Biomedical subjects

Anthony P Goldstone

Publications and source records attributed to Anthony P Goldstone.

11 recordsLinked to original sources

PubMed2006

Enhanced activation of reward mediating prefrontal regions in response to food stimuli in Prader-Willi syndrome.

BACKGROUND: Individuals with Prader-Willi syndrome (PWS) exhibit severe disturbances in appetite regulation, including delayed meal termination, early return of hunger after a meal, seeking and hoarding food and eating of non-food substances. Brain pathways involved in the control of appetite in humans are thought to include the hypothalamus, frontal cortex (including the orbitofrontal, ventromedial prefrontal, dorsolateral prefrontal and anterior cingulate areas), insula, and limbic and paralimbic areas. We hypothesised that the abnormal appetite in PWS results from aberrant reward processing of food stimuli in these neural pathways. METHODS: We compared functional MRI blood oxygen level dependent (BOLD) responses while viewing pictures of food in eight adults with PWS and eight normal weight adults after ingestion of an oral glucose load. RESULTS: Subjects with PWS demonstrated significantly greater BOLD activation in the ventromedial prefrontal cortex than controls when viewing food pictures. No significant differences were found in serum insulin, glucose or triglyceride levels between the groups at the time of the scan. CONCLUSIONS: Individuals with PWS had an increased BOLD response in the ventromedial prefrontal cortex compared with normal weight controls when viewing pictures of food after an oral glucose load. These findings suggest that an increased reward value for food may underlie the excessive hunger in PWS, and support the significance of the frontal cortex in modulating the response to food in humans. Our findings in the extreme appetite phenotype of PWS support the importance of the neural pathways that guide reward related behaviour in modulating the response to food in humans.

Adult↗

PubMed2006

Neurocognitive findings in Prader-Willi syndrome and early-onset morbid obesity.

OBJECTIVES: To examine whether early-onset morbid obesity is associated with cognitive impairment, neuropathologic changes, and behavioral problems. STUDY DESIGN: This case-control study compared head MRI scans and cognitive, achievement, and behavioral evaluations of subjects with Prader-Willi syndrome (PWS), early-onset morbid obesity (EMO), and normal-weight sibling control subjects from both groups. Head MRI was done on 17 PWS, 18 EMO, and 21 siblings, and cognitive, achievement, and behavioral evaluations were done on 19 PWS, 17 EMO, and 24 siblings. RESULTS: The mean General Intellectual Ability score of the EMO group was 77.4 +/- 17.8; PWS, 63.3 +/- 14.2; and control subjects, 106.4 +/- 13.0. Achievement scores for the three groups were EMO, 78.7 +/- 18.8; PWS, 71.2 +/- 17.0; and control subjects, 104.8 +/- 17.0. Significant negative behaviors and poor adaptive skills were found in the EMO group. White matter lesions were noted on brain MRI in 6 subjects with PWS and 5 with EMO. None of the normal-weight control subjects had these findings. CONCLUSIONS: Individuals with EMO have significantly lower cognitive function and more behavioral problems than control subjects with no history of childhood obesity. Both EMO and PWS subjects have white matter lesions on brain MRI that have not previously been described.

Achievement↗

PubMed2006

The hypothalamus, hormones, and hunger: alterations in human obesity and illness.

