Mechanisms Involved in the Link between Depression, Antidepressant Treatment, and Associated Weight Change.

Major depressive disorder is a severe mood disorder associated with a marked decrease in quality of life and social functioning, accompanied by a risk of suicidal behavior. Therefore, seeking out and adhering to effective treatment is of great personal and society-wide importance. Weight changes associated with antidepressant therapy are often cited as the reason for treatment withdrawal and thus are an important topic of interest. There indeed exists a significant mechanistic overlap between depression, antidepressant treatment, and the regulation of appetite and body weight. The suggested pathomechanisms include the abnormal functioning of the homeostatic (mostly humoral) and hedonic (mostly dopaminergic) circuits of appetite regulation, as well as causing neuromorphological and neurophysiological changes underlying the development of depressive disorder. However, this issue is still extensively discussed. This review aims to summarize mechanisms linked to depression and antidepressant therapy in the context of weight change.

Effects of White Potatoes Consumed With Eggs on Satiety, Food Intake, and Glycemic Response in Children and Adolescents.

Objective: Short-term studies in adults have shown that white potatoes increase satiety and suppress food intake (FI) compared with several other carbohydrate-containing foods; however, studies are limited in children. The objective was to compare the effects of white potatoes in mixed meals on satiety, FI, and glycemic response in 9-14-year-old children and adolescents.Methods: Using a within-subject, repeated-measures design, 21 children completed five counter-balanced test sessions. After an overnight fast, children consumed one of four isocaloric treatment meals (450 kcal) of French fries, mashed potatoes, or white beans served with a fixed portion of egg omelet (30 g of protein), a control meal with cereal, milk, and bread, or continued to fast (i.e., meal skipping). Subjective appetite was measured using visual analogue scales. FI at an ad libitum pizza meal at 180 min and rest of day diet record were used to measure lunch FI and rest of day energy intake, respectively. Total daily energy intake was calculated by adding the energy intake from the treatment meal, the ad libitum pizza lunch, and rest of day food record. Capillary blood samples were collected to assess glycemic response over 180 min.Results: Change from baseline subjective average appetite scores were lower after mashed potatoes compared with all other treatment conditions (p < 0.001), and higher after French fries compared with white beans (p = 0.04). Lunch FI (kcal) was significantly lower (p < 0.001) after French fries (1010±73) and mashed potatoes (1039±74) compared with the control meal (1257±92) and meal skipping (1235±74). Total daily energy intake (kcal) was lower after French fries compared with the control meal (2228±141 vs. 2624±137; p = 0.04). Change from baseline blood glucose was lower after white beans and French fries compared with mashed potatoes (p < 0.05) and the control meal (p < 0.001).Conclusion: In conclusion, white potatoes with eggs increased satiety, decreased short-term FI, and resulted in similar energy intakes compared with meal skipping.

Gestational folic acid content alters the development and function of hypothalamic food intake regulating neurons in Wistar rat offspring post-weaning.

Background: Folic acid plays an important role in early brain development of offspring, including proliferation and differentiation of neural stem cells known to impact the function of food intake regulatory pathways. Excess (10-fold) intakes of folic acid in the gestational diet have been linked to increased food intake and obesity in male rat offspring post-weaning.Objective: The present study examined the effects of folic acid content in gestational diets on the development and function of two hypothalamic neuronal populations, neuropeptide Y (NPY) and pro-opiomelanocortin (POMC), within food intake regulatory pathways of male Wistar rat offspring at birth and post-weaning.Results: Folic acid fed at 5.0-fold above recommended levels (5RF) to Wistar dams during pregnancy increased the number of mature NPY-positive neurons in the hypothalamus of male offspring, compared to control (RF), 0RF, 2.5RF, and 10RF at birth. Folic acid content had no effect on expression and maturation of POMC-positive neurons. Body weight and food intake were higher in all treatment groups (2.5-, 5.0-, and 10.0-fold folic acid) from birth to 9 weeks post-weaning compared to control. Increased body weight and food intake at 9-weeks post-weaning were accompanied by a reduced activation of POMC neurons in the arcuate nucleus (ARC).Conclusion: Gestational folic acid content modulates expression of mature hypothalamic NPY-positive neurons at birth and activation of POMC-positive neurons at 9-weeks post-weaning in the ARC of male Wistar rat offspring which may contribute to higher body weight and food intake later in life.

