[Show abstract][Hide abstract] ABSTRACT: Sexual dimorphism in adiposity is well described in adults but the age at which differences are first manifest is uncertain. Using a prospective cohort we describe longitudinal changes in directly measured adiposity and intrahepatocellular lipid (IHCL) in relation to sex in healthy term infants. At median ages of 13 and 63 days infants underwent quantification of adipose tissue depots by whole body magnetic resonance imaging and measurement of IHCL by in-vivo proton magnetic resonance spectroscopy. Longitudinal data were obtained from 70 infants (40 boys, 30 girls). In the neonatal period girls are more adipose in relation to body size than boys. At follow-up (median age 63 days) girls remained significantly more adipose. The greater relative adiposity that characterises girls is explained by more subcutaneous adipose tissue and this becomes increasingly apparent by follow-up. No significant sex differences were seen in IHCL. Sex specific differences in infant adipose tissue distribution are in keeping with those described in later life and suggest that sexual dimorphism in adiposity is established in early infancy.International Journal of Obesity accepted article preview online, 23 January 2015. doi:10.1038/ijo.2015.4.
International journal of obesity (2005) 01/2015; 39(4). DOI:10.1038/ijo.2015.4 · 5.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Maternal Body Mass Index (BMI) is positively associated with infant obesity risk. Breast milk contains a number of hormones that may influence infant metabolism during the neonatal period; these may have additional downstream effects on infant appetite regulatory pathways, thereby influencing propensity towards obesity in later life.
To conduct a systematic review of studies examining the association between maternal BMI and the concentration of appetite-regulating hormones in breast milk.
Pubmed was searched for studies reporting the association between maternal BMI and leptin, adiponectin, insulin, ghrelin, resistin, obestatin, Peptide YY and Glucagon-Like Peptide 1 in breast milk.
Twenty six studies were identified and included in the systematic review. There was a high degree of variability between studies with regard to collection, preparation and analysis of breast milk samples. Eleven of fifteen studies reporting breast milk leptin found a positive association between maternal BMI and milk leptin concentration. Two of nine studies investigating adiponectin found an association between maternal BMI and breast milk adiponectin concentration; however significance was lost in one study following adjustment for time post-partum. No association was seen between maternal BMI and milk adiponectin in the other seven studies identified. Evidence for an association between other appetite regulating hormones and maternal BMI was either inconclusive, or lacking.
A positive association between maternal BMI and breast milk leptin concentration is consistently found in most studies, despite variable methodology. Evidence for such an association with breast milk adiponectin concentration, however, is lacking with additional research needed for other hormones including insulin, ghrelin, resistin, obestatin, peptide YY and glucagon-like peptide-1. As most current studies have been conducted with small sample sizes, future studies should ensure adequate sample sizes and standardized methodology.
PLoS ONE 12/2014; 9(12):e115043. DOI:10.1371/journal.pone.0115043 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background and Aims Preterm birth is associated with raised blood pressure (BP) and other features of the metabolic syndrome in later life, but effect sizes and biological mechanisms are unknown. We conducted a meta-analysis to address these associations in adult life.
Methods We performed a systematic review and meta-analysis of studies in which metabolic syndrome associated indices were compared in adults (≥18 years of age) born preterm (< 37 weeks gestation) and at term (37–42 weeks gestation). Outcome measures included; systolic blood pressure (SBP), diastolic blood pressure (DBP), BMI, percentage fat mass and fasting plasma levels of lipids, glucose and insulin.
Results Data from 27 studies and 306,123 adults (16,094 preterm, 290,029 term) were included, with an average outcome age of 26.1 years. In adults, preterm compared with full-term birth was associated with significantly higher SBP (mean difference [95% confidence interval]: 4.2mmHg [2.7, 5.7], p<0.001), DBP (2.7mmHg [1.2, 4.2], p<0.001) and low density lipoprotein (LDL) (0.14mmol/L [0.05, 0.22], p=0.01). Meta-regression revealed a significant gender effect, with 3.0mmHg greater SBP in preterm compared to term women than in preterm-term men (95%CI: 1.3, 4.7, p=0.002); for DBP this difference was 2.1mmHg greater (0.6, 3.6, p=0.009).