Obesity is a major global epidemic, with over 300 million obese people worldwide, and nearly 1 billion overweight adults. Being overweight carries significant health risks, reduced quality of life, and impaired socioeconomic success, with profound consequences for health expenditure. The most successful treatment for obesity is gastric bypass surgery, which acts in part by reducing appetite through alterations in gut hormones. Circulating gut hormones, secreted or suppressed after eating food, act in the brain, particularly the hypothalamus, to alter hunger and fullness. Stomach-derived ghrelin increases food intake even in those with anorexia from chronic illness, while pancreatic polypeptide (PP), intestinal peptide YY 3-36 (PYY), oxyntomodulin, and other hormones reduce food intake and appetite. While obese subjects have appropriate reductions in orexigenic ghrelin, other gut-hormone disturbances may contribute to obesity such as reduced anorexigenic PYY and PP. Prader-Willi syndrome (PWS) arises from the loss of paternally inherited genes on chromosome 15q11-13, leading to life-threatening insatiable hunger and obesity from early childhood, through developmental brain, particularly hypothalamic defects. The study of genetically homogenous causes of abnormal-feeding behavior helps our understanding of appetite regulation. PWS subjects have inappropriately elevated plasma ghrelin for their obesity, at least partly explained by preserved insulin sensitivity. It remains unproven if their hyperghrelinemia or other gut-hormone abnormalities contribute to the hyperphagia in PWS, in addition to brain defects. Postmortem human hypothalamic studies and generation of animal models of PWS can also provide insight into the pathophysiology of abnormal-feeding behavior. Changes in orexigenic NPY and AGRP hypothalamic neurons, or anorexigenic oxytocin neurons have been found in illness and PWS. Functional neuroimaging studies, using PET and fMRI, will also allow us to tease apart the hormonal and brain pathways responsible for controlling human appetite, and their defects in obesity.

Brain Mapping↗

PubMed2005

Fasting and postprandial hyperghrelinemia in Prader-Willi syndrome is partially explained by hypoinsulinemia, and is not due to peptide YY3-36 deficiency or seen in hypothalamic obesity due to craniopharyngioma.

The cause of the unique elevation in fasting plasma levels of the orexigenic gastric hormone ghrelin in many patients with Prader-Willi syndrome (PWS) is unclear. We measured fasting and postprandial plasma ghrelin in nonobese (n = 16 fasting and n = 8 postprandial) and obese non-PWS adults (n = 16 and 9), adults with genetically confirmed PWS (n = 26 and 10), and patients with hypothalamic obesity from craniopharyngioma tumors (n = 9 and 6). We show that 1) plasma ghrelin levels decline normally after food consumption in PWS, but there is still fasting and postprandial hyperghrelinemia relative to the patient's obesity (2.0-fold higher fasting ghrelin, 1.8-fold higher postprandial ghrelin, adjusting for percentage of body fat); 2) the fasting and postprandial hyperghrelinemia in PWS appears to be at least partially, but possibly not solely, explained by the concurrent relative hypoinsulinemia and preserved insulin sensitivity for the patient's obesity (residual 1.3- to 1.6-fold higher fasting ghrelin, 1.2- to 1.5-fold higher postprandial ghrelin in PWS, adjusting for insulin levels or homeostasis model assessment of insulin resistance); 3) hyperghrelinemia and hypoinsulinemia are not found in craniopharyngioma patients with hypothalamic obesity, and indeed, these patients have relative hyperinsulinemia for their obesity; and 4) there is no deficiency of the anorexigenic intestinal hormone peptide YY(3-36) in PWS contributing to their hyperghrelinemia.

Adult↗

PubMed2004

Ghrelin--a hormone with multiple functions.

Ghrelin is brain-gut peptide with growth hormone-releasing and appetite-inducing activities. It is mainly secreted from the stomach mucosa but it is also expressed widely in different tissues and therefore may have both endocrine and paracrine effects. Ghrelin is the endogenous ligand of the G protein-coupled growth hormone secretagogue receptor. In the current review we comprehensively summarize (i) the data available regarding the structure, expression pattern and regulation of ghrelin and its receptor; (ii) the available information regarding the effect of ghrelin on the pituitary hormone axis, appetite regulation, cardiac and gastrointestinal function, carbohydrate metabolism, adipose and reproductive tissue, cell proliferation and behavioral effects; (iii) experimental and clinical data regarding circulating ghrelin levels observed in various physiological and pathological conditions; and (iv) data on gene variations of ghrelin and its receptor. It is apparent that ghrelin is involved in many more processes than originally envisaged, and in particular appears to have relatively less relevance to growth hormone physiology and more to the regulation of energy fluxes in the organism. Increasing data link ghrelin to the overall control of energy use and flow in situations where there is a limitation of energy sources and ghrelin appears to play a pivotal role in energy homeostasis.

Animals↗

PubMed2004

Elevated fasting plasma ghrelin in prader-willi syndrome adults is not solely explained by their reduced visceral adiposity and insulin resistance.