Teaching people to eat according to appetite - Does the method of glucose measurement matter?

BACKGROUND: Hunger training teaches people to eat according to their appetite using pre-prandial glucose measurement. Previous hunger training interventions used fingerprick blood glucose, however continuous glucose monitoring (CGM) offers a painless and convenient form of glucose monitoring. The aim of this randomised feasibility trial was to compare hunger training using CGM with fingerprick glucose monitoring in terms of adherence to the protocol, acceptability, weight, body composition, HbA1c, psychosocial variables, and the relationship between adherence measures and weight loss. METHODS: 40 adults with obesity were randomised to either fingerpricking or scanning with a CGM and followed identical interventions for 6 months, which included 1 month of only eating when glucose was under their individualised glucose cut-off. For months 2-6 participants relied on their sensations of hunger to guide their eating and filled in a booklet. RESULTS: 90% of the fingerpricking group and 85% of the scanning group completed the study. Those using the scanner measured their glucose an extra 1.9 times per day (95% CI 0.9, 2.8, p < 0.001) compared with those testing by fingerprick. Both groups lost similar amounts of weight over 6 months (on average 4 kg), were satisfied with the hunger training program and wanted to measure their glucose again within the next year. There were no differences between groups in terms of intervention acceptability, weight, body composition, HbA1c, eating behaviours, or psychological health. Frequency of glucose testing and booklet entry both predicted a clinically meaningful amount of weight loss. CONCLUSIONS: Either method of measuring glucose is effective for learning to eat according to hunger using the hunger training program. As scanning with a CGM encouraged better adherence to the protocol without sacrificing outcome results, future interventions should consider using this new technology in hunger training programs.

Differential relationship between physical activity and intake of added sugar and nutrient-dense foods: A cross-sectional analysis.

A curvilinear relationship exists between physical activity (PA) and dietary energy intake (EI), which is reduced in moderately active when compared to inactive and highly active individuals, but the impact of PA on eating patterns remains poorly understood. Our goal was to establish the relationship between PA and intake of foods with varying energy and nutrient density. Data from the 2009-2010 United States National Health and Nutrition Examination Survey were used to include a Dietary Screener Questionnaire for estimated intakes of added sugar, fruits and vegetables, whole grains, fiber, and dairy. Participants (n = 4766; 49.7% women) were divided into sex-specific quintiles based on their habitual PA. After adjustment for age, body mass index, household income, and education, intakes were compared between PA quartiles, using the lowest activity quintile (Q1) as reference. Women in the second to fourth quintile (Q2-Q4) consumed less added sugar from sugary foods (+2 tsp/day) and from sweetened beverages (+2 tsp/day; all p < 0.05 vs. Q1). In men, added sugar intake was elevated in the highest activity quintile (Q5: +3 ± 1 tsp/day, p = 0.007 vs. Q1). Fruit and vegetable intake increased (women: Q1-Q4 +0.3 ± 0.1 cup eq/day; p < 0.001; men: Q1-Q3 +0.3 ± 0.1 cup eq/day, p = 0.002) and stagnated in higher quintiles. Dairy intake increased with PA only in men (Q5: +0.3 ± 0.1 cup eq/day, p < 0.001 vs. Q1). Results demonstrate a differential relationship between habitual PA and dietary intakes, whereby moderate but not necessarily highest PA levels are associated with reduced added sugar and increased nutrient-dense food consumption. Future research should examine specific mechanisms of food choices at various PA levels to ensure dietary behaviors (i.e., increased sugary food intake) do not negate positive effects of PA.

Prolactin-Releasing Peptide: Physiological and Pharmacological Properties.

Prolactin-releasing peptide (PrRP) belongs to the large RF-amide neuropeptide family with a conserved Arg-Phe-amide motif at the C-terminus. PrRP plays a main role in the regulation of food intake and energy expenditure. This review focuses not only on the physiological functions of PrRP, but also on its pharmacological properties and the actions of its G-protein coupled receptor, GPR10. Special attention is paid to structure-activity relationship studies on PrRP and its analogs as well as to their effect on different physiological functions, mainly their anorexigenic and neuroprotective features and the regulation of the cardiovascular system, pain, and stress. Additionally, the therapeutic potential of this peptide and its analogs is explored.

