Acute Food Intake Research Articles

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

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

GDF15 linked to maternal risk of nausea and vomiting during pregnancy.

GDF15, a hormone acting on the brainstem, has been implicated in the nausea and vomiting of pregnancy, including its most severe form, hyperemesis gravidarum (HG), but a full mechanistic understanding is lacking1-4. Here we report that fetal production of GDF15 and maternal sensitivity to it both contribute substantially to the risk of HG. We confirmed that higher GDF15 levels in maternal blood are associated with vomiting in pregnancy and HG. Using mass spectrometry to detect a naturally labelled GDF15 variant, we demonstrate that the vast majority of GDF15 in the maternal plasma is derived from the feto-placental unit. By studying carriers of rare and common genetic variants, we found that low levels of GDF15 in the non-pregnant state increase the risk of developing HG. Conversely, women with β-thalassaemia, a condition in which GDF15 levels are chronically high5, report very low levels of nausea and vomiting of pregnancy. In mice, the acute food intake response to a bolus of GDF15 is influenced bi-directionally by prior levels of circulating GDF15 in a manner suggesting that this system is susceptible to desensitization. Our findings support a putative causal role for fetally derived GDF15 in the nausea and vomiting of human pregnancy, with maternal sensitivity, at least partly determined by prepregnancy exposure to the hormone, being a major influence on its severity. They also suggest mechanism-based approaches to the treatment and prevention of HG.

Effect of intra‐nasal insulin therapy on food intake among African American adults: the FIINAAL study

AbstractBackgroundIntranasal insulin is a promising treatment for cognitive decline in Alzheimer’s Disease (AD) and mild cognitive impairment (MCI). However, intranasal insulin has been shown to promote weight loss, leading to concerns about decreased appetite, decreased food intake, and unintentional weight loss as negative side effects among metabolic and ingestive behavior effects of intranasal insulin sprays among AD and MCI patients. But, side effects related to food intake and appetite are not well studied, particularly among African American adults who are under‐represented in AD research.Method39 middle‐aged, cognitively normal, community‐dwelling African American adults (Table 1) were enrolled in the Food Intake and Intranasal Insulin in African American Adults (FIINAAL) study assessing effects of intranasal insulin on acute food intake and appetite ratings. This double‐blind, placebo‐controlled, randomized crossover study compared a single intranasal dose of 10 IUs of Novologã insulin, delivered with the Kurveã device, to an intranasal placebo. Participants ate a eucaloric, macronutrient‐balanced lead‐in diet for three days prior to each dose. The dose was administered in the morning following an overnight fast. An ad libitum test lunch followed the dose and participants rated their appetite immediately before and after each dose, and after the meal. Mixed effects linear model t‐tests were used to compare differences in food intake and appetite ratings between insulin and placebo conditions.ResultThere were no significant differences in test lunch energy (calories) or macronutrient intake between insulin and placebo conditions. However, fullness ratings increased significantly more after receiving a dose of insulin than after a dose of placebo (Figure 1). In addition, desire to consume sweet and fatty foods decreased significantly more after insulin than after placebo (Figure 2).ConclusionIn middle aged African American adults, acute intranasal insulin administration was associated with a reduced desire to eat palatable foods and with increased feelings of fullness, but not with reduced food intake at a test meal. Because reduced appetite appears to be an acute side effect of intranasal insulin administration, future work should study whether chronic intranasal insulin administration results in reduced appetite and, consequently, reduced food intake and body weight over time.

Levels of Alzheimer's disease blood biomarkers are altered after food intake-A pilot intervention study in healthy adults.