Conclusions Preterm compared to term birth, is associated with higher blood pressure and LDL in adult life. Women born preterm appear to be at greater risk than men born preterm. Follow-up of older subjects born preterm will be required to determine if the effects we observe are exacerbated by age.
[Show abstract][Hide abstract] ABSTRACT: Early-life nutrition may influence later body composition. The effect of breastfeeding and formula feeding on infant body composition is uncertain.
We conducted a systematic review and meta-analysis of studies that examined body composition in healthy, term infants in relation to breastfeeding or formula feeding.
PubMed was searched for human studies that reported the outcomes fat-free mass, fat mass, or the percentage of fat mass in breastfed and formula-fed infants. Bibliographies were hand searched, and authors were contacted for additional data. The quality of studies was assessed. Differences in outcomes between feeding groups were compared at prespecified ages by using fixed-effects analyses except when heterogeneity indicated the use of random-effects analyses.
We identified 15 studies for inclusion in the systematic review and 11 studies for inclusion in the meta-analysis. In formula-fed infants, fat-free mass was higher at 3-4 mo [mean difference (95% CI): 0.13 kg (0.03, 0.23 kg)], 8-9 mo [0.29 kg (0.09, 0.49 kg)], and 12 mo [0.30 kg (0.13, 0.48 kg)], and fat mass was lower at 3-4 mo [-0.09 kg (-0.18, -0.01 kg)] and 6 mo [-0.18 kg (-0.34, -0.01 kg)] than in breastfed infants. Conversely, at 12 mo, fat mass was higher in formula-fed infants [0.29 kg (-0.03, 0.61 kg)] than in breastfed infants.
Compared with breastfeeding, formula feeding is associated with altered body composition in infancy.
American Journal of Clinical Nutrition 03/2012; 95(3):656-69. DOI:10.3945/ajcn.111.027284 · 6.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Obesity has become a major global health problem. Recently, attention has focused on the benefits of fermentable carbohydrates on modulating metabolism. Here, we take a system approach to investigate the physiological effects of supplementation with oligofructose-enriched inulin (In). We hypothesize that supplementation with this fermentable carbohydrate will not only lead to changes in body weight and composition, but also to modulation in neuronal activation in the hypothalamus. Male C57BL/6 mice were maintained on a normal chow diet (control) or a high fat (HF) diet supplemented with either oligofructose-enriched In or corn starch (Cs) for 9 weeks. Compared to HF+Cs diet, In supplementation led to significant reduction in average daily weight gain (mean ± s.e.m.: 0.19 ± 0.01 g vs. 0.26 ± 0.02 g, P < 0.01), total body adiposity (24.9 ± 1.2% vs. 30.7 ± 1.4%, P < 0.01), and lowered liver fat content (11.7 ± 1.7% vs. 23.8 ± 3.4%, P < 0.01). Significant changes were also observed in fecal bacterial distribution, with increases in both Bifidobacteria and Lactobacillius and a significant increase in short chain fatty acids (SCFA). Using manganese-enhanced MRI (MEMRI), we observed a significant increase in neuronal activation within the arcuate nucleus (ARC) of animals that received In supplementation compared to those fed HF+Cs diet. In conclusion, we have demonstrated for the first time, in the same animal, a wide range of beneficial metabolic effects following supplementation of a HF diet with oligofructose-enriched In, as well as significant changes in hypothalamic neuronal activity.