Dietary macronutrient composition and central neuropeptide Y injection affect dietary preference and hypothalamic gene expression in chicks.

OBJECTIVE: The objective of this study was to determine the influence of dietary macronutrient composition on central NPY's orexigenic effect in chicks. METHODS: Day-of-hatch chicks were fed one of three diets (3000 kcal ME/kg) ad libitum from hatch: high carbohydrate (HC), high fat (HF; 30% ME derived from soybean oil), and high protein (HP; 25 vs. 22% CP). In Experiment 1, chicks received intracerebroventricular injections of 0 (vehicle), 0.2, or 2.0 nmol NPY on day 4 and food intake was recorded for 6 hours. In Experiment 2, chicks were given all three diets before and after injection. In Experiment 3, hypothalamus was collected at 1-hour post-injection for gene expression analysis. RESULTS: The HC diet-fed chicks responded with a greater increase, while the chicks fed the HF diet had a lower threshold response in food intake to NPY. Neuropeptide Y dose-dependently increased food intake in chicks fed the HC and HP diets. Chicks administered 0.2 nmol NPY preferred the HC and HP diets over the HF diet. Relative quantities of hypothalamic NPYR1 and MC4R mRNA were reduced by NPY in chicks that consumed the HP and HC diets, respectively. DISCUSSION: Consumption of the HC diet was associated with the most robust NPY-induced increase in food intake. Injection of NPY accentuated differences among dietary groups in hypothalamic gene expression of several appetite-associated factors, results suggesting that the NPY/agouti-related peptide and melanocortin pathways are associated with some of the diet- and NPY-induced differences observed in this study.

Ghrelin in Senegalese sole (Solea senegalensis) post-larvae: Paracrine effects on food intake.

Successful food consumption and digestion depend on specifics anatomical and behavioral characteristics and corresponding physiological functions that should be ready to work at the appropriate time. The physiological regulation of appetite and ingestion involves a complex integration of peripheral and central signals by the brain. Ghrelin is a peptide hormone involved in the control of energy homeostasis and increases food intake in mammals, however ghrelin has species-specific actions on food intake in fish. The aim of this study was to investigate whether this peptide has an orexigenic or anorexigenic role in Senegalese sole (Solea senegalensis) in order to improve the knowledge of the physiological basis underlying feeding activity. Feed intake was measured at several sampling points to determine the overall action time of the peptide and its effect in Senegalese sole food intake. Artemia protein digestibility and retention were determined in order to analyze the ghrelin effect in fed and fasted Senegalese sole post-larvae. Results suggested that ghrelin acts as orexigenic hormone in Senegalese sole, with a response time around 25min. Results indicated that Senegalese sole post-larvae are able to maintain absorption and retention capacities independently of feeding rate and nutritional status. Furthermore, the present study gives insight for the first time of the fate of the retained amino acids, being mainly used for protein accretion (86.79% of retained amino acids recovered in protein and FAA fractions).

The cilium: a cellular antenna with an influence on obesity risk.

Primary cilia are organelles that are present on many different cell types, either transiently or permanently. They play a crucial role in receiving signals from the environment and passing these signals to other parts of the cell. In that way, they are involved in diverse processes such as adipocyte differentiation and olfactory sensation. Mutations in genes coding for ciliary proteins often have pleiotropic effects and lead to clinical conditions, ciliopathies, with multiple symptoms. In this study, we reviewed observations from ciliopathies with obesity as one of the symptoms. It shows that variation in cilia-related genes is itself not a major cause of obesity in the population but may be a part of the multifactorial aetiology of this complex condition. Both common polymorphisms and rare deleterious variants may contribute to the obesity risk. Genotype-phenotype relationships have been noticed. Among the ciliary genes, obesity differs with regard to severity and age of onset, which may relate to the influence of each gene on the balance between pro- and anti-adipogenic processes. Analysis of the function and location of the proteins encoded by these ciliary genes suggests that obesity is more linked to activities at the basal area of the cilium, including initiation of the intraflagellar transport, but less to the intraflagellar transport itself. Regarding the role of cilia, three possible mechanistic processes underlying obesity are described: adipogenesis, neuronal food intake regulation and food odour perception.

