The hypothalamus, hormones, and hunger: alterations in human obesity and illness
Section snippets
Obesity
Obesity is a major worldwide health issue affecting developed and developing nations. Over 300 million people worldwide are obese, and nearly 1 billion adults are overweight (Deitel, 2002; Kimm and Obarzanek, 2002; Thibault and Rolland-Cachera, 2003). In England in 2003, 60% of adults were overweight, and 23% obese (Department of Health, 2004). Of particular concern is the rise of childhood obesity (Speiser et al., 2005). Over 30% of children in the United States are overweight or obese (Fox,
Gut hormones and appetite
Appetite is controlled by a variety of peripheral signals that change in response to food intake or starvation, which act in the brain to alter feelings of hunger and fullness so as to determine meal initiation (‘hunger’ or ‘satiety’) and meal termination (‘satiation’) (Bray, 2000; De Graaf et al., 2004; Neary et al., 2004a; Badman and Flier, 2005) (Fig. 1). These signals may include a number of ascending neural inputs (e.g., vagus nerve signaling stomach distension), metabolic and hormonal
Gut hormones and downstream pathways
Rodent studies have revealed initial targets for the appetite effects of gut hormones as including the vagus nerve, brain stem (such as the nucleus of the solitary tract (NTS), area postrema, and ventral tegmental area), and the hypothalamus. These studies involve such methods as microinjection of peptides, postmortem neuropeptide, and c-fos peptide or mRNA expression as a marker of neuronal activation after peripheral hormone administration, brain and vagus nerve localization of hormone
Prader–Willi syndrome
Prader–Willi syndrome (PWS) is one of the commonest genetic causes of obesity, with a birth incidence of 1 in 29,000 (Whittington et al., 2001). Patients have additional phenotypes that include neonatal hypotonia, hypogonadism, growth hormone deficiency, sleep disturbance, learning difficulties, behavioral problems, and characteristic facial features, many of which suggest hypothalamic dysfunction (Holm et al., 1993; Whittington et al., 2002; Goldstone, 2004) (Fig. 5). PWS subjects have grossly
Hypothalamic neuropeptides and human illness
Human postmortem studies have revealed that hypothalamic NPY, AGRP, and GHRH neurons are activated during prolonged premortem illness which may mediate the neuroendocrine responses to illness (Van den Berghe, 2000; Goldstone et al., 2002, Goldstone et al., 2003 (Fig. 4, Fig. 6). Interestingly, despite plasma ghrelin being increased in malnutrition (Shimizu et al., 2003; Sturm et al., 2003; Korbonits et al., 2004), patients with anorexia of chronic illness such as renal patients receiving
Functional neuroimaging of appetite
In vivo functional neuroimaging can facilitate the study of the human-brain pathways involved in the control of appetite, and identification of how their dysregulation leads to excess caloric intake in obesity by reducing satiety and increasing hunger (Tataranni and Delparigi, 2003; De Graaf et al., 2004).
Functional magnetic resonance imaging (fMRI) studies have shown a reduction in resting blood oxygen level-dependent (BOLD) signal in the hypothalamus in response to ingestion of oral glucose (
Functional neuroimaging in obesity
Alterations in the PET rCBF changes in response to satiation have been reported in obese or postobese subjects compared to lean subjects, including the prefrontal cortex, OFC, insula and temporal cortex, hypothalamus, hippocampus, and amygdala (Del Parigi et al., 2002; Del Parigi et al., 2004). Impaired and delayed resting hypothalamic fMRI responses to ingestion of oral glucose have been reported in obese vs. lean subjects (Matsuda et al., 1999; Liu et al., 2000) (Fig. 9). These defects in
Functional neuroimaging in PWS
Several small studies have demonstrated abnormal functional neuroimaging of appetite in PWS subjects. The maximum time points for changes in the resting fMRI BOLD signal after ingestion of oral glucose are delayed in PWS subjects even longer than in both non-PWS obese and lean subjects, including decreases in fMRI signal in the hypothalamus, OFC, and nucleus accumbens, and increases in the dorsolateral prefrontal cortex and insula (Shapira et al., 2005). Meanwhile, a PET study found that PWS
Functional neuroimaging in the future
Similar functional neuroimaging studies could be used to study the neuroanatomical basis of abnormal feeding behavior in monogenic causes of human obesity, so as to reveal in humans where and how particular genes and signals act in the pathways that regulate appetite, and in time, more common genetic polymorphisms within the appetite pathways as well as assessing or perhaps even predicting the response to anorexigenic drugs or surgery (O’Rahilly et al., 2003; Bell et al., 2005; Le Roux and
Acknowledgments
The author wishes to acknowledge the technical support from all his colleagues and collaborators, including those at the Hammersmith Hospital, Imperial College, London; Netherlands Institute for Brain Research, Amsterdam; St. Bartholomew's Hospital, London; University of Florida College of Medicine, USA; and Royal Free Hospital, London. He extends his sincere gratitude to the UK Medical Research Council, the Royal Society of London, the UK and US PWS Associations, The Royal College of
References (127)
- et al.
