Anthony P. Goldstone

Ghrelin--a hormone with multiple functions.

The growth hormone secretagogue ghrelin is in the centre of interest since its discovery in 1999. It stimulates growth hormone, corticotropic hormone and prolactin secretion, but also plays an important role in the regulation of appetite, carbohydrate- and lipid metabolism and possibly on gastric acid secretion, gastric motility, heart function and as well as immune functions and cell proliferation. Ghrelin was originally identified from the stomach but it is also present in all tissue among others in: hypothalamus, pituitary, pancreas, lung, immune cells, placenta, ovary, testis, kidney and in different tumours including pituitary adenoma, neuroendocrine tumours, thyroid carcinomas, endocrine tumours of the pancreas and lung. The gene structure and its receptor are similar to motilin, they are both synthesized in the upper gastrointestinal tract and both have prokinetic activity on gut motility. The ghrelin receptor (growth hormone secretagogue receptor) is a member of G protein-coupled seven transmembrane domain receptor. The receptor is localised in the central nervous system, kidney, thyroid, pancreas, myocardium and spleen. Starvation and low body mass index decrease, while food intake, hyperglycaemia, elevated insulin levels and high body mass index increase the endogenous ghrelin levels. Although we know much about the ghrelin, number of questions remain unanswered, such as the effects of the locally-produced ghrelin or its role in the cell metabolism.

Prader-Willi syndrome: advances in genetics, pathophysiology and treatment.

Prader-Willi syndrome (PWS) is a complex human genetic disease that arises from lack of expression of paternally inherited imprinted genes on chromosome 15q11-q13. Identification of the imprinting control centre, novel imprinted genes and distinct phenotypes in PWS patients and mouse models has increased interest in this human obesity syndrome. In this review I focus on: (i) the chromosomal region and candidate genes associated with PWS, and the possible links with individual PWS phenotypes identified using mouse models; (ii) the metabolic and hormonal phenotypes in PWS; (iii) postmortem studies of human PWS hypothalami; and (iv) current and potential advances in the management of PWS and its complications. This could have benefits for a wide spectrum of endocrine, paediatric and neuropsychiatric diseases.

Repeated intracerebroventricular administration of glucagon-like peptide-1-(7-36) amide or exendin-(9-39) alters body weight in the rat.

Central nervous system glucagon-like peptide-1-(7-36) amide (GLP-1) administration has been reported to acutely reduce food intake in the rat. We here report that repeated intracerebroventricular (i.c.v.) injection of GLP-1 or the GLP-1 receptor antagonist, exendin-(9-39), affects food intake and body weight. Daily i.c.v. injection of 3 nmol GLP-1 to schedule-fed rats for 6 days caused a reduction in food intake and a decrease in body weight of 16 +/- 5 g (P < 0.02 compared with saline-injected controls). Daily i.c.v. administration of 30 nmol exendin-(9-39) to schedule-fed rats for 3 days caused an increase in food intake and increased body weight by 7 +/- 2 g (P < 0.02 compared with saline-injected controls). Twice daily i.c.v. injections of 30 nmol exendin-(9-39) with 2.4 nmol neuropeptide Y to ad libitum-fed rats for 8 days increased food intake and increased body weight by 28 +/- 4 g compared with 14 +/- 3 g in neuropeptide Y-injected controls (P < 0.02). There was no evidence of tachyphylaxis in response to i.c.v. GLP-1 or exendin-(9-39). GLP-1 may thus be involved in the regulation of body weight in the rat.Central nervous system glucagon-like peptide-1-(7–36) amide (GLP-1) administration has been reported to acutely reduce food intake in the rat. We here report that repeated intracerebroventricular (icv) injection of GLP-1 or the GLP-1 receptor antagonist, exendin-(9–39), affects food intake and body weight. Daily icv injection of 3 nmol GLP-1 to schedule-fed rats for 6 days caused a reduction in food intake and a decrease in body weight of 16 ± 5 g (P < 0.02 compared with saline-injected controls). Daily icv administration of 30 nmol exendin-(9–39) to schedule-fed rats for 3 days caused an increase in food intake and increased body weight by 7 ± 2 g (P < 0.02 compared with saline-injected controls). Twice daily icv injections of 30 nmol exendin-(9–39) with 2.4 nmol neuropeptide Y to ad libitum-fed rats for 8 days increased food intake and increased body weight by 28 ± 4 g compared with 14 ± 3 g in neuropeptide Y-injected controls (P < 0.02). There was no evidence of tachyphylaxis in response to icv GLP-1 o...