Neurohormonal response patterns to hunger, satiation, and postprandial fullness in normal weight, anorexia nervosa, and obesity.

BACKGROUND: Food intake is regulated by homeostatic and hedonic systems that interact in a complex neuro-hormonal network. Dysregulation in energy intake can lead to obesity (OB) or anorexia nervosa (AN). However, little is known about the neurohormonal response patterns to food intake in normal weight (NW), OB, and AN. MATERIAL & METHODS: During an ad libitum nutrient drink (Ensure®) test (NDT), participants underwent three pseudo-continuous arterial spin labeling (pCASL) MRI scans. The first scan was performed before starting the NDT after a > 12 h overnight fast (Hunger), the second after reaching maximal fullness (Satiation), and the third 30-min after satiation (postprandial fullness). We measured blood levels of ghrelin, cholecystokinin (CCK), glucagon-like peptide (GLP-1), and peptide YY (PYY) with every pCASL-MRI scan. Semiquantitative cerebral blood flow (CBF) maps in mL/100 gr brain/min were calculated and normalized (nCBF) with the CBF in the frontoparietal white matter. The hypothalamus (HT), nucleus accumbens [NAc] and dorsal striatum [DS] were selected as regions of interest (ROIs). RESULTS: A total of 53 participants, 7 with AN, 17 with NW (body-mass index [BMI] 18.5-24.9 kg/m2 ), and 29 with OB (BMI ≥30 kg/m2 ) completed the study. The NW group had a progressive decrease in all five ROIs during the three stages of food intake (hunger, satiation, and post-prandial fullness). In contrast, participants with OB showed a minimal change from hunger to postprandial fullness in all five ROIs. The AN group had a sustained nCBF in the HT and DS, from hunger to satiation, with a subsequent decrease in nCBF from satiation to postprandial fullness. All three groups had similar hormonal response patterns with a decrease in ghrelin, an increase in GLP-1 and PYY, and no change in CCK. CONCLUSION: Conditions of regulated (NW) and dysregulated (OB and AN) energy intake are associated with distinctive neurohormonal activity patterns in response to hunger, satiation, and postprandial fullness.

A low-glucose eating pattern is associated with improvements in glycemic variability among women at risk for postmenopausal breast cancer: an exploratory analysis.

Background: High glycemic variability (GV) is a biomarker of cancer risk, even in the absence of diabetes. The emerging concept of chrononutrition suggests that modifying meal timing can favorably impact metabolic risk factors linked to diet-related chronic disease, including breast cancer. Here, we examined the potential of eating when glucose levels are near personalized fasting thresholds (low-glucose eating, LGE), a novel form of timed-eating, to reduce GV in women without diabetes, who are at risk for postmenopausal breast cancer. Methods: In this exploratory analysis of our 16-week weight loss randomized controlled trial, we included 17 non-Hispanic, white, postmenopausal women (average age = 60.7 ± 5.8 years, BMI = 34.5 ± 6.1 kg/m2, HbA1c = 5.7 ± 0.3%). Participants were those who, as part of the parent study, provided 3-7 days of blinded, continuous glucose monitoring data and image-assisted, timestamped food records at weeks 0 and 16. Pearson's correlation and multivariate regression were used to assess associations between LGE and GV, controlling for concurrent weight changes. Results: Increases in LGE were associated with multiple unfavorable measures of GV including reductions in CGM glucose mean, CONGA, LI, J-Index, HBGI, ADDR, and time spent in a severe GV pattern (r = -0.81 to -0.49; ps < 0.044) and with increases in favorable measures of GV including M-value and LBGI (r = 0.59, 0.62; ps < 0.013). These associations remained significant after adjusting for weight changes. Conclusion: Low-glucose eating is associated with improvements in glycemic variability, independent of concurrent weight reductions, suggesting it may be beneficial for GV-related disease prevention. Further research in a larger, more diverse sample with poor metabolic health is warranted.Clinical trial registration: ClinicalTrials.gov, NCT03546972.

The Mechanism of the Gut-Brain Axis in Regulating Food Intake.

