The regulation of appetite by gut hormones

Food intake is essential to life, and thus the drive to eat is a priority. Hunger and satiety are governed by homeostatic and hedonic pathways. The homeostatic control of food intake is primarily mediated by nuclei of the hypothalamus and brainstem, while non-homeostatic control is predominantly afforded by the mesocortical and mesolimbic pathways. Hedonic drive to eat may override homeostatic control, leading to increased food intake. The increasing intake of calorie-dense, highly palatable food has contributed to escalating levels of obesity, which now represents a major public health burden. Thus, the development of appetite-reducing agents to combat the obesity epidemic is a priority. Non-specific appetite inhibitors often result in side-effects such as alterations in blood pressure, locomotor activity and disrupted eating patterns. If an appetite-reducing agent is observed to be acting specifically, it may represent a better target for the development of anti-obesity drugs. The anorectic gut hormones, peptide YY (PYY) and glucagon-like-peptide-1 (GLP-1), reduce food intake by peripheral mechanisms, and also have effects on central homeostatic and hedonic pathways. However, exogenous administration of these peptides results in nausea in humans and aversion in rodents at higher doses. This project investigated the effects of peripheral administration of GLP-1 and PYY on food intake, cardiovascular parameters and behaviour in rats. Feeding studies in fasted animals identified 1.5 nmol/kg as the minimally effective anorectic dose of PYY, while conditioned taste aversion (CTA) was present from doses of 2.5 nmol/kg PYY. Peripheral administration of 300 nmol/kg PYY significantly decreased food intake and led to significant changes in blood pressure. This dose also produced a trend for increased latency to feeding, and decreased activity. In c-Fos studies, peripheral administration of 300 nmol/kg PYY increased neuronal activation in several nuclei of the mesocorticolimbic pathways, and the area postrema (AP). Signalling in these pathways may mediate the aversive properties of PYY, while the AP may detect concurrent alterations in cardiovascular parameters. Feeding studies in fasted animals identified 10 nmol/kg as the minimally effective anorectic dose of GLP-1. Food intake was significantly reduced by 300 nmol/kg GLP-1, including decreased intake in the first feeding bout and a trend for increased latency to feeding. The same dose significantly depressed ambulatory activity and increased heart rate. A CTA was not established following peripheral GLP-1 administration at any dose tested, though patterns in activity and feeding would suggest that aversion was present at high doses. A dose of 300 nmol/kg GLP-1 increased neuronal activation in several areas important in the acquisition of aversion, including the central nucleus of the amygdala (CeA), nucleus of the solitary tract (NTS) and the mesocorticolimbic system. Activation of brain regions by high doses of PYY and GLP-1 correspond to neuronal activation by administration of LiCl. However, 32 mg/kg LiCl increased activation to a far greater degree, suggesting a distinction between substances that reduce food intake purely by aversion, and those that have endogenous homeostatic functions. The effects of GLP-1 and PYY on appetite and aversion are complex, but likely represent separate systems that are activated differentially by different circulating levels of these hormones. By collaborating with the Mathematical Department, Imperial College London, we hope to develop a mathematical model that distinguishes between specific satiety and aversive behaviours. Further work is now required to determine the utility of such modelling in detecting specific appetite inhibitors and reducing animal use.Open Acces

New Insights into the Experience of Long-Term Weight-Loss Maintenance in an Adaptive, Two-Year Weight Management Programme

The global rise in the prevalence of overweight and obesity, and the disappointing outcomes of long-term weight loss interventions, necessitated an in-depth exploration of effective strategies for sustained weight loss maintenance. This thesis presented a comprehensive study, initiated with a systematic review to identify key themes and behavioural aspects that enhance the likelihood of maintaining long-term weight loss outcomes. Building upon this framework, the research advanced to an empirical investigation involving a primary-care based cohort of 21 individuals with overweight and obesity. Selected from diverse backgrounds within an evidence-based weight-management programme, participants were interviewed at baseline, and subsequently after one and two years, providing quantitative self-assessments of their experiences with weight loss. The study revealed that agile and continuous self-monitoring, in conjunction with personalised, sustainable lifestyle adaptations, significantly correlated with successful weight management outcomes. Many participants reported substantial health benefits and maintained weight loss, frequently attributing their motivation to supportive peer networks. However, this research also identified challenges such as anxiety, disappointment, and life disruptions as significant obstacles to success. Long-term success was found to depend on a robust support system, encompassing healthcare professionals, friends, and family. This research highlighted the complex nature of long-term weight loss maintenance, confirming the persistence of certain universal themes whilst also acknowledging individual variations in their importance over time. The thesis underscored the significance of extended support systems in meeting the diverse needs of individuals striving for sustained weight loss, providing invaluable insights for healthcare professionals and policymakers in the development of more effective weight management strategies

SMEI observations of previously unseen pulsation frequencies in γ Doradus

Aims. As g-mode pulsators, gamma-Doradus-class stars may naïvely be expected to show a large number of modes. Taking advantage of the long photometric time-series generated by the solar mass ejection imager (SMEI) instrument, we have studied the star gamma Doradus to determine whether any other modes than the three already known are present at observable amplitude. Methods. High-precision photometric data from SMEI taken between April 2003 and March 2006 were subjected to periodogram analysis with the PERIOD04 package. Results. We confidently determine three additional frequencies at 1.39, 1.87, and 2.743 d−1. These are above and beyond the known frequencies of 1.320, 1.364, and 1.47 d−1. Conclusions. Two of the new frequencies, at 1.39 and 1.87 d−1, are speculated to be additional modes of oscillation, with the third frequency at 2.743−1 a possible combination frequency