Blood biomarkers accurately identify Alzheimer's disease (AD) pathophysiology and axonal injury. We investigated the influence of food intake on AD-related biomarkers in cognitively healthy, obese adults at high metabolic risk. One-hundred eleven participants underwent repeated blood sampling during 3 h after a standardized meal (postprandial group, PG). For comparison, blood was sampled from a fasting subgroup over 3 h (fasting group, FG). Plasma neurofilament light (NfL), glial fibrillary acidic protein (GFAP), amyloid-beta (Aβ) 42/40, phosphorylated tau (p-tau) 181 and 231, and total-tau were measured via single molecule array assays. Significant differences were found for NfL, GFAP, Aβ42/40, p-tau181, and p-tau231 between FG and PG. The greatest change to baseline occurred for GFAP and p-tau181 (120min postprandially, p<0.0001). Our data suggest that AD-related biomarkers are altered by food intake. Further studies are needed to verify whether blood biomarker sampling should be performed in the fasting state. Acute food intake alters plasma biomarkers of Alzheimer's disease in obese, otherwise healthy adults. We also found dynamic fluctuations in plasma biomarkers concentration in the fasting state suggesting physiological diurnal variations. Further investigations are highly needed to verify if biomarker measurements should be performed in the fasting state and at a standardized time of day to improve the diagnostic accuracy.

Acute exercise affects dual-energy X-ray absorptiometry body composition estimates but not standardised ultrasound measurements of subcutaneous adipose tissue.

Ultrasound has been demonstrated to be a highly accurate and reliable tool for measuring subcutaneous adipose tissue thickness and is robust against changes in hydration status or acute food or fluid intake. However, the effect of prior acute exercise is unexamined. This study examined the impact of an acute endurance exercise and resistance exercise session on standardised brightness-mode ultrasound measurements of subcutaneous adipose tissue thickness compared to skinfolds and dual-energy X-ray absorptiometry body composition estimates. In a randomised cross-over design, 30 active adults (24.2 ± 4.9 years) undertook physique assessment via standardised brightness-mode ultrasound, skinfolds and dual-energy X-ray absorptiometry before, immediately and 45 min after an acute endurance or resistance exercise session. The mean sum of eight subcutaneous adipose tissue thickness measured via standardised brightness-mode ultrasound increased (0.6 mm, p = 0.04) immediately postendurance exercise but was not meaningful when evaluated against the technical error of measurement of the investigator. A significant (p = 0.01) but not meaningful decrease in the sum of eight skinfolds occurred immediately (-1.1 ± 0.4 mm) and 45 min (-1.3 ± 0.4 mm) postresistance exercise. Comparatively, endurance exercise elicited a meaningful decrease of total mass (460 ± 30 g) and trunk lean mass (680 ± 90 g) dual-energy X-ray absorptiometry estimates. Findings from this study indicate standardised client presentation may be unnecessary when employing either standardised brightness-mode ultrasound or skinfolds for body composition assessment unlike dual-energy X-ray absorptiometry.

A single night of moderate at-home sleep restriction increases hunger and food intake in overweight young adults

ObjectivesExperimental studies under laboratory conditions have shown a close link between acute sleep restriction and metabolic disorders. The aim of this study was to assess the effect of a single night of moderate sleep restriction implemented under ambulatory settings on sleep organization, food intake, blood pressure, and heart rate in overweight young adults. MethodsIn a non-randomized experimental study, we evaluated 15 young, overweight adults (mean age [± SEM] 20.8 ± 0.6 y) with a mean body mass index (BMI) 27.5 ± 6.2 kg/m2 (BMI range 18.9–36.6 kg/m2). Each participant was recorded at home during two successive nights under:1) Regular sleep routine (from 2330 to 0730 h, ‘night1’) and2) Restricted sleep (6 h in bed, from 0300 to 0900 h, "night2").Sleep was assessed by a non-invasive mobile system (Watch-PAT200) placed on the non-dominant wrist, measuring peripheral arterial tonometry. We measured sleep duration, rapid eye movement sleep (REM), light sleep (LS), deep sleep (DS), and waking. Starting 2 d before night1, four consecutive food records assessed daily food intake. Preceding and succeeding each night, hunger/satiety feelings (measured by self-reported visual analog scales), blood pressure, and heart rate were also evaluated. ResultsTotal sleep time was reduced in night2 (P = 0.007), with higher DS percentage (P = 0.03). Sleep onset and REM sleep latencies, LS time, and the number of wake episodes did not differ between nights. Energy intake was increased the day after night2 (P = 0.007), with increased fat and protein intakes (both P < 0.01) and feelings of hunger (P = 0.002). Systolic blood pressure was higher and heart rate faster in the morning after night2 (both P < 0.05). ConclusionsAn acute moderate at-home sleep restriction exacerbated food intake and feelings of hunger, and impaired blood pressure and heart rate regulation in young, overweight adults.