[Show abstract][Hide abstract] ABSTRACT: Our investigation addresses the hypothesis that disruption of third trimester development by preterm birth alters multiple biological pathways affecting metabolic health in adult life. We compared healthy adult volunteers aged 18–27 y born at ≤33 wk gestation or at term. We used whole-body MRI, 1H magnetic resonance spectroscopy (MRS) of liver and muscle, metabonomic profiling of blood and urine, and anthropometric and blood pressure measurements. Preterm subjects had greater (mean difference (95% CI)) total [2.21 L (0.3, 4.1), p = 0.03] and abdominal adipose tissue [internal 0.51 (0.1, 0.9), p = 0.007]; blood pressure [systolic 6.5 mm Hg (2.2, 10.8), p = 0.004; diastolic 5.9 (1.8, 10.1), p = 0.006]; and ectopic lipid (ratio (95% CI)), intrahepatocellular lipid (IHCL) 3.01 (1.78, 5.28) p < 0.001, and tibialis-intramyocellular lipid (T-IMCL) [1.31 (1.02, 1.69) p = 0.04]. In preterm, compared with term men, there was greater internal adipose tissue [mean (SD); men: preterm 4.0 (1.6), term 2.7 (1.1) liters; women: preterm 2.6 (0.9); term 2.6 (0.5); gender-gestation interaction p = 0.048] and significant differences in the urinary metabolome (elevated methylamines and acetyl-glycoproteins, lower hippurate). We have identified multiple premorbid biomarkers in ex-preterm young adults, which are most marked in men and indicative of risks to later wellbeing. These data offer insight into biological trajectories affected by preterm birth and/or neonatal care.Abbreviations: IHCL, intrahepatocellular lipid; IMCL, intramyocellular lipid; S-IMCL, soleus-intramyocellular lipid; T-IMCL, tibialis-intramyocellular lipid
Pediatric Research 10/2011; 70(5):507-512. DOI:10.1203/PDR.0b013e31822d7860 · 2.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Manganese enhanced MRI (MEMRI) is an imaging paradigm that can be used to assess neuronal activity in vivo. Here we investigate, through the use of MEMRI, the influence of receptor dynamics on neuronal activity in the hypothalamus and hippocampus focusing on the glutamate receptor signalling system. We demonstrate that intraperitoneal (i.p.) administration of monosodium glutamate (MSG) and the ionotropic glutamate receptor (iGluR) agonists NMDA and AMPA resulted in significantly increased signal intensity (SI) in the arcuate nucleus (ARC), the suprachiasmatic nucleus (SCN) and the CA3 region of the hippocampus of mice consistent with increased neuronal activity. Administration of the NMDA receptor antagonist MK-801 resulted in significantly decreased SI in the paraventricular nucleus (PVN) consistent with decreased neuronal activity. Co-administration of MSG and the AMPA receptor antagonist NBQX attenuated the increase in SI observed in the ARC from MSG alone, suggesting MEMRI may be applicable to the study of receptor dynamics in vivo. We also observed that administration of the various iGluR agonists and antagonists modulated SI in the lateral ventricle and that high dose MSG (300 mg) caused a hitherto unseen enhancement in SI in the entire cortical/subarachnoid region. In conclusion, MEMRI reveals changes in neuronal activity in response to iGluR agonists and antagonists in the CNS in vivo as well as revealing multifaceted effects beyond those attributable to neuronal activity alone.