Plasma ghrelin is elevated in Prader-Willi syndrome (PWS). This might contribute to obesity or GH deficiency in such patients. Visceral adiposity and insulin resistance are reduced in PWS, which might lead to hyperghrelinemia. We measured fasting plasma ghrelin in control female (n = 39), PWS female (n = 12), and PWS male (n = 6) adults. In controls and PWS, ghrelin was negatively correlated with visceral adiposity, fasting insulin, and homeostasis model insulin resistance index. There was no significant correlation with serum IGF-I in PWS. In stepwise linear regression, visceral adiposity (P < 0.02) had a stronger inverse correlation with ghrelin than sc fat depots in controls and PWS, possibly through hyperinsulinemia, as the correlations with insulin resistance were even stronger (P < 0.01). PWS females had significantly (P < 0.001) elevated ghrelin (mean +/- SD, 661 +/- 360 pg/ml), compared with both nonobese (363 +/- 163) and obese (191 +/- 66) controls. Ghrelin was increased 3.4- to 3.6-fold in PWS females adjusting for total adiposity, 3.2- to 3.4-fold adjusting for visceral adiposity, and 3.0-fold adjusting for insulin resistance. Fasting plasma glucagon-like peptide-1 was normal in PWS females. The hyperghrelinemia in PWS adults is therefore not solely explained by their reduced visceral adiposity and relative hypoinsulinemia. Its cause and consequences await further elucidation.

Adipose Tissue↗

PubMed2004

Somatostatin infusion lowers plasma ghrelin without reducing appetite in adults with Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is characterized by life-threatening childhood-onset hyperphagia, obesity and, uniquely, high plasma levels of ghrelin, the orexigenic gastric hormone. Somatostatin suppresses ghrelin secretion in normal subjects. We therefore examined the effect of somatostatin on plasma ghrelin and appetite in four male PWS adults fasted overnight in a double-blind, placebo-controlled, randomized cross-over study. Subjects received an intravenous infusion of somatostatin (250 microg/hr) or saline for 300 min, and had blood samples taken every 30 min for measurement of plasma ghrelin and PYY3-36 (anorexigenic intestinal hormone) by radio-immunoassay, and glucose. Appetite was measured by counting sandwiches eaten over a 60 min free food access period from +120 min. Despite somatostatin lowering fasting plasma ghrelin by 60 +/- 2% (P = 0.04) to levels seen in non-PWS men, there was no associated reduction in food intake (105 +/- 9% of food intake during saline infusion, P = 0.6). Somatostatin also lowered plasma PYY levels by 45 +/- 16% (P = 0.04), and produced post-prandial hyperglycemia (P = 0.04). We conclude that either hyperghrelinemia may not contribute to hyperphagia in PWS adults, or perhaps concomitant reductions in anorexigenic gastrointestinal hormones by somatostatin counteracted any anorexigenic effect of lowering orexigenic ghrelin. Somatostatin analogues may therefore not be an effective therapy for obesity in PWS. Larger chronic studies with long-acting somatostatin analogues will be needed to determine their benefits and risks in treating PWS obesity.

Adult↗

PubMed2003

Hypothalamic growth hormone-releasing hormone (GHRH) cell number is increased in human illness, but is not reduced in Prader-Willi syndrome or obesity.

