenatales. RESULTADOS: 30 mujeres conformaron cada grupo. Después de la intervención, las mujeres del GC practicaron menos lactancia materna exclusiva, fueron propensas a subestimar o sobrestimar el peso del hijo y percibieron con menor intensidad las señales de hambre-saciedad (p < 0.05). El 80 % de los lactantes del GI presentaron peso normal y 63 % de los niños del GC, una combinación de sobrepeso y obesidad (p < 0.05). CONCLUSIONES: El programa de educación prenatal en mujeres embarazadas mostró un efecto significativo en el estado nutricional de los lactantes después de cuatro meses del nacimiento.

Effects of hunger, satiety and oral glucose on effective connectivity between hypothalamus and insular cortex.

The hypothalamus and insular cortex play an essential role in the integration of endocrine and homeostatic signals and their impact on food intake. Resting-state functional connectivity alterations of the hypothalamus, posterior insula (PINS) and anterior insula (AINS) are modulated by metabolic states and caloric intake. Nevertheless, a deeper understanding of how these factors affect the strength of connectivity between hypothalamus, PINS and AINS is missing. This study investigated whether effective (directed) connectivity within this network varies as a function of prandial states (hunger vs. satiety) and energy availability (glucose levels and/or hormonal modulation). To address this question, we measured twenty healthy male participants of normal weight twice: once after 36 â€‹h of fasting (except water consumption) and once under satiated conditions. During each session, resting-state functional MRI (rs-fMRI) and hormone concentrations were recorded before and after glucose administration. Spectral dynamic causal modeling (spDCM) was used to assess the effective connectivity between the hypothalamus and anterior and posterior insula. Using Bayesian model selection, we observed that the same model was identified as the most likely model for each rs-fMRI recording. Compared to satiety, the hunger condition enhanced the strength of the forward connections from PINS to AINS and reduced the strength of backward connections from AINS to PINS. Furthermore, the strength of connectivity from PINS to AINS was positively related to plasma cortisol levels in the hunger condition, mainly before glucose administration. However, there was no direct relationship between glucose treatment and effective connectivity. Our findings suggest that prandial states modulate connectivity between PINS and AINS and relate to theories of interoception and homeostatic regulation that invoke hierarchical relations between posterior and anterior insula.

An excitatory paraventricular nucleus to AgRP neuron circuit that drives hunger.

Hunger is a hard-wired motivational state essential for survival. Agouti-related peptide (AgRP)-expressing neurons in the arcuate nucleus (ARC) at the base of the hypothalamus are crucial to the control of hunger. They are activated by caloric deficiency and, when naturally or artificially stimulated, they potently induce intense hunger and subsequent food intake. Consistent with their obligatory role in regulating appetite, genetic ablation or chemogenetic inhibition of AgRP neurons decreases feeding. Excitatory input to AgRP neurons is important in caloric-deficiency-induced activation, and is notable for its remarkable degree of caloric-state-dependent synaptic plasticity. Despite the important role of excitatory input, its source(s) has been unknown. Here, through the use of Cre-recombinase-enabled, cell-specific neuron mapping techniques in mice, we have discovered strong excitatory drive that, unexpectedly, emanates from the hypothalamic paraventricular nucleus, specifically from subsets of neurons expressing thyrotropin-releasing hormone (TRH) and pituitary adenylate cyclase-activating polypeptide (PACAP, also known as ADCYAP1). Chemogenetic stimulation of these afferent neurons in sated mice markedly activates AgRP neurons and induces intense feeding. Conversely, acute inhibition in mice with caloric-deficiency-induced hunger decreases feeding. Discovery of these afferent neurons capable of triggering hunger advances understanding of how this intense motivational state is regulated.

The hypothalamic mechanism of neuropeptide S-induced satiety in Japanese quail (Coturnix japonica) involves the paraventricular nucleus and corticotropin-releasing factor.