[Show abstract][Hide abstract] ABSTRACT: Individual compartments of abdominal adiposity and lipid content within the liver and muscle are differentially associated with metabolic risk factors, obesity and insulin resistance. Subjects with greater intra-abdominal adipose tissue (IAAT) and hepatic fat than predicted by clinical indices of obesity may be at increased risk of metabolic diseases despite their "normal" size. There is a need for accurate quantification of these potentially hazardous depots and identification of novel subphenotypes that recognize individuals at potentially increased metabolic risk. We aimed to calculate a reference range for total and regional adipose tissue (AT) as well as ectopic fat in liver and muscle in healthy subjects. We studied the relationship between age, body-mass, BMI, waist circumference (WC), and the distribution of AT, using whole-body magnetic resonance imaging (MRI), in 477 white volunteers (243 male, 234 female). Furthermore, we used proton magnetic resonance spectroscopy (MRS) to determine intrahepatocellular (IHCL) and intramyocellular (IMCL) lipid content. The anthropometric variable which provided the strongest individual correlation for adiposity and ectopic fat stores was WC in men and BMI in women. In addition, we reveal a large variation in IAAT, abdominal subcutaneous AT (ASAT), and IHCL depots not fully predicted by clinically obtained measurements of obesity and the emergence of a previously unidentified subphenotype. Here, we demonstrate gender- and age-specific patterns of regional adiposity in a large UK-based cohort and identify anthropometric variables that best predict individual adiposity and ectopic fat stores. From these data we propose the thin-on-the-outside fat-on-the-inside (TOFI) as a subphenotype for individuals at increased metabolic risk.
[Show abstract][Hide abstract] ABSTRACT: Peptide YY (PYY) and pancreatic polypeptide (PP) are two appetite suppressing hormones, released post-prandially from the ileum and pancreas, respectively. PYY(3-36) , the major circulating form of the peptide, is considered to reduce food intake in humans and rodents via high affinity binding to the auto-inhibitory neuropeptide Y receptor Y2R, whereas PP is considered to act through the Y4R. Current evidence indicates the anorexigenic effects of both peptides occur via signalling in the brainstem and arcuate nucleus (ARC) of the hypothalamus. Manganese-enhanced magnetic resonance imaging (MEMRI) has previously been used to track hypothalamic neuronal activity in vivo in response to both nutritional interventions and gut hormone treatment. In the present study, we used MEMRI to demonstrate that s.c. administration of PP results in a significant reduction in signal intensity (SI) in the ARC, ventromedial hypothalamus and paraventricular nucleus of fasted mice. Subcutaneous delivery of PYY(3-36) resulted in a nonsignificant trend towards decreased SI in the hypothalamus of fasted mice. We found no SI change in the area postrema of the brainstem after s.c. injection of either peptide. These differences in hypothalamic SI profile between PP and PYY(3-36) occurred despite both peptides producing a comparable reduction in food intake. These results suggest that separate central pathways control the anorexigenic response for PP and PYY(3-36) , possibly via a differential effect of Y4 receptor versus Y2 receptor signalling. In addition, we performed a series of MEMRI scans at 0-2, 2-4 and 4-6 h post-injection of PYY(3-36) and a potent analogue of the peptide; PYY(3-36) (LT). We recorded a significant reduction in the ARC SI 2-4 h after PYY(3-36) (LT) injection compared to both saline and PYY(3-36) in fasted mice. The physiological differences between PYY(3-36) and its analogue were also observed in the long-term effects on food intake, with PYY(3-36) (LT) producing a more sustained anorexigenic effect. These data suggest that MEMRI can be used to investigate the long-term effects of gut peptide delivery on activity within the hypothalamus and brainstem.
Journal of Neuroendocrinology 04/2011; 23(4):371-80. DOI:10.1111/j.1365-2826.2011.02111.x · 3.51 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Manganese-enhanced magnetic resonance imaging (MEMRI) is a novel imaging technique capable of monitoring calcium influx, in vivo. Manganese (Mn2+) ions, similar to calcium ions (Ca2+), are taken up by activated cells where their paramagnetic properties afford signal enhancement in T(1)-weighted MRI methodologies. In this study we have assessed Mn2+ distribution in mice using magnetization-prepared rapid gradient echo (MP-RAGE) based MRI, by measuring changes in T(1)-effective relaxation times (T(1)-eff), effective R(1)-relaxation rates (R(1)-eff) and signal intensity (SI) profiles over time. The manganese concentration in the tissue was also determined using inductively coupled plasma atomic emission spectrometry (ICP-AES). Our results show a strong positive correlation between infused dose of MnCl2 and the tissue manganese concentration. Furthermore, we demonstrate a linear relationship between R(1)-eff and tissue manganese concentration and tissue-specific Mn2+ distribution in murine tissues following dose-dependent Mn2+ administration. This data provides an optimized MnCl2 dose regimen for an MP-RAGE based sequence protocol for specific target organs and presents a potential 3D MRI technique for in vivo imaging of Ca2+ entry during Ca2+-dependent processes in a wide range of tissues.