With the increasing prevalence of energy metabolism disorders such as diabetes, cardiovascular disease, obesity, and anorexia, the regulation of feeding has become the focus of global attention. The gastrointestinal tract is not only the site of food digestion and absorption but also contains a variety of appetite-regulating signals such as gut-brain peptides, short-chain fatty acids (SCFAs), bile acids (BAs), bacterial proteins, and cellular components produced by gut microbes. While the central nervous system (CNS), as the core of appetite regulation, can receive and integrate these appetite signals and send instructions to downstream effector organs to promote or inhibit the body's feeding behaviour. This review will focus on the gut-brain axis mechanism of feeding behaviour, discussing how the peripheral appetite signal is sensed by the CNS via the gut-brain axis and the role of the central "first order neural nuclei" in the process of appetite regulation. Here, elucidation of the gut-brain axis mechanism of feeding regulation may provide new strategies for future production practises and the treatment of diseases such as anorexia and obesity.

Exploring the Impact of Dawn Phenomenon on Glucose-Guided Eating Thresholds in Individuals With Type 2 Diabetes Using Continuous Glucose Monitoring: Observational Study.

BACKGROUND: Glucose-guided eating (GGE) improves metabolic markers of chronic disease risk, including insulin resistance, in adults without diabetes. GGE is a timed eating paradigm that relies on experiencing feelings of hunger and having a preprandial glucose level below a personalized threshold computed from 2 consecutive morning fasting glucose levels. The dawn phenomenon (DP), which results in elevated morning preprandial glucose levels, could cause typically derived GGE thresholds to be unacceptable or ineffective among people with type 2 diabetes (T2DM). OBJECTIVE: The aim of this study is to quantify the incidence and day-to-day variability in the magnitude of DP and examine its effect on morning preprandial glucose levels as a preliminary test of the feasibility of GGE in adults with T2DM. METHODS: Study participants wore a single-blinded Dexcom G6 Pro continuous glucose monitoring (CGM) system for up to 10 days. First and last eating times and any overnight eating were reported using daily surveys over the study duration. DP was expressed as a dichotomous variable at the day level (DP day vs non-DP day) and as a continuous variable reflecting the percent of days DP was experienced on a valid day. A valid day was defined as having no reported overnight eating (between midnight and 6 AM). ∂ Glucose was computed as the difference in nocturnal glucose nadir (between midnight and 6 AM) to morning preprandial glucose levels. ∂ Glucose ≥20 mg/dL constituted a DP day. Using multilevel modeling, we examined the between- and within-person effects of DP on morning preprandial glucose and the effect of evening eating times on DP. RESULTS: In total, 21 adults (59% female; 13/21, 62%) with non-insulin-treated T2DM wore a CGM for an average of 10.5 (SD 1.1) days. Twenty out of 21 participants (95%) experienced DP for at least 1 day, with an average of 51% of days (SD 27.2; range 0%-100%). The mean ∂ glucose was 23.7 (SD 13.2) mg/dL. People who experience DP more frequently had a morning preprandial glucose level that was 54.1 (95% CI 17.0-83.9; P<.001) mg/dL higher than those who experienced DP less frequently. For within-person effect, morning preprandial glucose levels were 12.1 (95% CI 6.3-17.8; P=.008) mg/dL higher on a DP day than on a non-DP day. The association between ∂ glucose and preprandial glucose levels was 0.50 (95% CI 0.37-0.60; P<.001). There was no effect of the last eating time on DP. CONCLUSIONS: DP was experienced by most study participants regardless of last eating times. The magnitude of the within-person effect of DP on morning preprandial glucose levels was meaningful in the context of GGE. Alternative approaches for determining acceptable and effective GGE thresholds for people with T2DM should be explored and evaluated.

The effects of Transcranial Direct Current Stimulation on food craving and food intake in individuals affected by obesity and overweight: a mini review of the magnitude of the effects.

