The Function of Intestinal Afferent Neurons in Regulating Satiety During Health and Obesity

Background and aim: Within the gastrointestinal tract, vagal afferents regulate satiety and food intake via chemical and mechanical mechanisms. Cysteinyl Leukotrienes (CysLTs) are lipid mediators that are believed to regulate food intake and body weight. However, the involvement of vagal afferents in this effect remains to be established. Conversely, Glucagon like peptide-1 (GLP-1) is a satiety and incretin peptide hormone. The effect of obesity on GLP-1 mediated gut-brain signaling has yet to be investigated. Since intestinal vagal afferents’ activity is reduced during obesity, it is intriguing to investigate their responses to GLP-1 in such conditions. Methods: Extracellular recordings were performed on intestinal afferents from normal C57Bl6, low fat fed (LFF), and high fat fed (HFF) mice. To examine the effect on neuronal calcium signaling, calcium-imaging experiments were performed on isolated nodose ganglion neurons. Food intake experiments were conducted using LFF and HFF mice. Oral glucose tolerance tests (OGTT) were carried out. Whole cell patch clamp recordings were performed on nodose ganglion neurons from A) normal C57Bl mice to test the effect of CysLTs on membrane excitability, B) LFF and HFF mice to examine GLP-1 effect on membrane excitability during obesity. c-Fos immunohistochemical techniques were performed to measure the level of neuronal activation in the brainstem of both LFF and HFF mice in response to Ex-4. Results: CysLTs increased intestinal afferent firing rate and mechanosensitivity. In single nodose neuron experiments, CysLTs increased excitability. The GLP-1 agonist Ex-4 significantly decreased food intake in LFF but not HFF mice. However, Ex-4 markedly attenuated the rise in blood glucose in both LFF and HFF mice. The observed increase in nerve firing and mechanosensitivity following the application of GLP-1 and Ex-4 was abolished in HFF mice. Cell membrane excitability was significantly increased by Ex-4 in nodose from LFF but not HFF mice. Ex-4 significantly increased the number of activated neurons in the NTS area of LFF mice but not in their HFF counterparts. Conclusion: The previous observations indicate that the role CysLTs play in regulating satiety is likely to be vagally mediated. Also that satiety, but not incretin, effects of GLP-1 are impaired during obesity.

Physiological mechanisms mediating aspartame-induced satiety

Aspartame has been previously shown to increase satiety. This study aimed to investigate a possible role for the satiety hormones cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1) in this effect. The effects of the constituents of aspartame, phenylalanine and aspartic acid, were also examined. Six subjects consumed an encapsulated preload consisting of either 400 mg aspartame, 176 mg aspartic acid + 224 mg phenylalanine, or 400 mg corn flour (control), with 1.5 g paracetamol dissolved in 450 ml water to measure gastric emptying. A 1983-kJ liquid meal was consumed 60 min later. Plasma CCK, GLP-1, glucose-dependent insulinotropic polypeptide (GIP), glucose, and insulin were measured over 0-120 min. Gastric emptying was measured from 0 to 60 min. Plasma GLP-1 concentrations decreased following the liquid meal (60-120 min) after both the aspartame and amino acids preloads (control, 2096.9 pmol/l min; aspartame, 536.6 pmol/l min; amino acids, 861.8 pmol/l min; incremental area under the curve [AUC] 60-120 min, P<.05). Desire to cat was reduced from 60 to 120 min following the amino acids preload (control, -337.1 mm min; aspartame, -505.4 mm min; amino acids, -1497.1 mm min; incremental AUC 60-120 min, P<.05). However, gastric emptying rates, plasma CCK, GIP, insulin, and glucose concentrations were unaffected. There was a correlation between the increase in plasma phenylalanine and decrease in desire to eat after the liquid meal following the constituent amino acids (r = -.9774, P=.004). In conclusion, it is unlikely that aspartame increases satiety via CCK- or GLP-1-mediated mechanisms, but small changes in circulating phenylalanine concentrations may influence appetite. (C) 2003 Elsevier Science Inc. All rights reserved.

STC-1 Cells

Gastrointestinal hormones such as cholecystokinin (CCK), glucagon like peptide 1 (GLP-1), and peptide YY (PYY) play an important role in suppressing hunger and controlling food intake. These satiety hormones are secreted from enteroendocrine cells present throughout the intestinal tract. The intestinal secretin tumor cell line (STC-1) possesses many features of native intestinal enteroendocrine cells. As such, STC-1 cells are routinely used in screening platforms to identify foods or compounds that modulate secretion of gastrointestinal hormones in vitro. This chapter describes this intestinal cell model focussing on it’s applications, advantages and limitations. A general protocol is provided for challenging STC-1 cells with test compounds.