NMR in Biomedicine 10/2010; 23(8):931-8. DOI:10.1002/nbm.1513 · 3.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: N-3 polyunsaturated fatty acids (n-3 PUFA) are known to have cardiovascular and neuroprotective properties in both humans and rodents. Here, we use manganese-enhanced magnetic resonance imaging (MEMRI) to compare the effects of these polyunsaturated fatty acids on the combined effects of neuronal activity and integrity of blood-brain barrier integrity with saturated fatty acids from buttermilk. C57BL/6 mice (4 weeks old) were fed isocaloric diets containing 3% fish oil (3% FO, n=5), 12% fish oil (FO, n=6), 3% buttermilk (3% BM, n=6) or 12% buttermilk (12% BM, n=6) for 6 months. Following metabolic cage analysis these mice were scanned using a standard MEMRI protocol at 28-32 weeks of age. Adult mice aged 28-32 weeks old (RM3, n=5) and 15-16 weeks old (YRM3, n=4) maintained on standard rodent chow were also studied to assess age-related changes in brain barrier systems and neuronal activity. Signal intensity (SI) in the anterior pituitary (AP), arcuate hypothalamic nucleus (ARC), ventromedial hypothalamic nucleus (VMH) and the paraventricular hypothalamic nucleus (PVN) was significantly reduced in young compared to older mice fed standard chow. Furthermore, fish oil supplementation led to a decrease in SI within the ARC and PVN, reaching significance in the VMH in age-matched controls. Interestingly, both fish oil and buttermilk supplementation resulted in a significant increase in SI within the AP, a structure outside the BBB. We conclude that MEMRI is able to detect the combined effects of the integrity of neuronal activity and blood-brain barrier permeability in the hypothalamus associated with dietary manipulation and aging.
[Show abstract][Hide abstract] ABSTRACT: The kisspeptins are neuropeptides that stimulate the hypothalamo-pituitary-gonadal (HPG) axis. The smallest endogenous kisspeptin, kisspeptin-10 (KP-10), binds to the receptor KISS1R with a similar affinity to the full-length peptide, kisspeptin-54 (KP-54), but is less effective in vivo, possibly because of increased enzymatic breakdown or clearance. The kisspeptin system may have therapeutic potential in the treatment of reproductive disorders and endocrine cancers. We have rationally modified the structure of KP-10 and tested the binding affinity of these analogs for the KISS1R. Those analogs that bound with relatively high affinity to KISS1R were tested for ability to stimulate ERK1/2 phosphorylation in vitro and for their ability to stimulate the HPG axis in vivo. One analog, [dY](1)KP-10, bound to KISS1R with lower affinity to KP-10 and exhibited similar bioactivity in vitro. However, in vivo peripheral administration of [dY](1)KP-10 increased plasma LH and testosterone more potently than KP-10 itself at 20 min postinjection in mice. In addition, 60 min postinjection, 0.15 nmol [dY](1)KP-10 significantly increased total testosterone levels in mice whereas the same dose of KP-10 had no significant effect. Should manipulation of the kisspeptin/KISS1R signaling system prove therapeutically useful, long-lasting analogs such as [dY](1)KP-10 may have greater therapeutic potential than endogenous forms of kisspeptin.