Effects of pre-meal whey protein consumption on acute food intake and energy balance over a 48-hour period

• Whey protein (20 g) reduced energy intake in both HW (193.4 kcal, 15.9 %) and OV/OB (215.81 kcal, 17.8 %) when consumed 20 min prior to mealtime, compared to placebo. • Energy deficits induced in an ad libitum test meal did not upregulate compensatory behaviours over the following 48 h. • A slowed eating rate may influence food intake following premeal whey ingestion. The effects of pre-meal whey protein consumption on acute food intake and subsequent energy balance measured over 48-h was investigated in males of healthy-weight (HW) or living with overweight and obesity (OV/OB). On two separate trial days, following a controlled breakfast (09:00) and lunch (13:00), 12 HW and 12 OV/OB males consumed either whey protein (20 g) or flavoured water beverages (16:40), and ad libitum test meal (17:00). A controlled 48-h assessment of energy intake and expenditure was used to determine any compensatory behaviour. Test meal energy intake reduced 15.9 % in HW (P = 0.003), and 17.8 % in OV/OB (P = 0.005) following whey protein, compared to placebo. We report no between-group differences and no changes in compensatory behaviour. A small dose of whey protein reduces energy intake at the next meal, without upregulating compensatory behaviours in both HW and OV/OB males. However, chronic effects on body composition and weight loss remain to be elucidated.

Effect Of Acute Feeding On Raw Bioimpedance Values And Body Water Estimates In Healthy Adults

Raw bioimpedance values of resistance (R), reactance (Xc), impedance (Z), and phase angle (PhA) are indicators of cell hydration, health, and membrane integrity. There is increasing interest in using these values as indicators of hydration and nutritional status, but effects of acute nutritional intake on raw bioimpedance values is currently unknown. PURPOSE: To determine the effects of acute feeding on raw bioimpedance values and derived body water estimates (total body water [TBW], extracellular water [ECW], intracellular water [ICW]) obtained from multi-frequency bioelectrical impedance spectroscopy (BIS). METHODS: Twenty-nine healthy young adults (59% Female; Age: 21.3 ± 2.7 yrs; Height: 172.5 ± 9.2 cm; Weight: 71.2 ± 10.3 kg) completed three randomly assigned feeding conditions: high carbohydrate (CHO: 116.5 g CHO; 882.5 g total; 0.83 ml fluid), high protein (PRO; 63.5 g PRO; 913 g total; 0.83 ml fluid), and fasted (FAST; 8 hrs fasted). Whole-body, multi-frequency BIS was completed one hour post-meal consumption. Differences in raw bioimpedance values and derived body water estimates between feeding conditions were evaluated using separate repeated measure ANOVAs covaried for average urine specific gravity to account for pre-visit hydration status. RESULTS: There were no significant differences in raw bioimpedance values [R (FAST, CHO, PRO means: 543.0, 545.1, 548.6 Ω; p = 0.418), Xc (67.2, 67.7, 67.7 Ω; p = 0.453), Z (547.2, 549.4, 552.8 Ω; p = 0.416), PhA (7.14, 7.16, 7.12°; p = 0.680)] or derived body water estimates [TBW (40.0, 40.0, 39.8 L; p = 0.289), ECW (16.1, 16.1, 16.1 L; p = 0.131), or ICW (23.9, 23.9, 23.8 L; p = 0.671)] between feeding conditions. CONCLUSION: Acute feeding did not alter raw bioimpedance values taken 1 hr post-meal in healthy young adults. Bioimpedance may not be sensitive to acute changes in nutrition/hydration or consumption of food/drink 1 hr prior to testing was not a long enough equilibration time. Acute food intake may not need to be restricted prior to bioimpedance measurements, which increases feasibility of application in clinical and athletic populations.

A Novel Truncated Liver Enriched Antimicrobial Peptide-2 Palmitoylated at its N-Terminal Antagonizes Effects of Ghrelin.

