Regulation Of Feeding Behavior Research Articles

GLUT2 expression by glial fibrillary acidic protein-positive tanycytes is required for promoting feeding-response to fasting

Feeding behavior is a complex process that depends on the ability of the brain to integrate hormonal and nutritional signals, such as glucose. One glucosensing mechanism relies on the glucose transporter 2 (GLUT2) in the hypothalamus, especially in radial glia-like cells called tanycytes. Here, we analyzed whether a GLUT2-dependent glucosensing mechanism is required for the normal regulation of feeding behavior in GFAP-positive tanycytes. Genetic inactivation of Glut2 in GFAP-expressing tanycytes was performed using Cre/Lox technology. The efficiency of GFAP-tanycyte targeting was analyzed in the anteroposterior and dorsoventral axes by evaluating GFP fluorescence. Feeding behavior, hormonal levels, neuronal activity using c-Fos, and neuropeptide expression were also analyzed in the fasting-to-refeeding transition. In basal conditions, Glut2-inactivated mice had normal food intake and meal patterns. Implementation of a preceeding fasting period led to decreased total food intake and a delay in meal initiation during refeeding. Additionally, Glut2 inactivation increased the number of c-Fos-positive cells in the ventromedial nucleus in response to fasting and a deregulation of Pomc expression in the fasting-to-refeeding transition. Thus, a GLUT2-dependent glucose-sensing mechanism in GFAP-tanycytes is required to control food consumption and promote meal initiation after a fasting period.

Black soybean seed coat polyphenol ameliorates the abnormal feeding pattern induced by high-fat diet consumption.

High-fat diet (HFD) consumption induces chronic inflammation and microglial accumulation in the mediobasal hypothalamus (MBH), the central regulator of feeding behavior and peripheral metabolism. As a result, the diurnal feeding rhythm is disrupted, leading to the development of obesity. Diet-induced obesity (DIO) can be prevented by restoring the normal feeding pattern. Therefore, functional foods and drugs that ameliorate hypothalamic inflammation and restore the normal feeding pattern may prevent or ameliorate DIO. Numerous functional foods and food-derived compounds with anti-obesity effects have been identified; however, few studies have been performed that assessed their potential to prevent the HFD-induced hypothalamic inflammation and disruption of feeding rhythm. In the present study, we found that polyphenols derived from black soybean seed coat (BE) significantly ameliorated the accumulation of activated microglia and pro-inflammatory cytokine expression in the arcuate nucleus of the hypothalamus of HFD-fed mice, and restored their feeding pattern to one comparable to that of standard diet-fed mice, thereby ameliorating DIO. Furthermore, cyanidin 3-O-glucoside—the principal anthocyanin in BE—was found to be a strong candidate mediator of these effects. This is the first study to show that BE has the potential to provide a variety of beneficial effects on health, which involve amelioration of the HFD-induced hypothalamic inflammation and abnormal feeding pattern. The results of this study provide new evidence for the anti-obesity effects of black soybean polyphenols.

Role of brain-gut-muscle axis in human health and energy homeostasis.

The interrelationship between brain, gut and skeletal muscle plays a key role in energy homeostasis of the body, and is becoming a hot topic of research. Intestinal microbial metabolites, such as short-chain fatty acids (SCFAs), bile acids (BAs) and tryptophan metabolites, communicate with the central nervous system (CNS) by binding to their receptors. In fact, there is a cross-talk between the CNS and the gut. The CNS, under the stimulation of pressure, will also affect the stability of the intestinal system, including the local intestinal transport, secretion and permeability of the intestinal system. After the gastrointestinal tract collects information about food absorption, it sends signals to the central system through vagus nerve and other channels to stimulate the secretion of brain-gut peptide and produce feeding behavior, which is also an important part of maintaining energy homeostasis. Skeletal muscle has receptors for SCFAs and BAs. Therefore, intestinal microbiota can participate in skeletal muscle energy metabolism and muscle fiber conversion through their metabolites. Skeletal muscles can also communicate with the gut system during exercise. Under the stimulation of exercise, myokines secreted by skeletal muscle causes the secretion of intestinal hormones, and these hormones can act on the central system and affect food intake. The idea of the brain-gut-muscle axis is gradually being confirmed, and at present it is important for regulating energy homeostasis, which also seems to be relevant to human health. This article focuses on the interaction of intestinal microbiota, central nervous, skeletal muscle energy metabolism, and feeding behavior regulation, which will provide new insight into the diagnostic and treatment strategies for obesity, diabetes, and other metabolic diseases.