[Show abstract][Hide abstract] ABSTRACT: Carbon-13 ((13)C) high-resolution magic angle spinning (HR-MAS) spectroscopy was used to investigate the neuroglial coupling mechanisms underlying appetite regulation in the brain of C57BL/6J mice metabolizing [1-(13)C]glucose. Control fed or overnight fasted mice received [1-(13)C]glucose (20 micromol/g intraperitoneally [i.p.]), 15 min prior to brain fixation by focused microwaves. The hypothalamic region was dissected from the rest of the brain and (13)C HR-MAS spectra were obtained from both biopsies. Fasting resulted in a significant increase in hypothalamic [3-(13)C]lactate and [2-(13)C]gamma-aminobutyric acid (GABA) relative to the remaining brain. Administration of the orexigenic peptide ghrelin (0.3 nmol/g i.p.) did not increase hypothalamic [3-(13)C]lactate or [2-(13)C]GABA, suggesting that ghrelin signaling is not sufficient to elicit all the metabolic consequences of hypothalamic activation by fasting. Our results indicate that the hypothalamic regulation of appetite involves, in addition to the well-known neuropeptide signaling, increased neuroglial lactate shuttling and augmented GABA concentrations.
Magnetic Resonance in Medicine 08/2009; 62(2):279-83. DOI:10.1002/mrm.22010 · 3.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The hypothalamic control of energy balance is regulated by a complex network of neuropeptide-releasing neurons. Although the effect of these neuropeptides on individual aspects of energy homoeostasis has been studied, the coordinated response of these effects has not been comprehensively investigated. We have simultaneously monitored a number of metabolic parameters following intracerebroventricular (ICV) administration of 1 and 3 nmol of neuropeptides with established roles in the regulation of feeding, activity and metabolism. Ad libitum- fed rats received the orexigenic neuropeptides neuropeptide Y (NPY), agouti-related protein (AgRP), melanin-concentrating hormone (MCH) or orexin-A. Overnight-food-deprived rats received an ICV injection of the anorectic peptides alpha-melanocyte-stimulating hormone (MSH), corticotrophin-releasing factor (CRF) or neuromedin U (NMU).
Our results reveal the temporal sequence of the effects of these neuropeptides on both energy intake and expenditure, highlighting key differences in their function as mediators of energy balance. NPY and AgRP increased feeding and decreased oxygen consumption, with the effects of AgRP being more prolonged. In contrast, orexin-A increased both feeding and oxygen consumption, consistent with an observed increase in activity. The potent anorexigenic effects of CRF were accompanied by a prolonged increase in activity, whereas NMU injection resulted in significant but short-lasting inhibition of food intake, ambulatory activity and oxygen consumption. alpha-MSH injection resulted in significant increases in both ambulatory activity and oxygen consumption, and reduced food intake following administration of 3 nmol of the peptide.
We have for the first time, simultaneously measured several metabolic parameters following hypothalamic administration of a number of neuropeptides within the same experimental system. This work has shown the interrelated effects of these neuropeotides on activity, energy expenditure and food intake, thus facilitating comparison between the different hypothalamic systems.
International journal of obesity (2005) 07/2009; 33(7):775-85. DOI:10.1038/ijo.2009.96 · 5.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The global increase in obesity has led to a redoubling of efforts directed at understanding the control of energy homeostasis. Insight into the mechanisms which govern appetite regulation is central to understanding the pathophysiology of obesity and the design of effective therapeutic interventions. Exploitation of hormonal satiety signals secreted by the gut requires greater insight into their interaction with central nervous system (CNS) circuits of appetite control. Manganese-enhanced magnetic resonance imaging is a novel technique, recently adapted to investigate the effects of gut peptides on CNS appetite circuits. Using manganese ion accumulation as a marker of neuronal activity, changes in signal intensity in key appetite centres within the hypothalamus following peripheral injection of gut hormones have been demonstrated. Manganese-enhanced magnetic resonance imaging offers several advantages over methodologies currently used for the study of gut hormone interactions with the CNS and has the potential for application in fields beyond appetite regulation.