Ghrelin is secreted in the stomach during fasting and targets the growth hormone secretagogue receptor (GHSR1a) in the hypothalamus and brainstem to exert its orexigenic effect. Recently, liver enriched antimicrobial peptide-2 (LEAP2) was identified as an endogenous high-affinity GHSR1a antagonist. LEAP2 is a 40-amino acid peptide with two disulfide bridges and GHRS1a affinity in the N-terminal hydrophobic part. In this study, we tested modified truncated N-terminal peptide LEAP2 (1-14), along with its myristoylated, palmitoylated, and stearoylated analogs, to determine their affinity to and activation of GHSR1a and their anorexigenic effects after acute peripheral administration. The lipidized analogs bound GHSR1a with affinity similar to that of natural LEAP2, and lipidization significantly enhanced the affinity of LEAP2(1-14) to GHSR1a. According to the beta-lactamase reporter gene response, the natural GHSR1a agonist ghrelin activated the receptor with nanomolar EC50 LEAP2(1-14) analogs behaved as inverse agonists of GHSR1a and suppressed internal activity of the receptor with EC50 values in the 10-8 M range. LEAP2(1-14) analogs significantly lowered acute food intake in overnight fasted mice, and palmitoylated LEAP2(1-14) was the most potent. In free-fed mice, all LEAP2(1-14) analogs significantly decreased the orexigenic effect of the stable ghrelin analog [Dpr3]Ghrelin. Moreover, palmitoylated LEAP2(1-14) inhibited the growth hormone (GH) release induced by [Dpr3] Ghrelin and exhibited an increased stability in rat plasma compared with LEAP2(1-14). In conclusion, palmitoylated LEAP2(1-14) had the most pronounced affinity for GHSR1a, had an anorexigenic effect, exhibited stability in rat plasma, and attenuated [Dpr3]Ghrelin-induced GH release. Such properties render palmitoylated LEAP2(1-14) a promising substance for antiobesity treatment. SIGNIFICANCE STATEMENT: The agonist and antagonist of one receptor are rarely found in one organism. For ghrelin receptor (growth hormone secretagogue receptor, GHSR), endogenous agonist ghrelin and endogenous antagonist/inverse agonist liver enriched antimicrobial peptide-2 (LEAP2) co-exist and differently control GHSR signaling. As ghrelin has a unique role in food intake regulation, energy homeostasis, and cytoprotection, lipidized truncated LEAP2 analogs presented in this study could serve not only to reveal the relationship between ghrelin and LEAP2 but also for development of potential anti-obesity agents.

1407-P: Deletion of the Abi3 Immune Gene Locus in Mice Results in Obesity and Systemic Metabolic Disruption

Obesity is a global epidemic that affects 13% of adults world-wide, and over 40% of adults in the United States. Further, obesity contributes substantially to global morbidity and mortality and acts as a major risk factor for type II diabetes, among many other diseases. Therefore, efforts to understand the pathobiology of obesity and generate novel methods of prevention are paramount. Recent findings suggest the importance of immune cells in the progression and onset of obesity, prominently including microglia, the immune cells of the central nervous system (CNS) , and peripheral macrophages. To this end, our project proposes to explore the role of these immune cells in the etiology and progression of obesity. Our laboratory found that deletion of the Abi3 gene locus, which is a gene primarily involved in the regulation of actin dynamics within immune cells, resulted in the induction of obesity in mice. Specifically, mice lacking Abi3 had increased body weight and body fat percentage compared to wild-type mice. Additionally, mice without Abi3 showed impaired glucose tolerance and insulin sensitivity, but no changes in acute energy expenditure or food intake. Further, through RNA-seq analysis, we observed that deletion of the Abi3 gene locus substantially altered the expression of immune genes in both the CNS and peripheral tissue. Through this study, we aimed to metabolically characterize mice with and without the Abi3 gene locus in order to discover the mechanisms by which this deletion alters central and peripheral immune cells to facilitate the onset of obesity. This and future studies will enable us to understand how perturbations to microglia and peripheral immune cells alter metabolic regulation to mediate susceptibility to metabolic disease. Disclosure D.C.Smith: None. H.Karahan: None. H.Wijeratne: None. M.Al amin: None. B.Mccord: None. Y.Moon: None. J.Kim: None. Funding Indiana University Diabetes and Obesity Research Training Program, DK064466