Fat body phospholipid state dictates hunger-driven feeding behavior.

Diet-induced obesity leads to dysfunctional feeding behavior. However, the precise molecular nodes underlying diet-induced feeding motivation dysregulation are poorly understood. The fruit fly is a simple genetic model system yet displays significant evolutionary conservation to mammalian nutrient sensing and energy balance. Using a longitudinal high-sugar regime in Drosophila, we sought to address how diet-induced changes in adipocyte lipid composition regulate feeding behavior. We observed that subjecting adult Drosophila to a prolonged high-sugar diet degrades the hunger-driven feeding response. Lipidomics analysis reveals that longitudinal exposure to high-sugar diets significantly alters whole-body phospholipid profiles. By performing a systematic genetic screen for phospholipid enzymes in adult fly adipocytes, we identify Pect as a critical regulator of hunger-driven feeding. Pect is a rate-limiting enzyme in the phosphatidylethanolamine (PE) biosynthesis pathway and the fly ortholog of human PCYT2. We show that disrupting Pect activity only in the Drosophila fat cells causes insulin resistance, dysregulated lipoprotein delivery to the brain, and a loss of hunger-driven feeding. Previously human studies have noted a correlation between PCYT2/Pect levels and clinical obesity. Now, our unbiased studies in Drosophila provide causative evidence for adipocyte Pect function in metabolic homeostasis. Altogether, we have uncovered that PE phospholipid homeostasis regulates hunger response.

The limitations of investigating appetite through circuit manipulations: are we biting off more than we can chew?

Disordered eating can underpin a number of debilitating and prevalent chronic diseases, such as obesity. Broader advances in psychopharmacology and biology havemotivated some neuroscientists to address diet-induced obesity through reductionist, pre-clinical eating investigations on the rodent brain. Specifically, chemogenetic and optogenetic methods developed in the 21st century allow neuroscientists to perform in vivo, region-specific/projection-specific/promoter-specific circuit manipulations and immediately assess the impact of these manipulations on rodent feeding. These studies are able to rigorously conclude whether a specific neuronal population regulates feeding behaviour in the hope of eventually developing a mechanistic neuroanatomical map of appetite regulation. However, an artificially stimulated/inhibited rodent neuronal population that changes feeding behaviour does not necessarily represent a pharmacological target for treating eating disorders in humans. Chemogenetic/optogenetic findings must therefore be triangulated with the array of theories that contribute to our understanding of appetite. The objective of this review is to provide a wide-ranging discussion of the limitations of chemogenetic/optogenetic circuit manipulation experiments in rodents that are used to investigate appetite. Stepping into and outside of medical science epistemologies, this paper draws on philosophy of science, nutrition, addiction biology and neurophilosophy to prompt more integrative, transdisciplinary interpretations of chemogenetic/optogenetic appetite data. Through discussing the various technical and epistemological limitations of these data, we provide both an overview ofchemogenetics and optogenetics accessible to non-neuroscientist obesity researchers, as well as a resource for neuroscientists to expand the number of lenses through which they interpret their circuit manipulation findings.

Dietary Choice Reshapes Metabolism in Drosophila by Affecting Consumption of Macronutrients.

The precise regulation of metabolism and feeding behavior is important for preventing the development of metabolic diseases. Here we examine the effects on Drosophila metabolism of dietary choice. These changes are predicted to be dependent on both the quantity and quality of the chosen diet. Using a geometric framework for both no-choice and two-choice conditions, we found that feeding decisions led to higher glucose and trehalose levels but lower triglycerides pools. The feeding regimens had similar strategies for macronutrient balancing, and both maximized hemolymph glucose and glycogen content under low protein intake. In addition, the flies showed significant differences in the way they regulated trehalose and triglyceride levels in response to carbohydrate and protein consumption between choice and no-choice nutrition. Under choice conditions, trehalose and triglyceride levels were maximized at the lowest protein and carbohydrate consumption. Thus, we suggest that these changes in carbohydrate and lipid metabolism are caused by differences in the macronutrients consumed by flies. Food choice elicits rapid metabolic changes to maintain energy homeostasis. These results contribute to our understanding of how metabolism is regulated by the revealed nutrient variation in response to food decisions.