Soy isoflavones increase preprandial peptide YY (PYY), but have no effect on ghrelin and body weight in healthy postmenopausal women

Background: Soy isoflavones show structural and functional similarities to estradiol. Available data indicate that estradiol and estradiol-like components may interact with gut "satiety hormones" such as peptide YY (PYY) and ghrelin, and thus influence body weight. In a randomized, double-blind, placebo-controlled, cross-over trial with 34 healthy postmenopausal women (59 ± 6 years, BMI: 24.7 ± 2.8 kg/m2), isoflavone-enriched cereal bars (50 mg isoflavones/day; genistein to daidzein ratio 2:1) or non-isoflavone-enriched control bars were consumed for 8 weeks (wash-out period: 8-weeks). Seventeen of the subjects were classified as equol producers. Plasma concentrations of ghrelin and PYY, as well as energy intake and body weight were measured at baseline and after four and eight weeks of each intervention arm. Results: Body weight increased in both treatment periods (isoflavone: 0.40 ± 0.94 kg, P < 0.001; placebo: 0.66 ± 0.87 kg, P = 0.018), with no significant difference between treatments. No significant differences in energy intake were observed (P = 0.634). PYY significantly increased during isoflavone treatment (51 ± 2 pmol/L vs. 55 ± 2 pmol/L), but not during placebo (52 ± 3 pmol/L vs. 50 ± 2 pmol/L), (P = 0.010 for treatment differences, independent of equol production). Baseline plasma ghrelin was significantly lower in equol producers (110 ± 16 pmol/L) than in equol non-producers (162 ± 17 pmol/L; P = 0.025). Conclusion: Soy isoflavone supplementation for eight weeks did not significantly reduce energy intake or body weight, even though plasma PYY increased during isoflavone treatment. Ghrelin remained unaffected by isoflavone treatment. A larger and more rigorous appetite experiment might detect smaller differences in energy intake after isoflavone consumption. However, the results of the present study do not indicate that increased PYY has a major role in the regulation of body weight, at least in healthy postmenopausal women.

Link between increased gut hormones signaling satiety and reduced food reward following gastric bypass surgery for obesity

CONTEXT: Roux-en-Y gastric bypass (RYGB) surgery is an effective long-term intervention for weight loss maintenance, reducing appetite, and also food reward, via unclear mechanisms. OBJECTIVE: To investigate the role of elevated satiety gut hormones after RYGB, we examined food hedonic-reward responses after their acute post-prandial suppression. DESIGN: These were randomized, placebo-controlled, double-blind, crossover experimental medicine studies. PATIENTS: Two groups, more than 5 months after RYGB for obesity (n = 7-11), compared with nonobese controls (n = 10), or patients after gastric banding (BAND) surgery (n = 9) participated in the studies. INTERVENTION: Studies were performed after acute administration of the somatostatin analog octreotide or saline. In one study, patients after RYGB, and nonobese controls, performed a behavioral progressive ratio task for chocolate sweets. In another study, patients after RYGB, and controls after BAND surgery, performed a functional magnetic resonance imaging food picture evaluation task. MAIN OUTCOME MEASURES: Octreotide increased both appetitive food reward (breakpoint) in the progressive ratio task (n = 9), and food appeal (n = 9) and reward system blood oxygen level-dependent signal (n = 7) in the functional magnetic resonance imaging task, in the RYGB group, but not in the control groups. RESULTS: Octreotide suppressed postprandial plasma peptide YY, glucagon-like peptide-1, and fibroblast growth factor-19 after RYGB. The reduction in plasma peptide YY with octreotide positively correlated with the increase in brain reward system blood oxygen level-dependent signal in RYGB/BAND subjects, with a similar trend for glucagon-like peptide-1. CONCLUSIONS: Enhanced satiety gut hormone responses after RYGB may be a causative mechanism by which anatomical alterations of the gut in obesity surgery modify behavioral and brain reward responses to food.