Liver energy homeostasis impacts hypothalamus gene expression and food intake regulation

Several neuronal populations within the hypothalamus are known to modulate feeding behavior in mammals. Specifically, the arcuate nucleus contains appetite‐suppressing neurons pro‐opiomelanocortin (POMC), and appetite‐stimulating neurons neuropeptide Y (NPY)/agouti‐related peptide (AgRP) neurons. These neurons receive peripheral signals through blood and peripheral vagal afferents fibers. However, it is not well understood how peripheral signals, such as liver energy metabolism, may impact these neuronal populations to modulate feeding behavior. Herein, we used a hepatocyte‐specific PGC1a heterozygous (LPGC1a) mouse model, with associated reductions in mitochondrial fatty acid oxidation and respiratory capacity, to assess the role of liver energy homeostasis in the expression of arcuate nucleus genes involved in food intake regulation, and acute feeding behavior after peripheral delivery of nutrient or peripheral satiation hormones. To assess the impact of liver energy changes on arcuate nucleus gene expression, we used a fasting/refeeding paradigm (16‐hour fast, 2‐hour food withdrawal, and 16‐hour fast with a 4‐hour refeed). We observed reductions in liver PGC1a mRNA expression in LPGC1a compared to wildtype (WT) during all fasting and refed states. LPGC1a mice had significantly lower liver ATP and increased AMP during a fasted state. Suggesting that during a fasted state, the LPGC1a mice struggle to maintain liver energy homeostasis. Furthermore, LPGC1a mice had significantly increased AgRP mRNA expression in the hypothalamus during a fast. Interestingly, POMC expression was lower in LPGC1a mice at 2hrs and refed compared to WT and showed no change across any of the energy states. Importantly, acute food intake following 2 hr food withdrawal was not inhibited by intraperitoneal glucose or GLP‐1 in LPGC1a mice. Together these results suggest that a reduced liver energy state modulates activity of hypothalamic POMC and AgRP neurons, potentially contributing to alterations in feeding behavior of LPGC1a mice previously observed.

Food and fluid intake and hydration status does not affect ultrasound measurements of subcutaneous adipose tissue in active adults

ObjectivesTo investigate the impact of acute food and fluid intake or hydration status on the standardised brightness-mode ultrasound measurement of subcutaneous adipose tissue thickness. DesignThirty active adults (female n = 10) participated in a randomised cross over study. MethodsParticipants completed three body composition assessment sessions via standardised brightness-mode ultrasound and Dual-energy X-ray absorptiometry. Participants were assessed under standardised presentation during ‘food only’ and ‘food plus water’ sessions at baseline and reassessed after their allotted intake. ‘Hypohydration plus water’ was undertaken in a hypohydrated state at baseline and reassessed after water intake. ResultsThe sum of eight subcutaneous adipose tissue thickness was lower when measured after ‘food only’ or ‘food plus water’ compared to baseline (−0.1 to −0.9 mm; p < 0.01). However, these changes were less than the 95% confidence interval of the technical error of measurement of the investigator. Body mass, dual-energy x-ray absorptiometry total and trunk mass, lean mass and trunk lean mass estimates increased (p < 0.01) following ‘food only’ or ‘food plus water’, and decreased with hypohydration (p < 0.01). Total and regional fat mass estimates were not impacted. ConclusionsThe sum of eight subcutaneous adipose tissue thickness measured via standardised brightness-mode ultrasound was unaffected by acute food and fluid consumption or hydration status changes. Comparatively, these interventions altered dual-energy x-ray absorptiometry body composition estimates, especially that of lean mass components. Standardised brightness-mode ultrasound can therefore be used to monitor changes in fat patterning when standardised client presentation is not practically achievable.