Oral feeding skills in premature infants: A concept analysis.

The delay in developing oral feeding skills becomes a problem experienced by premature infants. One of the reasons for the delay may be related to inconsistent definitions of oral feeding skills, which can cause discrepancies in the provision of nursing care. This study aimed to clarify the concept of oral feeding skills in premature infants. The Walker and Avant concept analysis method was used. A literature search was also conducted from five databases: CINAHL, PubMed, ProQuest, EMBASE, and Google Scholar, to find articles between January 2020 and December 2022. The literature search obtained 20 articles on oral feeding skills from various disciplines. Five attributes were developed from the concept analysis, including (1) coordination ability to suck, swallow, and breathe, (2) the ability to regulate oral-motor functions, (3) the ability to regulate sensory functions, (4) the ability to maintain the stability of physiology function, and (5) the ability to regulate feeding behavior. Antecedents to oral feeding skills include immaturity of the nervous system, gestational age, feeding intolerance, increased length of stay and cost of care, increased rehospitalization, stress on parents, and increased morbidity and mortality. Consequences include optimization of growth and development, reduction of length of stay and cost of hospitalization, increased bonding attachment, increased self-efficacy of parents in caring for premature infants, and improvement of the quality of life of premature infants. The concept analysis provides five comprehensive attributes and their antecedents and consequences. However, this concept can be used to provide nursing care to premature infants, assess the criteria for discharge, and optimize nutrition for the growth and development of premature infants.

Effect of Ghrelin on the Cardiovascular System.

Simple SummaryGhrelin is an octanoylated peptide that was initially isolated from rat and human stomachs in the process of searching for an endogenous ligand to the orphan growth hormone secretagogue receptor (GHS-R), a G-protein-coupled receptor. Exogenous or endogenous ghrelin secreted from the stomach binds to GHS-R on gastric vagal nerve terminals, and the signals are transmitted to the central nervous system via the vagal afferent nerve to facilitate growth hormone (GH) secretion, feeding, sympathetic inhibition, parasympathetic activation, and anabolic effects. Ghrelin also binds directly to the pituitary GHS-R and stimulates GH secretion. Ghrelin has beneficial effects on the cardiovascular system, including cardioprotective effects such as anti-heart failure, anti-arrhythmic, and anti-inflammatory actions, and it enhances vascular activity via GHS-R-dependent stimulation of GH/IGF-1 (insulin-like growth factor-1) and modulation of the autonomic nervous system. The anti-heart failure effects of ghrelin could be useful as a new therapeutic strategy for chronic heart failure.Ghrelin, an n-octanoyl-modified 28-amino-acid-peptide, was first discovered in the human and rat stomach as an endogenous ligand for the growth hormone secretagogue receptor (GHS-R). Ghrelin-GHS-R1a signaling regulates feeding behavior and energy balance, promotes vascular activity and angiogenesis, improves arrhythmia and heart failure, and also protects against cardiovascular disease by suppressing cardiac remodeling after myocardial infarction. Ghrelin’s cardiovascular protective effects are mediated by the suppression of sympathetic activity; activation of parasympathetic activity; alleviation of vascular endothelial dysfunction; and regulation of inflammation, apoptosis, and autophagy. The physiological functions of ghrelin should be clarified to determine its pharmacological potential as a cardiovascular medication.

The Small Molecule PPARγ Agonist GL516 Induces Feeding-Stimulatory Effects in Hypothalamus Cells Hypo-E22 and Isolated Hypothalami.