Obesity represents one of the wellness diseases concurring to increase the incidence of diabetes, cardiovascular diseases, and cancer. One of the main perpetuating factors of obesity is food craving, which is characterized by an urgent desire to eat a large and various amount of food, regardless of calories requirement or satiety signals, and it might be addressed to the alteration of the dorsolateral prefrontal cortex (DLPFC) activity. Despite most of the gold-standard therapies focus on symptom treatment only, non-invasive brain stimulation techniques such as transcranial direct current stimulation (tDCS) could help treat overeating by modulating specific neural pathways. The current systematic review was conducted to identify whether convergent evidence supporting the usefulness of tDCS to deal with food craving are present in the literature. The review was conducted by searching articles published up to January 1st 2022 on MEDLINE, Scopus and PsycInfo databases. We included studies investigating the effects of tDCS on food craving in subjects affected by overweight and obesity. According to eligibility criteria, 5 articles were included. Results showed that tDCS targeting left DLPFC with unipolar montage induced ameliorating effects on food craving. Controversial results were shown for the other studies, that might be ascribable to the use of bipolar montage, and the choice of other target areas. Further investigations including expectancy effect control, larger sample sizes and follow-up are needed to support more robust conclusions. To conclude, tDCS combined with the use of psychoeducative intervention, diet and physical activity, might represents a potential to manage food craving in individuals with overweight and obesity.

Integrative Hedonic and Homeostatic Food Intake Regulation by the Central Nervous System: Insights from Neuroimaging.

Food intake regulation in humans is a complex process controlled by the dynamic interaction of homeostatic and hedonic systems. Homeostatic regulation is controlled by appetitive signals from the gut, adipose tissue, and the vagus nerve, while conscious and unconscious reward processes orchestrate hedonic regulation. On the one hand, sight, smell, taste, and texture perception deliver potent food-related feedback to the central nervous system (CNS) and influence brain areas related to food reward. On the other hand, macronutrient composition stimulates the release of appetite signals from the gut, which are translated in the CNS into unconscious reward processes. This multi-level regulation process of food intake shapes and regulates human ingestive behavior. Identifying the interface between hormones, neurotransmitters, and brain areas is critical to advance our understanding of conditions like obesity and develop better therapeutical interventions. Neuroimaging studies allow us to take a glance into the central nervous system (CNS) while these processes take place. This review focuses on the available neuroimaging evidence to describe this interaction between the homeostatic and hedonic components in human food intake regulation.

How much and what: Using a buffet to determine self-regulation of food intake among young school-age children.

Energy compensation indices are commonly used to examine self-regulation of food intake in children. However, previous studies failed to consider children's ability to self-regulate under complete autonomy. This study examined self-regulation of food intake among young children and the effect of calorie manipulation on food/nutrient intake using an unlimited lunch buffet paradigm. Participants were 66 children (Mage = 6.14, SD = 1.15 years; 68.2% male; 89.4% Latinx; 59.1% overweight/obese [OV/OB]). Children participated in a crossover research trial, one week apart. Participants consumed 2 different types of preloads followed by an ad-libitum lunch during each trial. A compensation index (COMPX) was calculated to identify the level of self-regulation in food intake. Food/nutrient intake was compared between both sessions. Results indicated OV/OB children showed poorer self-regulation compared to healthy weight children (t = 2.19, p = 0.032; Hedges' g = 0.55). There were significant differences in food intake/selection between OV/OB and healthy weight groups. OV/OB children consumed a higher amount of calorie, fat, and cholesterol after the high energy preload compared to healthy weight children (d's range: 0.31-0.48). Our findings support differences between the amount of self-regulation between normal and OV/OB children as well as the items they select in order to compensate.

Critical changes in hypothalamic gene networks in response to pancreatic cancer as found by single-cell RNA sequencing.

OBJECTIVE: Cancer cachexia is a devastating chronic condition characterized by involuntary weight loss, muscle wasting, abnormal fat metabolism, anorexia, and fatigue. However, the molecular mechanisms underlying this syndrome remain poorly understood. In particular, the hypothalamus may play a central role in cachexia, given that it has direct access to peripheral signals because of its anatomical location and attenuated blood-brain barrier. Furthermore, this region has a critical role in regulating appetite and metabolism. METHODS: To provide a detailed analysis of the hypothalamic response to cachexia, we performed single-cell RNA-seq combined with RNA-seq of the medial basal hypothalamus (MBH) in a mouse model for pancreatic cancer. RESULTS: We found many cell type-specific changes, such as inflamed endothelial cells, stressed oligodendrocyes and both inflammatory and moderating microglia. Lcn2, a newly discovered hunger suppressing hormone, was the highest induced gene. Interestingly, cerebral treatment with LCN2 not only induced many of the observed molecular changes in cachexia but also affected gene expression in food-intake decreasing POMC neurons. In addition, we found that many of the cachexia-induced molecular changes found in the hypothalamus mimic those at the primary tumor site. CONCLUSION: Our data reveal that multiple cell types in the MBH are affected by tumor-derived factors or host factors that are induced by tumor growth, leading to a marked change in the microenvironment of neurons critical for behavioral, metabolic, and neuroendocrine outputs dysregulated during cachexia. The mechanistic insights provided in this study explain many of the clinical features of cachexia and will be useful for future therapeutic development.