Recommendations for the diagnosis and management of Prader-Willi syndrome

OBJECTIVE The objective of the study was to provide recommendations for the diagnosis and management of Prader-Willi syndrome throughout the life span to guide clinical practice. PARTICIPANTS An open international multidisciplinary expert meeting was held in October 2006 in Toulouse, France, with 37 invited speakers and session chairs (see Acknowledgments) and 85 additional registered participants. The meeting was supported by an unrestricted educational grant from Pfizer. EVIDENCE Invited participants with particular expertise reviewed the published evidence base for their specialist topic and unpublished data from personal experience, previous national and international PWS conferences, and PWS Association clinical advisory groups. Sessions covered epidemiology, psychiatric, and behavioral disorders; breathing and sleep abnormalities; genetics; endocrinology; and management in infancy, childhood, transition, and adulthood. CONSENSUS PROCESS This included group meetings including open discussion after each session. The guidelines were written by the Scientific Committee (authors), using the conclusions provided by the sessions chairs and summary provided by each speaker, including incorporation of changes suggested after review by selected meeting participants (see Acknowledgments). CONCLUSIONS The diagnosis and management of this complex disorder requires a multidisciplinary approach with particular emphasis on the importance of early diagnosis using accredited genetic testing, use and monitoring of GH therapy from early childhood, control of the food environment and regular exercise, appropriate management of transition, consideration of group home placement in adulthood, and distinction of behavioral problems from psychiatric illness.

Fasting biases brain reward systems towards high-calorie foods.

Nutritional state (e.g. fasted vs. fed) and different food stimuli (e.g. high‐calorie vs. low‐calorie, or appetizing vs. bland foods) are both recognized to change activity in brain reward systems. Using functional magnetic resonance imaging, we have studied the interaction between nutritional state and different food stimuli on brain food reward systems. We examined how blood oxygen level‐dependent activity within a priori regions of interest varied while viewing pictures of high‐calorie and low‐calorie foods. Pictures of non‐food household objects were included as control stimuli. During scanning, subjects rated the appeal of each picture. Twenty non‐obese healthy adults [body mass index 22.1 ± 0.5 kg/m2 (mean ± SEM), age range 19–35 years, 10 male] were scanned on two separate mornings between 11:00 and 12:00 h, once after eating a filling breakfast (‘fed’: 1.6 ± 0.1 h since breakfast), and once after an overnight fast but skipping breakfast (‘fasted’: 15.9 ± 0.3 h since supper) in a randomized cross‐over design. Fasting selectively increased activation to pictures of high‐calorie over low‐calorie foods in the ventral striatum, amygdala, anterior insula, and medial and lateral orbitofrontal cortex (OFC). Furthermore, fasting enhanced the subjective appeal of high‐calorie more than low‐calorie foods, and the change in appeal bias towards high‐calorie foods was positively correlated with medial and lateral OFC activation. These results demonstrate an interaction between homeostatic and hedonic aspects of feeding behaviour, with fasting biasing brain reward systems towards high‐calorie foods.

Appetite regulation: from the gut to the hypothalamus

these proportions had increased to 26% and 22%, respectively, with 55% of women and 66% of men being overweight (BMI > 25 kg/m 2 ; Health Survey for England, 2001), reflecting a worldwide trend which is most marked in, but not restricted to, the developed world. Most of us in affluent countries live in a privileged land of plenty where high calorie foods are easily available and in which we have a limited need for exercise. The rising prevalence of obesity in children is of particular concern (Chinn & Rona, 2001).