Fight or flight: The effect of heart rate reactivity on acute stress-induced food intake

The ‘fight-or-flight-reaction’ describes the suppression of all irrelevant functions like food intake during the acute stress response. However, heart rate reactivity and food intake under acute stress has not been investigated. Therefore, the aim of this study was to investigate the effect of high and low heart rate reactivity on food intake following an acute laboratory stress paradigm in individuals with healthy weight. Fifty-six men and women with healthy weight (BMI: M = 21.82 ± 1.53 kg/m²) were categorized into high heart rate reactors (H-HRR) and low heart rate reactors (L-HRR). After the stress paradigm of the Trier Social Stress Test (TSST), total energy intake was measured in a standardized laboratory meal. H-HRR demonstrated a significantly lower appetite (z = -3.133, p≤ 0.01) and food intake (t(49.13) = 2.253, p≤ 0.05, d= 0.68) after the TSST compared to the L-HRR. No differences in the stress perception and cognitive appraisal could be found between the two reactor groups. These results suggest that the stress-induced heart rate reactivity might be a responsible factor in the stress-eating paradox. In view of the divergent results of stress-induced eating studies in laboratory setting with acute stressors, it is highly important to control the effect of the heart rate reactivity on food intake.

CNS GNPDA2 Does Not Control Appetite, but Regulates Glucose Homeostasis.

GNPDA2 has been associated with human obesity and type-2 diabetes by using a GWAS approach. GNPDA2 is an enzyme involved in the hexosamine biosynthesis pathway, which is known to be important for nutrient sensing in various organism. Its counter enzyme, GFAT, has previously been shown to be important to the development of insulin resistance in diabetes. The implication of GNPDA2 and GFAT in metabolism is scarce and the effect of both enzymes over appetite and glucose homeostasis is unknown.Aim: Identify the role of GNPDA2 and GFAT in nutrient sensing circuits of the CNS that are important for the regulation of both appetite and glucose homeostasis.Methods: Using Long Evans rats, we administered either a GNPDA2 or GFAT antagonist or vehicle in i3vt.Key Findings: GNPDA2 is highly expressed in hypothalamus and adipose tissue, followed by muscle and liver. GNPDA2 is expressed in different hypothalamic nuclei (ARC, DMH, LHA, PVN). GNPDA2 is downregulated in hypothalamus under diet-induced obesity (as previously described), but GFAT expression does not change. Moreover, i3vt infusion of GNPDA2 or GFAT inhibitor resulted in increased c-Fos in areas related to appetite and glucose homeostasis control as PVN and DMH and to a lesser extent in the LHA and ARC. Central inhibition of GNPDA2 does not alter either acute food intake or body weight; however, GFAT inhibition diminished appetite and body weight due to visceral illness. In addition, central administration of the GNPDA2 antagonist, prior to an intraperitoneal glucose tolerance test, resulted in glucose intolerance in comparison to vehicle without altering insulin levels.Significance: These results suggest that central GNPDA2 does not control appetite, but regulates glucose homeostasis.

Carbohydrate Taste Is Associated with Food Intake and Body Mass in Healthy Australian Adults.

Background: The taste of carbohydrates may drive their intake. Sensitivity to carbohydrate taste varies among individuals, thus, it is important to understand how differences in sensitivity influence eating behaviour and body mass. Objective: The aims of this study were to assess associations among carbohydrate taste sensitivity, habitual and acute food intake, and body mass; as well as assess the reliability of the carbohydrate detection threshold (DT) test within and across days. Methods: Carbohydrate DT was assessed six times across three sessions in 36 healthy adult participants (22 female) using a three-alternate forced choice methodology. Moreover, 24 h diet records were completed on the days prior to testing sessions, and food intake at a buffet lunch was collected following each session. Anthropometry was also measured. Linear mixed regression models were fitted. Results: The DT test required at least three measures within a given day for good reliability (ICC = 0.76), but a single measure had good reliability when compared at the same time across days (ICC = 0.54–0.86). Carbohydrate DT was associated with BMI (kg/m2: β = −0.38, p = 0.014), habitual carbohydrate intake (g: β = −41.8, p = 0.003) and energy intake (kJ: β = −1068, p = 0.019) from the 24-h diet records, as well as acute intake of a buffet lunch (food weight (g): β = −76.1, p = 0.008). Conclusions: This suggests that individuals who are more sensitive to carbohydrate are more likely to consume greater quantities of carbohydrates and energy, resulting in a greater body mass.