Effect of female sex hormones on Chlamydia trachomatis growth and gene expression

Transmissible diseases are re-emerging as a global problem, with Sexually Transmitted Diseases (STDs) becoming endemic. Chlamydia trachomatis is the leading cause of bacterially-acquired STD worldwide, with the Australian cost of infection estimated at $90 - $160 million annually. Studies using animal models of genital tract Chlamydia infection suggested that the hormonal status of the genital tract epithelium at the time of exposure may influence the outcome of infection. Oral contraceptive use also increased the risk of contracting chlamydial infections compared to women not using contraception. Generally it was suggested that the outcome of chlamydial infection is determined in part by the hormonal status of the epithelium at the time of exposure. Using the human endolmetrial cell line ECC-1 this study investigated the effects of C. trachomatis serovar D infection, in conjunction with the female sex hormones, 17β-estradiol and progesterone, on chlamydial gene expression. While previous studies have examined the host response, this is the first study to examine C.trachomatis gene expression under different hormonal conditions. We have highlighted a basic model of C. trachomatis gene regulation in the presence of steroid hormones by identifying 60 genes that were regulated by addition of estradiol and/or progesterone. In addition, the third chapter of this thesis discussed and compared the significance of the current findings in the context of data from other research groups to improve our understanding of the molecular basis of chlamydial persistence under hormonal different conditions. In addition, this study analysed the effects of these female sex hormones and C. trachomatis Serovar D infection, on host susceptibility and bacterial growth. Our results clearly demonstrated that addition of steroid hormones not only had a great impact on the level of infectivity of epithelial cells with C.trachomatis serovar D, but also the morphology of chlamydial inclusions was affected by hormone supplementation.

Dual-process action of exercise on appetite control : increase in orexigenic drive but improvement in meal-induced satiety

Background: Exercise could contribute to weight loss by altering the sensitivity of the appetite regulatory system. Objective: The aim of this study was to assess the effects of 12 wk of mandatory exercise on appetite control. Design: Fifty-eight overweight and obese men and women [mean (±SD) body mass index (in kg/m2) = 31.8 ± 4.5, age = 39.6 ± 9.8 y, and maximal oxygen intake = 29.1 ± 5.7 mL · kg–1 · min–1] completed 12 wk of supervised exercise in the laboratory. The exercise sessions were designed to expend 2500 kcal/wk. Subjective appetite sensations and the satiating efficiency of a fixed breakfast were compared at baseline (week 0) and at week 12. An Electronic Appetite Rating System was used to measure subjective appetite sensations immediately before and after the fixed breakfast in the immediate postprandial period and across the whole day. The satiety quotient of the breakfast was determined by calculating the change in appetite scores relative to the breakfast's energy content. Results: Despite large variability, there was a significant reduction in mean body weight (3.2 ± 3.6 kg), fat mass (3.2 ± 2.2 kg), and waist circumference (5.0 ± 3.2 cm) after 12 wk. The analysis showed that a reduction in body weight and body composition was accompanied by an increase in fasting hunger and in average hunger across the day (P < 0.0001). Paradoxically, the immediate and delayed satiety quotient of the breakfast also increased significantly (P < 0.05). Conclusions: These data show that the effect of exercise on appetite regulation involves at least 2 processes: an increase in the overall (orexigenic) drive to eat and a concomitant increase in the satiating efficiency of a fixed meal.

Appetite sensations and satiety quotient : predictors of energy intake and weight loss

PURPOSE: The aim of this study was to further evaluate the validity and clinical meaningfulness of appetite sensations to predict overall energy intake as well as body weight loss. METHODS: Men (n=176) and women (n=139) involved in six weight loss studies were selected to participate in this study. Visual analogue scales were used to measure appetite sensations before and after a fixed test meal. Fasting appetite sensations, 1 h post-prandial area under the curve (AUC) and the satiety quotient (SQ) were used as predictors of energy intake and body weight loss. Two separate measures of energy intake were used: a buffet style ad libitum test lunch and a three-day self-report dietary record. RESULTS: One-hour post-prandial AUC for all appetite sensations represented the strongest predictors of ad libitum test lunch energy intake (p0.001). These associations were more consistent and pronounced for women than men. Only SQ for fullness was associated with ad libitum test lunch energy intake in women. Similar but weaker relationships were found between appetite sensations and the 3-day self-reported energy intake. Weight loss was associated with changes in appetite sensations (p0.01) and the best predictors of body weight loss were fasting desire to eat; hunger; and PFC (p0.01). CONCLUSIONS: These results demonstrate that appetite sensations are relatively useful predictors of spontaneous energy intake, free-living total energy intake and body weight loss. They also confirm that SQ for fullness predicts energy intake, at least in women.