Neuropeptide S (NPS), a 20-amino acid neuropeptide, is produced in the brain and is associated with appetite suppression.Our group was the first to report this anorexigenic effect in birds using chicken as a model, although a hypothalamic molecular mechanism remains to be elucidated. Thus, we designed the present study using Japanese quail(Coturnix japonica).In Experiment 1, quail intracerebroventricularly injected with NPS reduced both food and water intake. In Experiment 2, food-restricted quail injected with NPS displayed a reduction in water intake.In Experiment 3, NPS-injected quail reduced their feeding and exploratory pecks.In Experiment 4, we quantified the number of cells expressing the early intermediate gene product c-Fos (as a marker of neuronal activation) in appetite associated hypothalamic nuclei and found that immunoreactivity was increased in the paraventricular nucleus (PVN). In Experiment 5, we utilized real-time PCR to screen for neuropeptide changes within the PVN of NPS-injected quail. Mesotocin and corticotropin-releasing factor (CRF) mRNAs increased in response to NPS injection. In Experiment 6, co-injection of astressin, a CRF receptor antagonist, was sufficient to block the food intake-suppressive effects of NPS, but in Experiment 7, co-injection of an oxytocin receptor antagonist was not sufficient to block the food intake-suppressive effects of NPS. Collectively, results support that NPS induces an anorexigenic response in Japanese quail that is mediated within the PVN and is associated with CRF.

Free Fatty Acid-Induced Peptide YY Expression Is Dependent on TG Synthesis Rate and Xbp1 Splicing.

Gut-derived satiety hormones provide negative feedback to suppress food intake and maintain metabolic function in peripheral tissues. Despite the wealth of knowledge of the systemic effects of these hormones, very little is known concerning the mechanisms by which nutrients, such as dietary fats, can promote the expression of genes involved in L-cell hormone production. We have tested the role of various dietary fats and found that after hydrolysis into free fatty acids (FFA's), there is a differential response in the extent to which they induce PYY gene and protein production. The effect of FFA's also seems to relate to triglyceride (TG) re-esterification rate, with MUFA re-esterifying faster with lower PYY production. We have also found that there are differences in potency of FFA's based on their desaturation patterns in vitro. The potency effect of FFA's is influenced by the rate of TG re-esterification, such that the longer FFA's are in contact with L-cells, the more PYY they produce. We found that chronic consumption of high-fat diets enables the small intestine to re-esterify FFA's into TG faster and earlier which resulted in a blunted postprandial PYY response. Lastly, we found that FFA's induce X-box-binding protein-1 activation (Xbp1s) in L-cells and that adenoviral delivery of Xbp1s was sufficient to induce PYY gene expression. Taken together, the present work indicates that dietary fat can induce satiety, in part, prior to re-esterification. Chronic high-fat diet consumption increases the rate of re-esterification which diminishes satiety and may lead to increased food intake. Targeting intestinal TG synthesis may prove beneficial in restoring obesity-associated reductions in postprandial satiety.

Conditional microglial depletion in rats leads to reversible anorexia and weight loss by disrupting gustatory circuitry.

Microglia are highly sensitive to dietary influence, becoming activated acutely and long-term by high fat diet. However, their role in regulating satiety and feeding in healthy individuals remains unclear. Here we show that microglia are essential for the normal regulation of satiety and metabolism in rats. Short-term microglial depletion in a Cx3cr1-Dtr rat led to a dramatic weight loss that was largely accounted for by an acute reduction in food intake. This weight loss and anorexia were not likely due to a sickness response since the rats did not display peripheral or central inflammation, withdrawal, anxiety-like behavior, or nausea-associated pica. Hormonal and hypothalamic anatomical changes were largely compensatory to the suppressed food intake, which occurred in association with disruption of the gustatory circuitry at the paraventricular nucleus of the thalamus. Thus, microglia are important in supporting normal feeding behaviors and weight, and regulating preference for palatable food. Inhibiting this circuitry is able to over-ride strong compensatory drives to eat, providing a potential target for satiety control.