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Nature Communications May 2024AgRP neurons in the arcuate nucleus of the hypothalamus (ARC) coordinate homeostatic changes in appetite associated with fluctuations in food availability and leptin...
AgRP neurons in the arcuate nucleus of the hypothalamus (ARC) coordinate homeostatic changes in appetite associated with fluctuations in food availability and leptin signaling. Identifying the relevant transcriptional regulatory pathways in these neurons has been a priority, yet such attempts have been stymied due to their low abundance and the rich cellular diversity of the ARC. Here we generated AgRP neuron-specific transcriptomic and chromatin accessibility profiles from male mice during three distinct hunger states of satiety, fasting-induced hunger, and leptin-induced hunger suppression. Cis-regulatory analysis of these integrated datasets enabled the identification of 18 putative hunger-promoting and 29 putative hunger-suppressing transcriptional regulators in AgRP neurons, 16 of which were predicted to be transcriptional effectors of leptin. Within our dataset, Interferon regulatory factor 3 (IRF3) emerged as a leading candidate mediator of leptin-induced hunger-suppression. Measures of IRF3 activation in vitro and in vivo reveal an increase in IRF3 nuclear occupancy following leptin administration. Finally, gain- and loss-of-function experiments in vivo confirm the role of IRF3 in mediating the acute satiety-evoking effects of leptin in AgRP neurons. Thus, our findings identify IRF3 as a key mediator of the acute hunger-suppressing effects of leptin in AgRP neurons.
Topics: Animals; Male; Mice; Agouti-Related Protein; Arcuate Nucleus of Hypothalamus; Fasting; Gene Expression Regulation; Hunger; Interferon Regulatory Factor-3; Leptin; Mice, Inbred C57BL; Neurons; Signal Transduction; Transcriptome; Chromatin; Epigenesis, Genetic
PubMed: 38821928
DOI: 10.1038/s41467-024-48885-y -
Veterinary and Animal Science Jun 2024The jejunum is a critical site for nutrient digestion and absorption, and variation in its ability to take up nutrients within the jejunum is likely to affect feed...
The jejunum is a critical site for nutrient digestion and absorption, and variation in its ability to take up nutrients within the jejunum is likely to affect feed efficiency. The purpose of this study was to determine differences in gene expression in the jejunum of beef steers divergent for residual feed intake (RFI) in one cohort of steers (Year 1), and to validate those genes in animals from a second study (Year 2). Steers from Year 1 ( = 16) were selected for high and low RFI. Jejunum mucosal tissue was obtained for RNA-seq. Thirty-two genes were differentially expressed (≤0.15), and five were over-represented in pathways including inflammatory mediator, cholecystokinin receptor (CCKR) signaling, and p38 MAPK pathways. Several differentially expressed genes (, and ) have been previously associated with RFI in other studies. Real-time qPCR was used to validate nine differentially expressed genes in the Year 1 steers used for RNA-seq, and in the Year 2 validation cohort. Six genes were validated as differentially expressed ( < 0.1) using RT-qPCR in the Year 1 population. In the Year 2 population, five genes displayed the same direction of expression as the Year 1 population and 3 were differentially expressed ( < 0.1). The CCKR pathway is involved in digestion, appetite control, and regulation of body weight making it a compelling candidate for feed efficiency in cattle, and the validation of these genes in a second population of cattle is suggestive of a role in feed efficiency.
PubMed: 38812584
DOI: 10.1016/j.vas.2024.100357 -
Neuropharmacology Sep 2024Diets high in sucrose and fat are becoming more prevalent the world over, accompanied by a raised prevalence of cardiovascular diseases, cancers, diabetes, obesity, and...