A Role for Peripheral Anandamide and 2-Arachidonoylglycerol in Short-Term Food Intake and Orexigenic Hypothalamic Responses in a Species with Continuous Nutrient Delivery.

The endocannabinoid system (ECS) plays a pivotal role in the complex control and regulation of food intake. Pharmacological ECS activation could improve health in energy-deficient stages by increasing food intake, at least in intermittent feeders. However, knowledge of the mechanism regulating appetite in species with continued nutrient delivery is incomplete. The objectives of this pilot study were to investigate the effect of the intraperitoneal (i.p.) administration of the endocannabinoids (ECs) anandamide (AEA) and 2-arachidonoylglycerol (2-AG) on food intake, plasma EC concentrations and hypothalamic orexigenic signaling, and to study how the circulatory EC tone changes in response to short-term food deprivation in dairy cows, a species with continuous nutrient delivery. The administration of EC resulted in higher food intake during the first hour after treatment. Plasma AEA concentrations were significantly increased 2.5 h after AEA injection, whereas plasma 2-AG concentrations remained unchanged 2.5 h after 2-AG injection. The hypothalamic immunoreactivity of cannabinoid receptor 1, agouti-related protein, and orexin-A was not affected by either treatment; however, neuropeptide Y and agouti-related protein mRNA abundances were downregulated in the arcuate nucleus of AEA-treated animals. Short-term food deprivation increased plasma 2-AG, while plasma AEA remained unchanged. In conclusion, i.p.-administered 2-AG and AEA increase food intake in the short term, but only AEA accumulates in the circulation. However, plasma 2-AG concentrations are more responsive to food deprivation than AEA.

The ups and downs of growth hormone secretagogue receptor signaling.

The growth hormone secretagogue receptor (GHSR) has emerged as one of the most fascinating molecules from the perspective of neuroendocrine control. GHSR is mainly expressed in the pituitary and the brain, and plays key roles regulating not only growth hormone secretion but also food intake, adiposity, body weight, glucose homeostasis and other complex functions. Quite atypically, GHSR signaling displays a basal constitutive activity that can be up- or downregulated by two digestive system-derived hormones: the octanoylated-peptide ghrelin and the liver-expressed antimicrobial peptide 2 (LEAP2), which was recently recognized as an endogenous GHSR ligand. The existence of two ligands with contrary actions indicates that GHSR activity can be tightly regulated and that the receptor displays the capability to integrate such opposing inputs in order to provide a balanced intracellular signal. This article provides a summary of the current understanding of the biology of ghrelin, LEAP2 and GHSR and discusses the reconceptualization of the cellular and physiological implications of the ligand-regulated GHSR signaling, based on the latest findings.

Integration of Nutrient Sensing in Fish Hypothalamus.

The knowledge regarding hypothalamic integration of metabolic and endocrine signaling resulting in regulation of food intake is scarce in fish. Available studies pointed to a network in which the activation of the nutrient-sensing (glucose, fatty acid, and amino acid) systems would result in AMP-activated protein kinase (AMPK) inhibition and activation of protein kinase B (Akt) and mechanistic target of rapamycin (mTOR). Changes in these signaling pathways would control phosphorylation of transcription factors cAMP response-element binding protein (CREB), forkhead box01 (FoxO1), and brain homeobox transcription factor (BSX) leading to food intake inhibition through changes in the expression of neuropeptide Y (NPY), agouti-related peptide (AgRP), pro-opio melanocortin (POMC), and cocaine and amphetamine-related transcript (CART). The present mini-review summarizes information on the topic and identifies gaps for future research.