PPARγ agonists are implicated in the regulation of diabetes and metabolic syndrome and have therapeutic potential in brain disorders. PPARγ modulates appetite through its central effects, especially on the hypothalamic arcuate nucleus (ARC). Previous studies demonstrated that the small molecule GL516 is a PPARγ agonist able to reduce oxidative stress and apoptosis with a potential neuroprotective role. Herein, we investigated the effects of GL516, in vitro and ex vivo, on the levels of hypothalamic dopamine (DA) and serotonin (5-HT). The gene expressions of neuropeptide Y, CART, AgRP, and POMC, which play master roles in the neuroendocrine regulation of feeding behavior and energy balance, were also evaluated. HypoE22 cells were treated with H2O2 (300 μM) for 2 h e 30’ and with different concentrations of GL516 (1 nM-100 µM). The cell viability was evaluated after 24 and 48 h of culturing using the MTT test. DA and 5-HT levels in the HypoE22 cell supernatants were analyzed through HPLC; an ex vivo study on isolated hypothalamic specimens challenged with scalar concentrations of GL516 (1–100 µM) and with pioglitazone (10 µM) was carried out. The gene expressions of CART, NPY, AgRP, and POMC were also determined by a quantitative real-time PCR. The results obtained showed that GL516 was able to reduce DA and 5-HT turnover; moreover, it was effective in stimulating NPY and AgRP gene expressions with a concomitant reduction in CART and POMC gene expressions. These results highlight the capability of GL516 to modulate neuropeptide pathways deeply involved in appetite control suggesting an orexigenic effect. These findings emphasize the potential use of GL516 as a promising candidate for therapeutical applications in neurodegenerative diseases associated with the reduction in food intake and stimulation of catabolic pathways.

Electrophysiological complexity in the rat dorsomedial hypothalamus and its susceptibility to daily rhythms and high-fat diet.

The dorsomedial hypothalamus (DMH) in amongst the most important brain structures involved in the regulation of feeding behaviour and metabolism. In contrast to other hypothalamic centres, its main role is related to the circadian rhythmicity of food intake and energy homeostasis; both reported to be disrupted in obesity. In modern world, overweight and obesity reached global epidemic proportions. Thus, not only is it important to study their negative implications but also the mechanism responsible for their development. Here, we exposed rats to short-term (2-4weeks) high-fat diet (HFD)-not long enough to induce obesity. Next, we performed electrophysiological patch-clamp recordings ex vivo from neurons in the DMH either during the day or at night. Our results showed a day-to-night change in the firing frequency of DMH cells, with higher activity during the dark phase. This was abolished by HFD consumption, resulting in a decreased threshold for action potential generation during the day and therefore increased electrical activity at this phase. We propose this electrophysiological disturbance as a mechanism for the induction of abnormal daytime feeding, previously observed for HFD-fed animals, which might in turn contribute to the development of obesity. In addition, we provide an electrophysiological characteristic of DMH neurons with a separation into three anatomically and functionally distinct subpopulations, namely, the compact part, separating the structure into the ventral and dorsal divisions. Our study is the first to show electrophysiological complexity of the DMH with its sensitivity to diet and daily rhythms.

Physiological Role of Orexinergic System for Health.

Orexins, or hypocretins, are excitatory neuropeptides involved in the regulation of feeding behavior and the sleep and wakefulness states. Since their discovery, several lines of evidence have highlighted that orexin neurons regulate a great range of physiological functions, giving it the definition of a multitasking system. In the present review, we firstly describe the mechanisms underlining the orexin system and their interactions with the central nervous system (CNS). Then, the system’s involvement in goal-directed behaviors, sleep/wakefulness state regulation, feeding behavior and energy homeostasis, reward system, and aging and neurodegenerative diseases are described. Advanced evidence suggests that the orexin system is crucial for regulating many physiological functions and could represent a promising target for therapeutical approaches to obesity, drug addiction, and emotional stress.

Distribution of neuropeptide Y in the brain of the male native Thai chicken.