Diets high in sucrose and fat are becoming more prevalent the world over, accompanied by a raised prevalence of cardiovascular diseases, cancers, diabetes, obesity, and metabolic syndrome. Clinical studies link unhealthy diets with the development of mental health disorders, particularly depression. Here, we investigate the effects of 12 days of sucrose consumption administered as 2 L of 25% sucrose solution daily for 12 days in Göttingen minipigs on the function of brain receptors involved in reward and motivation, regulating feeding, and pre- and post-synaptic mechanisms. Through quantitative autoradiography of cryostat sections containing limbic brain regions, we investigated the effects of sucrose restricted to a 1-h period each morning, on the specific binding of [H]raclopride on dopamine D2/3 receptors, [H]UCB-J at synaptic vesicle glycoprotein 2A (SV2A), [H]MPEPγ at metabotropic glutamate receptor subtype 5 (mGluR5) and [H]SR141716A at the cannabinoid receptor 1 (CB1). Compared to control diet animals, the sucrose group showed significantly lower [H]UCB-J and [H]MPEPγ binding in the prefrontal cortex. The sucrose-consuming minipigs showed higher hippocampal CB1 binding, but unaltered dopamine D2/3 binding compared to the control group. We found that the sucrose diet reduced the synaptic density marker while increasing CB1 binding in limbic brain structures, which may subserve maladaptive changes in appetite regulation and feeding. Further studies of the effects of diets and lifestyle habits on brain neuroreceptor and synaptic density markers are warranted.
Topics: Animals; Swine, Miniature; Swine; Sucrose; Male; Receptor, Metabotropic Glutamate 5; Receptors, Cannabinoid; Synapses; Receptor, Cannabinoid, CB1; Receptors, Dopamine D2; Brain; Female; Receptors, Dopamine D3
PubMed: 38810925
DOI: 10.1016/j.neuropharm.2024.110018 -
Biomedicine & Pharmacotherapy =... Jul 2024GDF15 is a stress response cytokine and a distant member of the transforming growth factor beta (TGFβ) superfamily, its levels increase in response to cell stress and... (Review)
Review
GDF15 is a stress response cytokine and a distant member of the transforming growth factor beta (TGFβ) superfamily, its levels increase in response to cell stress and certain diseases in the serum. To exert its effects, GDF15 binds to glial-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL), which was firstly identified in 2017 and highly expressed in the brain stem. Many studies have demonstrated that elevated serum GDF15 is associated with anorexia and weight loss. Herein, we focus on the biology of GDF15, specifically how this circulating protein regulates appetite and metabolism in influencing energy homeostasis through its actions on hindbrain neurons to shed light on its impact on diseases such as obesity and anorexia/cachexia syndromes. It works as an endocrine factor and transmits metabolic signals leading to weight reduction effects by directly reducing appetite and indirectly affecting food intake through complex mechanisms, which could be a promising target for the treatment of energy-intake disorders.
Topics: Humans; Growth Differentiation Factor 15; Animals; Metabolic Diseases; Energy Metabolism; Obesity; Anorexia; Appetite
PubMed: 38810400
DOI: 10.1016/j.biopha.2024.116809 -
Physiological Genomics May 2024Commercial culture of channel catfish () occurs in earthen ponds that are characterized by diel swings in dissolved oxygen concentration that can fall to severe levels...
Commercial culture of channel catfish () occurs in earthen ponds that are characterized by diel swings in dissolved oxygen concentration that can fall to severe levels of hypoxia which can suppress appetite and lead to suboptimal growth. Given the significance of the hypothalamus in regulating these processes in other fishes, an investigation into the hypothalamus transcriptome was conducted to identify specific genes and expression patterns responding to hypoxia. Channel catfish in normoxic water were compared to catfish subjected to 12 hours of hypoxia (20% oxygen saturation; 1.8 mg O/L; 27 °C) followed by 12 hours of recovery in normoxia to mimic 24-hours in a catfish aquaculture pond. Fish were sampled at 0-, 6-, 12-, 18-, and 24-hour time points, with the 6- and 12-hour samplings occurring during hypoxia. A total of 190 genes were differentially expressed during the experiment, with most occurring during hypoxia and returning to baseline values within 6 hours of normoxia. Differentially expressed genes were sorted by function into Gene Ontology biological processes and revealed that most were categorized as "response to hypoxia", "sprouting angiogenesis", and "cellular response to xenobiotic stimulus". The patterns of gene expression reported here suggest that transcriptome responses to hypoxia are broad and quickly reversibly with the onset of normoxia. Although no genes commonly reported to modulate appetite were found to be differentially expressed in this experiment, several candidates were identified for future studies investigating the interplay between hypoxia and appetite in channel catfish, including , , , and .