The effects of exercise-induced weight loss on appetite-related peptides and motivation to eat

Context: The magnitude of exercise-induced weight loss depends on the extent of compensatory responses. An increase in energy intake is likely to result from changes in the appetite control system toward an orexigenic environment; however, few studies have measured how exercise impacts on both orexigenic and anorexigenic peptides. ---------- Objective: The aim of the study was to investigate the effects of medium-term exercise on fasting/postprandial levels of appetite-related hormones and subjective appetite sensations in overweight/obese individuals. ---------- Design and Setting: We conducted a longitudinal study in a university research center. ---------- Participants and Intervention: Twenty-two sedentary overweight/obese individuals (age, 36.9 ± 8.3 yr; body mass index, 31.3 ± 3.3 kg/m2) took part in a 12-wk supervised exercise programme (five times per week, 75% maximal heart rate) and were requested not to change their food intake during the study. ---------- Main Outcome Measures: We measured changes in body weight and fasting/postprandial plasma levels of glucose, insulin, total ghrelin, acylated ghrelin (AG), peptide YY, and glucagon-like peptide-1 and feelings of appetite. ---------- Results: Exercise resulted in a significant reduction in body weight and fasting insulin and an increase in AG plasma levels and fasting hunger sensations. A significant reduction in postprandial insulin plasma levels and a tendency toward an increase in the delayed release of glucagon-like peptide-1 (90–180 min) were also observed after exercise, as well as a significant increase (127%) in the suppression of AG postprandially. ---------- Conclusions: Exercise-induced weight loss is associated with physiological and biopsychological changes toward an increased drive to eat in the fasting state. However, this seems to be balanced by an improved satiety response to a meal and improved sensitivity of the appetite control system.

Ovarian steroid hormones: effects on immune responses and Chlamydia trachomatis infections of the female genital tract

Female sex hormones are known to regulate the adaptive and innate immune functions of the female reproductive tract. This review aims to update our current knowledge of the effects of the sex hormones estradiol and progesterone in the female reproductive tract on innate immunity, antigen presentation, specific immune responses, antibody secretion, genital tract infections caused by Chlamydia trachomatis, and vaccine-induced immunity.

Hormones down under: Hormone therapy use after the Women's Health Initiative

Aims:  The primary objective was to describe the usage pattern of hormone therapy (HT) in a sample of urban Australian women in 2001 and to assess the characteristics of users vs. non-users. The second objective was to determine whether there had been any change in usage since the publication of the results of the combined oestrogen plus progestagen arm of the Women's Health Initiative (WHI) in 2002. Methods:  A cohort of 374 postmenopausal women aged 50–80 years participated in this substudy of the LAW (Longitudinal Assessment of Ageing in Women) project: a 5-year multidisciplinary, observational study. Participants completed an annual medical assessment including details of the use of HT and the reasons for use, as well as demographic and psychosocial data. Results:  In December 2001, 30.8% of the participants were using HT, whereas 55.4% were ever users. The management of vasomotor symptoms and mood disturbance were the primary reasons for use. Of those who had been using HT in December 2001 (24.4%) women ceased using HT in the 3 months following publication of the WHI results. The percentage of women using HT in December 2003 (13.9%) was less than half of that of December 2001. Conclusion:  The rate of HT use and the reasons for use, in 2001 in Brisbane was similar to that of other Australian regions. Usage of HT decreased since the publication of the WHI results in 2002 which may reflect changing attitudes by patients and practitioners regarding HT.

‘Expected satiety’ changes hunger and fullness in the inter-meal interval

Previously, we have shown that foods differ markedly in the satiety that they are expected to confer (compared calorie-for-calorie). In the present study we tested the hypothesis that ‘expected satiety’ plays a causal role in the satiety that is experienced after a food has been consumed. Before lunch, participants (N = 32) were shown the ingredients of a fruit smoothie. Half were shown a small portion of fruit and half were shown a large portion. Participants then assessed the expected satiety of the smoothie and provided appetite ratings, before, and for three hours after its consumption. As anticipated, expected satiety was significantly higher in the ‘large portion’ condition. Moreover, and consistent with our hypothesis, participants reported significantly less hunger and significantly greater fullness in the large portion condition. Importantly, this effect endured throughout the test period (for three hours). Together, these findings confirm previous reports indicating that beliefs and expectations can have marked effects on satiety and they show that this effect can persist well into the inter-meal interval. Potential explanations are discussed, including the prospect that satiety is moderated by memories of expected satiety that are encoded around the time that a meal is consumed.