Obese patients after gastric bypass surgery have lower brain-hedonic responses to food than after gastric banding

Objectives Roux-en-Y gastric bypass (RYGB) has greater efficacy for weight loss in obese patients than gastric banding (BAND) surgery. We hypothesise that this may result from different effects on food hedonics via physiological changes secondary to distinct gut anatomy manipulations. Design We used functional MRI, eating behaviour and hormonal phenotyping to compare body mass index (BMI)-matched unoperated controls and patients after RYGB and BAND surgery for obesity. Results Obese patients after RYGB had lower brain-hedonic responses to food than patients after BAND surgery. RYGB patients had lower activation than BAND patients in brain reward systems, particularly to high-calorie foods, including the orbitofrontal cortex, amygdala, caudate nucleus, nucleus accumbens and hippocampus. This was associated with lower palatability and appeal of high-calorie foods and healthier eating behaviour, including less fat intake, in RYGB compared with BAND patients and/or BMI-matched unoperated controls. These differences were not explicable by differences in hunger or psychological traits between the surgical groups, but anorexigenic plasma gut hormones (GLP-1 and PYY), plasma bile acids and symptoms of dumping syndrome were increased in RYGB patients. Conclusions The identification of these differences in food hedonic responses as a result of altered gut anatomy/physiology provides a novel explanation for the more favourable long-term weight loss seen after RYGB than after BAND surgery, highlighting the importance of the gut–brain axis in the control of reward-based eating behaviour.

Nutritional Phases in Prader–Willi Syndrome

Prader–Willi syndrome (PWS) is a complex neurobehavioral condition which has been classically described as having two nutritional stages: poor feeding, frequently with failure to thrive (FTT) in infancy (Stage 1), followed by hyperphagia leading to obesity in later childhood (Stage 2). We have longitudinally followed the feeding behaviors of individuals with PWS and found a much more gradual and complex progression of the nutritional phases than the traditional two stages described in the literature. Therefore, this study characterizes the growth, metabolic, and laboratory changes associated with the various nutritional phases of PWS in a large cohort of subjects. We have identified a total of seven different nutritional phases, with five main phases and sub‐phases in phases 1 and 2. Phase 0 occurs in utero, with decreased fetal movements and growth restriction compared to unaffected siblings. In phase 1 the infant is hypotonic and not obese, with sub‐phase 1a characterized by difficulty feeding with or without FTT (ages birth—15 months; median age at completion: 9 months). This phase is followed by sub‐phase 1b when the infant grows steadily along a growth curve and weight is increasing at a normal rate (median age of onset: 9 months; age quartiles 5–15 months). Phase 2 is associated with weight gain—in sub‐phase 2a the weight increases without a significant change in appetite or caloric intake (median age of onset 2.08 years; age quartiles 20–31 months;), while in sub‐phase 2b the weight gain is associated with a concomitant increased interest in food (median age of onset: 4.5 years; quartiles 3–5.25 years). Phase 3 is characterized by hyperphagia, typically accompanied by food‐seeking and lack of satiety (median age of onset: 8 years; quartiles 5–13 years). Some adults progress to phase 4 which is when an individual who was previously in phase 3 no longer has an insatiable appetite and is able to feel full. Therefore, the progression of the nutritional phases in PWS is much more complex than previously recognized. Awareness of the various phases will aid researchers in unraveling the pathophysiology of each phase and provide a foundation for developing rational therapies. Counseling parents of newly diagnosed infants with PWS as to what to expect with regard to these nutritional phases may help prevent or slow the early‐onset of obesity in this syndrome.

Leptin interacts with glucagon-like peptide-1 neurons to reduce food intake and body weight in rodents

The adipose tissue hormone, leptin, and the neuropeptide glucagon‐like peptide‐1 (7–36) amide (GLP‐1) both reduce food intake and body weight in rodents. Using dual in situ hybridization, long isoform leptin receptor (OB‐Rb) was localized to GLP‐1 neurons originating in the nucleus of the solitary tract. ICV injection of the specific GLP‐1 receptor antagonist, exendin(9–39), at the onset of dark phase, did not affect feeding in saline pre‐treated controls, but blocked the reduction in food intake and body weight of leptin pre‐treated rats. These findings suggest that GLP‐1 neurons are a potential target for leptin in its control of feeding.

The missing risk: MRI and MRS phenotyping of abdominal adiposity and ectopic fat.

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.