Intranasal Delivery of a Methyllanthionine-Stabilized Galanin Receptor-2-Selective Agonist Reduces Acute Food Intake

The regulatory (neuro)peptide galanin is widely distributed in the central and peripheral nervous systems, where it mediates its effects via three G protein-coupled receptors (GAL1-3R). Galanin has a vast diversity of biological functions, including modulation of feeding behavior. However, the clinical application of natural galanin is not practicable due to its rapid in vivo breakdown by peptidases and lack of receptor subtype specificity. Much effort has been put into the development of receptor-selective agonists and antagonists, and while receptor selectivity has been attained to some degree, most ligands show overlapping affinity. Therefore, we aimed to develop a novel ligand with specificity to a single galanin receptor subtype and increased stability. To achieve this, a lanthionine amino acid was enzymatically introduced into a galanin-related peptide. The residue’s subsequent cyclization created a conformational constraint which increased the peptide’s receptor specificity and proteolytic resistance. Further exchange of certain other amino acids resulted in a novel methyllanthionine-stabilized galanin receptor agonist, a G1pE-T3N-S6A-G12A-methyllanthionine[13–16]-galanin-(1–17) variant, termed M89b. M89b has exclusive specificity for GAL2R and a prolonged half-life in serum. Intranasal application of M89b to unfasted rats significantly reduced acute 24 h food intake inducing a drop in body weight. Combined administration of M89b and M871, a selective GAL2R antagonist, abolished the anorexigenic effect of M89b, indicating that the effect of M89b on food intake is indeed mediated by GAL2R. This is the first demonstration of in vivo activity of an intranasally administered lanthipeptide. Consequently, M89b is a promising candidate for clinical application as a galanin-related peptide-based therapeutic.

Energy homeostasis deregulation is attenuated by TUDCA treatment in streptozotocin-induced Alzheimer\u2019s disease mice model

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia. While cognitive deficits remain the major manifestation of AD, metabolic and non-cognitive abnormalities, such as alterations in food intake, body weight and energy balance are also present, both in AD patients and animal models. In this sense, the tauroursodeoxycholic acid (TUDCA) has shown beneficial effects both in reducing the central and cognitive markers of AD, as well as in attenuating the metabolic disorders associated with it. We previously demonstrated that TUDCA improves glucose homeostasis and decreases the main AD neuromarkers in the streptozotocin-induced AD mouse model (Stz). Besides that, TUDCA-treated Stz mice showed lower body weight and adiposity. Here, we investigated the actions of TUDCA involved in the regulation of body weight and adiposity in Stz mice, since the effects of TUDCA in hypothalamic appetite control and energy homeostasis have not yet been explored in an AD mice model. The TUDCA-treated mice (Stz + TUDCA) displayed lower food intake, higher energy expenditure (EE) and respiratory quotient. In addition, we observed in the hypothalamus of the Stz + TUDCA mice reduced fluorescence and gene expression of inflammatory markers, as well as normalization of the orexigenic neuropeptides AgRP and NPY expression. Moreover, leptin-induced p-JAK2 and p-STAT3 signaling in the hypothalamus of Stz + TUDCA mice was improved, accompanied by reduced acute food intake after leptin stimulation. Taken together, we demonstrate that TUDCA treatment restores energy metabolism in Stz mice, a phenomenon that is associated with reduced food intake, increased EE and improved hypothalamic leptin signaling. These findings suggest treatment with TUDCA as a promising therapeutic intervention for the control of energy homeostasis in AD individuals.

Reduced Liver-Specific PGC1a Increases Susceptibility for Short-Term Diet-Induced Weight Gain in Male Mice.