Product labelling can confer sustained increases in expected and actual satiety

Expected satiety has been shown to play a key role in decisions around meal size. Recently it has become clear that these expectations can also influence the satiety that is experienced after a food has been consumed. As such, increasing the expected and actual satiety a food product confers without increasing its caloric content is of importance. In this study we sought to determine whether this could be achieved via product labelling. Female participants (N=75) were given a 223-kcal yoghurt smoothie for lunch. In separate conditions the smoothie was labelled as a diet brand, a highly-satiating brand, or an ‘own brand’ control. Expected satiety was assessed using rating scales and a computer-based ‘method of adjustment’, both prior to consuming the smoothie and 24 hours later. Hunger and fullness were assessed at baseline, immediately after consuming the smoothie, and for a further three hours. Despite the fact that all participants consumed the same food, the smoothie branded as highly-satiating was consistently expected to deliver more satiety than the other ‘brands’; this difference was sustained 24 hours after consumption. Furthermore, post-consumption and over three hours, participants consuming this smoothie reported significantly less hunger and significantly greater fullness. These findings demonstrate that the satiety that a product confers depends in part on information that is present around the time of consumption. We suspect that this process is mediated by changes to expected satiety. These effects may potentially be utilised in the development of successful weight-management products.

Modulation of the Chlamydia trachomatis In vitro transcriptome response by the sex hormones estradiol and progesterone

BACKGROUND:Chlamydia trachomatis is a major cause of sexually transmitted disease in humans. Previous studies in both humans and animal models of chlamydial genital tract infection have suggested that the hormonal status of the genital tract epithelium at the time of exposure can influence the outcome of the chlamydial infection. We performed a whole genome transcriptional profiling study of C. trachomatis infection in ECC-1 cells under progesterone or estradiol treatment.RESULTS:Both hormone treatments caused a significant shift in the sub-set of genes expressed (25% of the transcriptome altered by more than 2-fold). Overall, estradiol treatment resulted in the down-regulation of 151 genes, including those associated with lipid and nucleotide metabolism. Of particular interest was the up-regulation in estradiol-supplemented cultures of six genes (omcB, trpB, cydA, cydB, pyk and yggV), which suggest a stress response similar to that reported previously in other models of chlamydial persistence. We also observed morphological changes consistent with a persistence response. By comparison, progesterone supplementation resulted in a general up-regulation of an energy utilising response.CONCLUSION:Our data shows for the first time, that the treatment of chlamydial host cells with key reproductive hormones such as progesterone and estradiol, results in significantly altered chlamydial gene expression profiles. It is likely that these chlamydial expression patterns are survival responses, evolved by the pathogen to enable it to overcome the host's innate immune response. The induction of chlamydial persistence is probably a key component of this survival response.

Infertility, medical advice and treatment with fertility hormones and/or in vitro fertilisation: a population perspective from the Australian Longitudinal Study on Women's Health

OBJECTIVE: To identify the factors associated with infertility, seeking advice and treatment with fertility hormones and/or in vitro fertilisation (IVF) among a general population of women. METHODS: Participants in the Australian Longitudinal Study on Women's Health aged 28-33 years in 2006 had completed up to four mailed surveys over 10 years (n=9,145). Parsimonious multivariate logistic regression was used to identify the socio-demographic, biological (including reproductive histories), and behavioural factors associated with infertility, advice and hormonal/IVF treatment. RESULTS: For women who had tried to conceive or had been pregnant (n=5,936), 17% reported infertility. Among women with infertility (n=1031), 72% (n=728) sought advice but only 50% (n=356) used hormonal/IVF treatment. Women had higher odds of infertility when: they had never been pregnant (OR=7.2, 95% CI 5.6-9.1) or had a history of miscarriage (OR range=1.5-4.0) than those who had given birth (and never had a miscarriage or termination). CONCLUSION: Only one-third of women with infertility used hormonal and/or IVF treatment. Women with PCOS or endometriosis were the most proactive in having sought advice and used hormonal/IVF treatment. IMPLICATIONS: Raised awareness of age-related declining fertility is important for partnered women aged approximately 30 years to encourage pregnancy during their prime reproductive years and reduce the risk of infertility.