Neuropeptide Y (NPY), a 36 amino acid neurotransmitter/neuromodulator, is involved in food intake and parental cares in birds. NPY is associated with the regulation of the reproductive system in the female native Thai chickens. However, the role of NPY in the male native Thai chicken has not been studied. Therefore, the objective of this study was to investigate the distributions of NPY immunoreactive (-ir) neurons and fibers in the brain of the male native Thai chickens. The distribution of NPY-ir neurons and fibers in the hen brain was elucidated utilizing immunohistochemical technique. The distributions of NPY-ir neurons and fibers were located throughout the brain, predominantly in the hypothalamus. The numbers of NPY-ir neurons within the nucleus paraventricularis magnocellularis (PVN) were significantly higher than those of the nucleus septalis lateralis (SL), nucleus supraopticus (SOv), and nucleus inferioris hypothalami and nucleus infundibuli hypothalami (IH-IN). In addition, the numbers of NPY-ir neurons within the SL, SOv, and IH-IN were significantly higher than those of the tractus septomesencephalicus and nucleus dorsolateralis anterior thalami. These results indicated, for the first time, that the distributions of NPY-ir neurons and fibers in the brain of the male native Thai chickens were markedly observed in the hypothalamus, especially within the PVN, implicating that the NPYergic system within the PVN might be related to the regulation of feeding behavior and parental cares in this equatorial species.

TRPV1-Mediated Sensing of Sodium and Osmotic Pressure in POMC Neurons in the Arcuate Nucleus of the Hypothalamus.

The central melanocortin system conducted by anorexigenic pro-opiomelanocortin (POMC) neurons and orexigenic agouti-related peptide (AgRP) neurons in the arcuate nucleus of the hypothalamus (ARC) not only regulates feeding behavior but also blood pressure. Excessive salt intake raises the Na+ concentration ([Na+]) in the cerebrospinal fluid (CSF) and worsens hypertension. The blood–brain barrier is immature in the ARC. Therefore, both AgRP and POMC neurons in the ARC have easy access to the electrolytes in the blood and can sense changes in their concentrations. However, the sensitivity of AgRP and POMC neurons to Na+ remains unclear. This study aimed to explore how the changes in the extracellular Na+ concentration ([Na+]) influence these neurons by measuring the cytosolic Ca2+ concentration ([Ca2+]i) in the single neurons isolated from the ARC that were subsequently immunocytochemically identified as AgRP or POMC neurons. Both AgRP and POMC neurons responded to increases in both [Na+] and osmolarity in C57BL/6 mice. In contrast, in transient receptor potential vanilloid 1 (TRPV1) knockout (KO) mice, POMC neurons failed to respond to increases in both [Na+] and osmolarity, while they responded to high glucose and angiotensin II levels with increases in [Ca2+]i. Moreover, in KO mice fed a high-salt diet, the expression of POMC was lower than that in wild-type mice. These results demonstrate that changes in [Na+] and osmolarity are sensed by the ARC POMC neurons via the TRPV1-dependent mechanism.

The c.612A>G mutation of MC4R affects constitutive activity and signaling in domestic goats.

As a key gene for balancing energy and regulating feeding behavior, MC4R is relevant to the growth of ruminants. In this presentation, a highly conserved c.612A>G site in the coding sequence (CDS) of MC4R has been selected during a selective sweep analysis of 35 Yiling goats and 20 other wild goats. This site mutation results in an amino acid change from Ile to Met. The genotyping analysis of the c.612A>G site revealed that the A allele was the dominant allele in the domestic goat populations, while the wild goat individuals only had the G allele. For a better understanding of the biological significance of this site, we examined the protein localization and signal detection to explain the function of the two MC4R receptors. The results showed that both the M204 and I204 receptors can normally localize on the membrane. When stimulating the M204 type without α-MSH, it was defective at the level of basal cAMP and decreased significantly against the I204 type. In contrast, the signaling capacity of the M204 receptor was also lower than that of I204 under the stimulation of α-MSH. In the ERK1/2 pathway, stimulating MC4R with NDP-α-MSH, both the M204 and I204 receptors had normal pERK1/2 levels. These results indicate that the p.I204M mutation may change the function by damaging the constitutive activity and signaling, and thus may regulate goats' appetite. This study has potential application for rearing domestic goats.