The central integration of peripheral neural signals is one mechanism by which systemic energy homeostasis is regulated. Previously, increased acute food intake following the chemical reduction of hepatic fatty acid oxidation and ATP levels was prevented by common hepatic branch vagotomy (HBV). However, possible offsite actions of the chemical compounds confound the precise role of liver energy metabolism. Herein, we used a hepatocyte PGC1a heterozygous (LPGC1a) mouse model, with associated reductions in mitochondrial fatty acid oxidation and respiratory capacity, to assess the role of liver energy metabolism in systemic energy homeostasis. LPGC1a male, but not female, mice had a 70% greater high-fat/high-sucrose (HFHS) diet-induced weight gain compared to wildtype (WT) mice (p < 0.05). The greater weight gain was associated with altered feeding behavior and lower activity energy expenditure during the HFHS diet in LPGC1a males. WT and LPGC1a mice underwent sham surgery or HBV to assess whether vagal signaling was involved in the HFHS-induced weight gain of male LPGC1a mice. HBV increased HFHS-induced weight gain (85%, p < 0.05) in male WT mice, but not LPGC1a mice. These data demonstrate a sex-specific role of reduced liver energy metabolism in acute diet-induced weight gain, and the need for a more nuanced assessment of the role of vagal signaling in short-term diet-induced weight gain.

KBP-066A, a long-acting dual amylin and calcitonin receptor agonist, induces weight loss and improves glycemic control in obese and diabetic rats

ObjectiveDual amylin and calcitonin receptor agonists (DACRAs) are novel therapeutic agents that not only improve insulin sensitivity but also work as an adjunct to established T2DM therapies. DACRAs are currently administered once daily, though it is unknown whether DACRAs with increased plasma half-life can be developed as a once-weekly therapy. MethodsThe in vitro potencies of the KBP-066A and KBP-066 (non-acylated) were assessed using reporter assays. Acylation functionality was investigated by a combination of pharmacokinetics and acute food intake in rats. in vivo efficacies were investigated head-to-head in obese (HFD) and T2D (ZDF) models. ResultsIn in vitro, KBP-066A activated the CTR and AMY-R potently, with no off-target activity. Acylation functionality was confirmed by acute tests, as KBP-066A demonstrated a prolonged PK and PD response compared to KBP-066. Both compounds induced potent and dose-dependent weight loss in the HFD rat model. In ZDF rats, fasting blood glucose/fasting insulin levels (tAUC) were reduced by 39%/50% and 36%/47% for KBP-066 and KBP-066A, respectively. This effect resulted in a 31% and 46% vehicle-corrected reduction in HbA1c at the end of the study for KBP-066 and KBP-066A, respectively. ConclusionsHere, we present pre-clinical data on an acylated DACRA, KBP-066A. The in vivo efficacy of KBP-066A is significantly improved compared to its non-acylated variant regarding weight loss and glycemic control in obese (HFD) and obese diabetic rats (ZDF). This compendium of pre-clinical studies highlights KBP-066A as a promising, once-weekly therapeutic agent for treating T2DM and obesity.

Acute Daily Stress, Daily Food Consumption, and the Moderating Effect of Disordered Eating among Adolescents with Overweight/Obesity.

Objective: The purpose of this study was to examine the associations between acute daily stress dimensions (frequency, sum) and food intake in adolescents with overweight/obesity, and to explore the potential moderating effect of disordered eating behaviors on these associations. Methods: One hundred eighty-two adolescents with overweight/obesity (65% females; 68.7% non-white; 16.2 ± 1.8 years of age) were included in this analysis. Acute daily stress was measured using the Daily Stress Inventory, and daily caloric intake was measured using a food frequency questionnaire. Disordered eating behavior was assessed using the Eating Attitudes Test (EAT-26). Results: Acute daily stress frequency (B = 0.013 ± 0.003; p < 0.001) and acute daily stress sum (B = 0.003 ± 0.001; p < 0.001) were associated with greater daily caloric intake. Disordered eating behavior moderated the association between acute daily stress frequency and caloric intake (pinteraction = 0.039), with greater daily caloric intake among those with higher levels of disordered eating. Disordered eating behavior did not significantly moderate the association between acute daily stress sum and daily caloric intake (pinteraction = 0.053). Conclusions: These findings suggest that greater exposure to acute daily stressors may increase daily food intake in adolescents with overweight/obesity, with greater susceptibility among those engaging in high levels of disordered eating. Longitudinal research is warranted to elucidate the long-term effect of acute daily stressors and disordered eating on food intake among adolescents with overweight/obesity. The Health and Culture Project is registered at www.clinicaltrials.gov (No. NCT02938663).