PubMed: 38808773
DOI: 10.1152/physiolgenomics.00007.2024 -
Appetite May 2024Food insecurity - defined as having limited access to nutritious foods - is linked with obesity. Previous research has also shown that food insecurity is associated with...
Food insecurity - defined as having limited access to nutritious foods - is linked with obesity. Previous research has also shown that food insecurity is associated with lower levels of leisure-time physical activity (physical activity performed outside of essential activities). This association may occur in part due to concerns about preserving levels of energy during times of food shortage. Currently, no scale exists which measures this construct. Therefore, we aimed to develop and validate such a scale - the food insecurity physical activity concerns scale (FIPACS). Participants (N = 603, individuals with food insecurity = 108) completed an online survey, consisting of the FIPACS, the International Physical Activity Questionnaire short-form (IPAQ), the restraint subscale of the Dutch Eating Behaviour Questionnaire (DEBQ), the amotivation subscale of the Behaviour Regulation In Exercise Questionnaire-2 (BREQ-2), and the Behavioural Inhibition System/Behavioural Approach System Reactivity scale (BIS/BAS) to assess convergent and divergent validity. An exploratory factor analysis revealed a four-factor model of the FIPACS - namely 'Concerns relating to hunger', 'Concerns of replenishment and calories', 'Concerns of physiological effects of exercise' and 'Compensatory behaviours' which was verified through a confirmatory factor analysis. To assess test-retest reliability, 100 participants completed the FIPACS again two weeks later. The FIPACS had good internal, test-retest reliability and divergent validity. However, there was limited evidence of convergent validity. Future studies could incorporate this scale when investigating the association between food insecurity and physical activity.
PubMed: 38801996
DOI: 10.1016/j.appet.2024.107516 -
Appetite May 2024Terminating a meal after achieving satiation is a critical step in maintaining a healthy energy balance. Despite the extensive collection of information over the last... (Review)
Review
Terminating a meal after achieving satiation is a critical step in maintaining a healthy energy balance. Despite the extensive collection of information over the last few decades regarding the neural mechanisms controlling overall eating, the mechanism underlying different temporal phases of eating behaviors, especially satiation, remains incompletely understood and is typically embedded in studies that measure the total amount of food intake. In this review, we summarize the neural circuits that detect and integrate satiation signals to suppress appetite, from interoceptive sensory inputs to the final motor outputs. Due to the well-established role of cholecystokinin (CCK) in regulating the satiation, we focus on the neural circuits that are involved in regulating the satiation effect caused by CCK. We also discuss several general principles of how these neural circuits control satiation, as well as the limitations of our current understanding of the circuits function. With the application of new techniques involving sophisticated cell-type-specific manipulation and mapping, as well as real-time recordings, it is now possible to gain a better understanding of the mechanisms specifically underlying satiation.
PubMed: 38801994
DOI: 10.1016/j.appet.2024.107512 -
Nutrients May 2024Unhealthy lifestyles (high-fat diet, smoking, alcohol consumption, too little exercise, etc.) in the current society are prone to cause lipid metabolism disorders... (Review)
Review
Unhealthy lifestyles (high-fat diet, smoking, alcohol consumption, too little exercise, etc.) in the current society are prone to cause lipid metabolism disorders affecting the health of the organism and inducing the occurrence of diseases. Saponins, as biologically active substances present in plants, have lipid-lowering, inflammation-reducing, and anti-atherosclerotic effects. Saponins are thought to be involved in the regulation of lipid metabolism in the body; it suppresses the appetite and, thus, reduces energy intake by modulating pro-opiomelanocortin/Cocaine amphetamine regulated transcript (POMC/CART) neurons and neuropeptide Y/agouti-related peptide (NPY/AGRP) neurons in the hypothalamus, the appetite control center. Saponins directly activate the AMP-activated protein kinase (AMPK) signaling pathway and related transcriptional regulators such as peroxisome-proliferator-activated-receptors (PPAR), CCAAT/enhancer-binding proteins (C/EBP), and sterol-regulatory element binding proteins (SREBP) increase fatty acid oxidation and inhibit lipid synthesis. It also modulates gut-liver interactions to improve lipid metabolism by regulating gut microbes and their metabolites and derivatives-short-chain fatty acids (SCFAs), bile acids (BAs), trimethylamine (TMA), lipopolysaccharide (LPS), et al. This paper reviews the positive effects of different saponins on lipid metabolism disorders, suggesting that the gut-liver axis plays a crucial role in improving lipid metabolism processes and may be used as a therapeutic target to provide new strategies for treating lipid metabolism disorders.