BACKGROUND: Acute illness leads to increased GH, but reduced IGF-I secretion, while both are reduced in chronic illness. Prader-Willi syndrome (PWS) is a genetic obesity syndrome, with GH deficiency a feature independent of obesity. Reduced GH secretion may result from decreased hypothalamic release of GH-releasing hormone (GHRH). OBJECTIVE: To quantify hypothalamic GHRH neurone cell number in control subjects with various lengths of premorbid illness duration, PWS and non-PWS obese subjects. DESIGN: We examined GHRH neurones in the infundibular nucleus/median eminence complex of control subjects (n = 26, including four children), PWS (n = 6) and non-PWS (n = 4) obese adults and PWS children (n = 2), by quantitative immunocytochemistry, using postmortem material. RESULTS: We found: (i) higher GHRH cell number during prolonged illness prior to death in both control adults (r = +0.62, P = 0.002, cell number vs. premorbid illness duration) and PWS adults (r = +0.90, P = 0.02); (ii) higher GHRH cell number in female than male adults [by 53% (95% confidence interval 28-83%) in controls, P = 0.005, correcting for premorbid illness duration]; (iii) no difference in GHRH cell number between PWS adults and control or non-PWS obese adults (P = 0.7 and P = 0.4, adjusting for sex and illness duration); and (iv) low GHRH cell number in only one PWS child (who had been receiving exogenous GH therapy). CONCLUSIONS: These findings suggest continued activation of GHRH neurones during prolonged illness. There is no evidence that the GH deficiency in PWS results from reduced GHRH cell number, and GHRH neuronal responses to illness and exogenous GH treatment appear normal in PWS.

Acute Disease↗

PubMed2002

Resting metabolic rate, plasma leptin concentrations, leptin receptor expression, and adipose tissue measured by whole-body magnetic resonance imaging in women with Prader-Willi syndrome.

BACKGROUND: Obesity in Prader-Willi syndrome (PWS) may be related to abnormalities in the adipocyte-leptin-hypothalamic pathway and may be exacerbated by reductions in the resting metabolic rate (RMR). OBJECTIVE: We compared body composition, body-composition- adjusted RMR, and adiposity-adjusted plasma leptin between women with PWS and control women. We also examined leptin receptor expression in the PWS group. DESIGN: We studied body composition using whole-body magnetic resonance imaging and measured plasma leptin by radioimmunoassay in 45 control women aged 18-56 y and in 13 women with PWS aged 20-38 y. RMR was measured by indirect calorimetry in 41 control women and in 8 women with PWS. Age, body composition, and regional adipose tissue (AT) depots were corrected for by multiple regression analysis. Messenger RNA expression of the leptin receptor was examined by reverse transcriptase-polymerase chain reaction in lymphocytes. RESULTS: In the PWS group, fat mass was greater after correction for fat-free mass, and RMR was normal after correction for both fat-free mass and fat mass. Leptin was influenced primarily by subcutaneous AT volume in both subject groups. Leptin concentrations were not significantly different between the 2 groups after adjustment for age and AT content or distribution. Full-length leptin receptor messenger RNA was expressed in the lymphocytes of the PWS group. CONCLUSIONS: Differences in RMR in women with PWS are explained by abnormal body composition, suggesting that energy expenditure is normal at the tissue level in PWS. There is no evidence that defective leptin production causes obesity in PWS, and leptin receptor deficiency is not a primary consequence of the gene defects leading to leptin resistance.

Adipose Tissue↗

PubMed2002

Hypothalamic NPY and agouti-related protein are increased in human illness but not in Prader-Willi syndrome and other obese subjects.

Animal studies have demonstrated the importance of orexigenic NPY and agouti-related protein (AGRP) hypothalamic neurons, which are inhibited by the adipocyte hormone leptin, in the regulation of body weight and neuroendocrine secretion. We have examined NPY and AGRP neurons in postmortem human hypothalami from controls, Prader-Willi syndrome and other obese subjects, using quantitative immunocytochemistry (ICC) and in situ hybridization, to identify causes of leptin resistance in human obesity. Using combined ICC and in situ hybridization, AGRP, but not POMC, was colocalized with NPY in infundibular nucleus neurons. Infundibular nucleus (including median eminence) NPY ICC staining or mRNA expression, and AGRP ICC staining, increased with premorbid illness duration. NPY ICC staining and mRNA expression were reduced in obese subjects, but AGRP ICC staining was unchanged, correcting for illness duration. This suggests normal responses of NPY and AGRP neurons to peripheral signals, such as leptin and insulin, in human illness and obesity. The pathophysiology of obesity and illness-associated anorexia appear to lie in downstream or separate neuronal circuits, but the infundibular neurons may mediate neuroendocrine responses to illness. The implications for pharmacological treatment of human obesity are discussed.

Adult↗

PubMedDate not supplied

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.

Animals↗