Asteroseismology of red giants: photometric observations of Arcturus by SMEI

We present new results on oscillations of the K1.5 III giant Arcturus (alpha Boo), from analysis of just over 2.5 yr of precise photometric observations made by the Solar Mass Ejection Imager (SMEI) on board the Coriolis satellite. A strong mode of oscillation is uncovered by the analysis, having frequency 3.51+/-0.03 micro-Hertz. By fitting its mode peak, we are able offer a highly constrained direct estimate of the damping time (tau = 24+/-1 days). The data also hint at the possible presence of several radial-mode overtones, and maybe some non-radial modes. We are also able to measure the properties of the granulation on the star, with the characteristic timescale for the granulation estimated to be 0.50+/-0.05 days.Comment: 6 pages, 5 figures; accepted for publication in MNRAS Letter

The impact of hearing impairment and the provision of hearing aids on poverty, mental health, quality of life and activity participation in Guatemala

The World Health Organisation estimates that 466 million people worldwide have disabling hearing loss and 80% of those affected are living in low and middle income countries. Data on the impact of hearing loss or hearing aid provision in low and middle income countries is lacking. The purpose of this research project was to address the evidence gap and assess the multi-dimensional impact of hearing impairment and the provision of hearing aids on poverty, mental health, quality of life and activity participation of adults living in Guatemala. In this non-randomised controlled study 180 adult cases with an audio-metrically assessed, bilateral, disabling hearing impairment of moderate to profound severity were compared with 143 age and sex matched control participants with confirmed ‘normal’ hearing or mild, non-disabling hearing loss. All cases and controls were interviewed using a structured questionnaire. Case participants were then assessed and fitted with hearing aids. After a mean period of 7.5 months, cases and controls were re-interviewed to assess the impact of this intervention. Twenty-two in-depth interviews complemented the quantitative research. At baseline, individual earnings were 43% significantly lower among the cases than the control group. Total monthly household expenditure and per capita expenditure were significantly higher (p value = 0.001) in controls ($611,$203) as compared with cases. There was a positive association between hearing loss and the experience of depressive symptoms, but not depression. Cases were identified as having a poorer quality of life across a range of domains. At follow-up, the majority (71%) of cases reported that they used their hearing aids on a daily basis. There was no significant change in employment status for both case and control groups. Household income increased among the cases between baseline and follow-up, but not among the controls. There was no significant change to case participant’s per capita expenditure at household or 4 individual level. In contrast, for the control group there was a significant decline in the level of both household and individual per capita expenditure. There was a reduction in depression and its related symptoms and severity as well as a significant improvement in the quality of life of cases across all domains, except for social relationships. A high level of satisfaction with hearing aid use was reported globally and across a range of constituent satisfaction with amplification in daily life scores. These quantitative findings were broadly supported by the qualitative data. The research has demonstrated the positive impact that hearing aids, as part of a comprehensive fitting and aural aftercare programme may have on significantly improving quality of life and reducing symptoms of depression for people living in Guatemala. Some of the key barriers and challenges to intervention include lack of ear and hearing health awareness, stigma, financial cost and audiology clinic accessibility. The outcomes of this research have implications for ministerial advocacy, aural rehabilitation programme development and community outreach expansion

Oscillations in β Ursae Minoris

Aims. From observations of the K4III star β UMi we attempt to determine whether oscillations or any other form of variability is present. Methods. A high-quality photometric time series of ≈1000 days in length obtained from the SMEI instrument on the Coriolis satellite is analysed. Various statistical tests were performed to determine the significance of features seen in the power density spectrum of the light curve. Results. Two oscillations with frequencies 2.44 and 2.92 μHz have been identified. We interpret these oscillations as consecutive overtones of an acoustic spectrum, implying a large frequency spacing of 0.48 μHz. Using derived asteroseismic parameters in combination with known astrophysical parameters, we estimate the mass of β UMi to be 1.3 ± 0.3 M. Peaks of the oscillations in the power density spectrum show width, implying that modes are stochastically excited and damped by convection. The mode lifetime is estimated at 18 ± 9 days

L-Arginine promotes gut hormone release and reduces food intake in rodents

Aims: To investigate the anorectic effect of L‐arginine (L‐Arg) in rodents. Methods: We investigated the effects of L‐Arg on food intake, and the role of the anorectic gut hormones glucagon‐like peptide‐1 (GLP‐1) and peptide YY (PYY), the G‐protein‐coupled receptor family C group 6 member A (GPRC6A) and the vagus nerve in mediating these effects in rodents. Results: Oral gavage of L‐Arg reduced food intake in rodents, and chronically reduced cumulative food intake in diet‐induced obese mice. Lack of the GPRC6A in mice and subdiaphragmatic vagal deafferentation in rats did not influence these anorectic effects. L‐Arg stimulated GLP‐1 and PYY release in vitro and in vivo. Pharmacological blockade of GLP‐1 and PYY receptors did not influence the anorectic effect of L‐Arg. L‐Arg‐mediated PYY release modulated net ion transport across the gut mucosa. Intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) administration of L‐Arg suppressed food intake in rats. Conclusions: L‐Arg reduced food intake and stimulated gut hormone release in rodents. The anorectic effect of L‐Arg is unlikely to be mediated by GLP‐1 and PYY, does not require GPRC6A signalling and is not mediated via the vagus. I.c.v. and i.p. administration of L‐Arg suppressed food intake in rats, suggesting that L‐Arg may act on the brain to influence food intake. Further work is required to determine the mechanisms by which L‐Arg suppresses food intake and its utility in the treatment of obesity