Topics: Saponins; Lipid Metabolism; Humans; Liver; Gastrointestinal Microbiome; Animals; Signal Transduction; Gastrointestinal Tract
PubMed: 38794751
DOI: 10.3390/nu16101514 -
Nature Metabolism Jun 2024Nutrient handling is an essential function of the gastrointestinal tract. Hormonal responses of small intestinal enteroendocrine cells (EECs) have been extensively...
Nutrient handling is an essential function of the gastrointestinal tract. Hormonal responses of small intestinal enteroendocrine cells (EECs) have been extensively studied but much less is known about the role of colonic EECs in metabolic regulation. To address this core question, we investigated a mouse model deficient in colonic EECs. Here we show that colonic EEC deficiency leads to hyperphagia and obesity. Furthermore, colonic EEC deficiency results in altered microbiota composition and metabolism, which we found through antibiotic treatment, germ-free rederivation and transfer to germ-free recipients, to be both necessary and sufficient for the development of obesity. Moreover, studying stool and blood metabolomes, we show that differential glutamate production by intestinal microbiota corresponds to increased appetite and that colonic glutamate administration can directly increase food intake. These observations shed light on an unanticipated host-microbiota axis in the colon, part of a larger gut-brain axis, that regulates host metabolism and body weight.
Topics: Animals; Enteroendocrine Cells; Gastrointestinal Microbiome; Mice; Colon; Obesity; Mice, Inbred C57BL; Glutamic Acid; Brain-Gut Axis; Hyperphagia
PubMed: 38777856
DOI: 10.1038/s42255-024-01044-5 -
Poultry Science Jul 2024Adrenomedullin has various physiological roles including appetite regulation. The objective of present study was to determine the effects of ICV injection of...
Adrenomedullin has various physiological roles including appetite regulation. The objective of present study was to determine the effects of ICV injection of adrenomedullin and its interaction with NPY and CCK receptors on food intake regulation. In experiment 1, chickens received ICV injection of saline and adrenomedullin (1, 2, and 3 nmol). In experiment 2, birds injected with saline, B5063 (NPY receptor antagonist, 1.25 µg), adrenomedullin (3 nmol) and co-injection of B5063+adrenomedullin. Experiments 3 to 5 were similar to experiment 2 and only SF22 (NPY receptor antagonist, 1.25 µg), SML0891 (NPY receptor antagonist, 1.25 µg) and CCK (1 nmol) were injected instead of B5063. In experiment 6, ICV injection of saline and CCK (0.125, 0.25, and 0.5 nmol) were done. In experiment 7, chickens injected with saline, CCK (0.125 nmol), adrenomedullin (3 nmol) and co-injection of CCK+adrenomedullin. After ICV injection, birds were returned to their individual cages immediately and cumulative food intake was measured at 30, 60, and 120 min after injection. Adrenomedullin (2 and 3 nmol) decreased food intake compared to control group (P < 0.05). Coinjection of B5063+adrenomedullin amplified hypophagic effect of adrenomedullin (P < 0.05). The ICV injection of the CCK (0.25 and 0.5 nmol) reduced food intake (P < 0.05). Co-injection of the CCK+adrenomedullin significantly potentiated adrenomedullin-induced hypophagia (P < 0.05). Administration of the SF22, SML0891 and CCK had no effect on the anorexigenic response evoked by adrenomedullin (P > 0.05). These results suggested that the hypophagic effect of the adrenomedullin is mediated by NPY and CCK receptors. However, our novel results should form the basis for future experiments.
Topics: Animals; Adrenomedullin; Chickens; Injections, Intraventricular; Neuropeptide Y; Eating; Female; Avian Proteins; Appetite Regulation; Male; Receptors, Cholecystokinin; Cholecystokinin
PubMed: 38772088
DOI: 10.1016/j.psj.2024.103819