Molecular cloning, expression and appetite regulation function of adiponectin in Siberian sturgeon (Acipenser baerii)

Adiponectin (AdipoQ) as an adipocytokine has the potential to regulate feeding behavior, but the information about adipoq in fish is limited. In this study, Siberian sturgeon adiponectin (Ssadipoq) gene was cloned encoding 264 amino acids. The amino acid identity of SsAdipoQ was low compared with that of mammals, birds, amphibians and teleost fishes. The expression of Ssadipoq in the hypothalamus was significantly decreased at 1 h and 3 h post feeding, and increased after 15-day fasting. The mature domain of AdipoQ (fAd) was inserted into expression vector pET32a and successfully expressed in Escherichia coli BL21 (DE3) after stimulated by isopropyl-β-d-thiogalactoside. Food intake at 1 h and 3 h post treatment with SsfAd protein decreased significantly (P < 0.05). The mRNA expression of pyy and cck in the valvula intestine was promoted and hypothalamic npy, agrp and pomc mRNA expression were inhibited after treatment with SsfAd protein. Furthermore, hypothalamic ampk subunits expression was associated with peripheral SsfAd treatment. In summary, present study indicate that SsfAd plays an important role in the regulation of food intake and appetite signals in Siberian sturgeon, which provides a basis for further study application of prokaryotic AdipoQ in feeding behavior regulation.

Nesfatin-1'in anoreksijenik fonksiyonunun gün içinde değişimi sirkadiyen ritimle ilişkili olabilir mi?

Nutrition is a body function exhibited to provide the metabolic needs of the organism. The regulation of feeding behavior is provided by homeostatic mechanisms. Food consumption of individuals is time-dependently coordinated by the brain throughout the approximately 24-hour circadian cycle. The biological clocks in the body set the daily intervals in which food consumption can occur in the circadian rhythm. These time zones are usually in the active period phase. The biological clocks that provide circadian control of food intake are a light-entrained master clock in the suprachiasmatic nucleus of the hypothalamus and numerous secondary oscillators in the brain and other tissues of the body. Nesfatin-1 is a hormone derived from the precursor protein of nucleobindin 2 and has strong effects on appetite. The anorexigenic effect of Nesfatin-1 is more pronounced, especially in the dark period of the day. This raises the question of whether the hormone in question has a circadian rhythm. In our review, the findings obtained from the studies on the subject are discussed cross-sectionally, and the possible relationship between the regulation of feeding behavior and the effects of nesfatin-1 with the circadian rhythm is evaluated.

1356-P: Investigating the Metabolic Function of an Orphan G Protein–Coupled Receptor in the Intestinal Epithelium

G protein-coupled receptors (GPCRs) in the gastrointestinal tract are involved in maintaining glucose and energy homeostasis by regulating the release of gut hormones in response to luminal dietary nutrients as well as microbial metabolites. We recently identified that an orphan GPCR, Gpr17, was co-expressed in glucagon-like peptide-1 (GLP-1) -expressing EECs in human and rodent intestinal epithelium. However, it is unknown how Gpr17 ablation in the intestinal epithelium affects feeding behavior and satiety regulation. To address this question, we used genetic knockout approach to generate intestinal Gpr17-deficient mice and analyzed their glucose metabolism and feeding behavior. We showed that intestinal Gpr17-deficient mice had similar growth curve, body composition, and ad libitum food intake compared with littermate controls. We found that acute genetic ablation of Gpr17 in intestinal epithelium (iKO) improved oral glucose tolerance and glucose-stimulated insulin secretion (GSIS) in female and male mice. iKO mice responded to glucose or lipid ingestion with increased secretion of GLP-1, but not the other incretin glucose-dependent insulinotropic polypeptide (GIP) . Intestinal Gpr17-deficient mice responded to fasting-refeeding challenge with reduced fasting locomotor activity and less food intake after refeeding, suggesting increased satiety during the phase of rebound hyperphagia. Furthermore, comprehensive studies including gut morphology, gut epithelium heterogeneity by scRNA-seq, and microbiome analysis were examined but none of them was changed because of intestinal Gpr17 ablation. In addition, male Gpr17 whole body knockout mice have improved intraperitoneal glucose tolerance, and increased insulin sensitivity in hyperinsulinemic-euglycemic clamp studies. In conclusion, our work showed that ablation of intestinal Gpr17 signaling led to improved neurohormonal regulation to maintain metabolic homeostasis. Disclosure H.Ren: None. Funding National Institute of Health (R01DK120772)

GPR83 engages endogenous peptides from two distinct precursors to elicit differential signaling.