[Show abstract][Hide abstract] ABSTRACT: We have used manganese-enhanced magnetic resonance imaging (MEMRI) to show distinct patterns of neuronal activation within the hypothalamus and brainstem of fasted mice in response to peripheral injection of the anorexigenic agents glucagon-like peptide-1 (GLP-1), oxyntomodulin (OXM) and lithium chloride. Administration of both GLP-1 and OXM resulted in a significant increase in signal intensity (SI) in the area postrema of fasted mice, reflecting an increase in neuronal activity within the brainstem. In the hypothalamus, GLP-1 administration induced a significant reduction in SI in the paraventricular nucleus and an increase in the ventromedial hypothalamic nucleus whereas OXM reduced SI in the arcuate and supraoptic nuclei of the hypothalamus. These data indicate that whilst these related peptides both induce a similar effect on neuronal activity in the brainstem they generate distinct patterns of activation within the hypothalamus. Furthermore, the hypothalamic pattern of signal intensity generated by GLP-1 closely matches that generated by peripheral injection of LiCl, suggesting the anorexigenic effects of GLP-1 may be in part transmitted via nausea circuits. This work provides a framework by which the temporal effects of appetite modulating agents can be recorded simultaneously within hypothalamic and brainstem feeding centres.
[Show abstract][Hide abstract] ABSTRACT: Peptide YY (PYY) is secreted postprandially from the endocrine L cells of the gastrointestinal tract. PYY(3-36), the major circulating form of the peptide, is thought to reduce food intake in humans and rodents via high-affinity binding to the autoinhibitory neuropeptide Y (NPY) receptor within the arcuate nucleus. We studied the effect of early light-phase injection of PYY(3-36) on food intake in mice fasted for 0, 6, 12, 18, 24, and 30 h and show that PYY(3-36) produces an acute anorexigenic effect regardless of the duration of fasting. We also show evidence of a delayed orexigenic effect in ad libitum-fed mice injected with PYY(3-36) in the early light phase. This delayed orexigenic effect also occurs in mice administered a potent analog of PYY(3-36), d-Allo Ile(3) PYY(3-36), but not following injection of other anorectic agents (glucagon-like-peptide 1, oxyntomodulin, and lithium chloride). Early light-phase injection of PYY(3-36) to ad libitum-fed mice resulted in a trend toward increased levels of hypothalamic NPY and agouti-related peptide mRNA and a decrease in proopiomelanocortin mRNA at the beginning of the dark phase. Furthermore, plasma levels of ghrelin were increased significantly, and there was a trend toward decreased plasma PYY(3-36) levels at the beginning of the dark phase. These data indicate that PYY(3-36) injection results in an acute anorexigenic effect followed by a delayed orexigenic effect.
[Show abstract][Hide abstract] ABSTRACT: Hormonal satiety signals secreted by the gut play a pivotal role in the physiological control of appetite. However, therapeutic exploitation of the gut-brain axis requires greater insight into the interaction of gut hormones with CNS circuits of appetite control. Using the manganese ion (Mn2+) as an activity-dependent magnetic resonance imaging (MRI) contrast agent, we showed an increase in signal intensity (SI) in key appetite-regulatory regions of the hypothalamus, including the arcuate, paraventricular, and ventromedial nuclei, after peripheral injection of the orexigenic peptide ghrelin. Conversely, administration of the anorexigenic hormone peptide YY(3-36) caused a reduction in SI. In both cases, the changes in SI recorded in the hypothalamic arcuate nucleus preceded the effect of these peptides on food intake. Intravenous Mn2+ itself did not significantly alter ghrelin-mediated expression of the immediate early gene product c-Fos, nor did it cause abnormalities of behavior or metabolic parameters. We conclude that manganese-enhanced MRI constitutes a powerful tool for the future investigation of the effects of drugs, hormones, and environmental influences on neuronal activity.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 12/2007; 27(45):12341-8. DOI:10.1523/JNEUROSCI.2391-07.2007 · 6.75 Impact Factor