PEN is an abundant neuropeptide that activates GPR83, a G protein-coupled receptor that is considered a novel therapeutic target due to its roles in regulation of feeding, reward, and anxiety-related behaviors. The major form of PEN in the brain is 22 residues in length. Previous studies have identified shorter forms of PEN in mouse brain and neuroendocrine cells; these shorter forms were named PEN18, PEN19 and PEN20, with the number reflecting the length of the peptide. The C-terminal five residues of PEN20 are identical to the C-terminus of a procholecystokinin (proCCK)-derived peptide, named proCCK56-62, that is present in mouse brain. ProCCK56-62 is highly conserved across species although it has no homology to the bioactive cholecystokinin domain. ProCCK56-62 and a longer form, proCCK56-63 were tested for their ability to engage GPR83. Both peptides bind GPR83 with high affinity, activate second messenger pathways, and induce ligand-mediated receptor endocytosis. Interestingly, the shorter PEN peptides, ProCC56-62, and ProCCK56-63 differentially activate signal transduction pathways. Whereas PEN22 and PEN20 facilitate receptor coupling to Gai, PEN18, PEN19 and ProCCK peptides facilitate coupling to Gas. Furthermore, the ProCCK peptides exhibit dose dependent Ga subtype selectivity in that they faciliate coupling to Gas at low concentrations and Gai at high concentrations. These data demonstrate that peptides derived from two distinct peptide precursors can differentially activate GPR83, and that GPR83 exhibits Ga subtype preference depending on the nature and concentration of the peptide. These results are consistent with the emerging idea that endogenous neuropeptides function as biased ligands. Significance Statement We found that peptides derived from proCCK bind and activate GPR83, a G protein-coupled receptor that is known to bind peptides derived from proSAAS. Different forms of the proCCK- and proSAAS-derived peptides show biased agonism, activating Gas or Gai depending on the length of the peptide and/or its concentration.

Transgenic mice encoding modern imaging probes: Properties and applications.

SUMMARYModern biology is increasingly reliant on optical technologies, including visualization and longitudinal monitoring of cellular processes. The major limitation here is the availability of animal models to track the molecules and cells in their natural environment in vivo. Owing to the integrity of the studied tissue and the high stability of transgene expression throughout life, transgenic mice encoding fluorescent proteins and biosensors represent unique tools for in vivo studies in norm and pathology. We review the strategies for targeting probe expression in specific tissues, cell subtypes, or cellular compartments. We describe the application of transgenic mice expressing fluorescent proteins for tracking protein expression patterns, apoptotic events, tissue differentiation and regeneration, neurogenesis, tumorigenesis, and cell fate mapping. We overview the possibilities of functional imaging of secondary messengers, neurotransmitters, and ion fluxes. Finally, we provide the rationale and perspectives for the use of transgenic imaging probes in translational research and drug discovery.

A D2 to D1 shift in dopaminergic inputs to midbrain 5-HT neurons causes anorexia in mice.

Midbrain dopamine (DA) and serotonin (5-HT) neurons regulate motivated behaviors, including feeding, but less is known about how these circuits may interact. In this study, we found that DA neurons in the mouse ventral tegmental area bidirectionally regulate the activity of 5-HT neurons in the dorsal raphe nucleus (DRN), with weaker stimulation causing DRD2-dependent inhibition and overeating, while stronger stimulation causing DRD1-dependent activation and anorexia. Furthermore, in the activity-based anorexia (ABA) paradigm, which is a mouse model mimicking some clinical features of human anorexia nervosa (AN), we observed a DRD2 to DRD1 shift of DA neurotransmission on 5-HTDRN neurons, which causes constant activation of these neurons and contributes to AN-like behaviors. Finally, we found that systemic administration of a DRD1 antagonist can prevent anorexia and weight loss in ABA. Our results revealed regulation of feeding behavior by stimulation strength-dependent interactions between DA and 5-HT neurons, which may contribute to the pathophysiology of AN.