Effect of peptide YY on gastric, pancreatic, and biliary function in humans
Gastroenterology
(1985) - et al.
AMP-activated protein kinase plays a role in the control of food intake
J. Biol. Chem.
(2004) - et al.
Characterization of the effects of pancreatic polypeptide in the regulation of energy balance
Gastroenterology
(2003) - et al.
Oxyntomodulin and glucagon-like peptide-1 differentially regulate murine food intake and energy expenditure
Gastroenterology
(2004) - et al.
Pancreatic polypeptide infusions reduce food intake in Prader–Willi syndrome
Peptides
(1993) Mind versus metabolism in the control of food intake and energy balance
Physiol. Behav.
(2004)Drug treatment of obesity
Baillieres Best Pract. Res. Clin. Endocrinol. Metab.
(1999)- et al.
Enhancement of feeding suppression by PYY(3-36) in rats with area postrema ablations
Peptides
(2004) - et al.
The role of the gastric afferent vagal nerve in ghrelin-induced feeding and growth hormone secretion in rats
Gastroenterology
(2002) - et al.
Biomarkers of satiation and satiety
Am. J. Clin. Nutr.
(2004)
Obesity wars: molecular progress confronts an expanding epidemic
Cell
Prader–Willi syndrome: advances in its genetics, pathophysiology and treatment
Trends Endocrinol. Metab.
Effect of leptin on hypothalamic GLP-1 peptide and brain-stem pre-proglucagon mRNA
Biochem. Biophys. Res. Commun.
Neural mechanisms underlying food motivation in children and adolescents
Neuroimage
Integration of endocannabinoid and leptin signaling in an appetite-related neural circuit
Neuron
Cortical and limbic activation during viewing of high- versus low-calorie foods
Neuroimage
Ghrelin — a hormone with multiple functions
Front. Neuroendocrinol.
Food for thought: hedonic experience beyond homeostasis in the human brain
Neuroscience
The functional neuroanatomy of the human orbitofrontal cortex: evidence from neuroimaging and neuropsychology
Prog. Neurobiol.
Hypothalamic serotonin in control of eating behavior, meal size, and body weight
Biol. Psychiatry
Satiety effects of cholecystokinin in humans
Gastroenterology
Ghrelin induces feeding in the mesolimbic reward pathway between the ventral tegmental area and the nucleus accumbens
Peptides
Functional magnetic resonance imaging of human hypothalamic responses to sweet taste and calories
Am. J. Clin. Nutr.
Functional MRI of human hypothalamic responses following glucose ingestion
Neuroimage
Functional neuroimaging of gastric distention
J. Gastrointest. Surg.
Effects of peptide YY and neuropeptide Y on gastric emptying in man
Digestion
Systematic review of the long-term effects and economic consequences of treatments for obesity and implications for health improvement
Health Technol. Assess.
The gut and energy balance: visceral allies in the obesity wars
Science
Inhibition of food intake in obese subjects by peptide YY3-36
N. Engl. J. Med.
Gut hormone PYY(3-36) physiologically inhibits food intake
Nature
Pancreatic polypeptide reduces appetite and food intake in humans
J. Clin. Endocrinol. Metab.
The genetics of human obesity
Nat. Rev. Genet.
Post-embryonic ablation of AgRP neurons in mice leads to a lean, hypophagic phenotype
FASEB J.
Afferent signals regulating food intake
Proc. Nutr. Soc.
Mice lacking pro-opiomelanocortin are sensitive to high-fat feeding but respond normally to the acute anorectic effects of peptide-YY(3-36)
Proc. Natl. Acad. Sci. USA
Evidence for genetic modifiers of postnatal lethality in PWS-IC deletion mice
Hum. Mol. Genet.
Oxyntomodulin suppresses appetite and reduces food intake in humans
J. Clin. Endocrinol. Metab.
Peripheral oxyntomodulin reduces food intake and body weight gain in rats
Endocrinology
The International Obesity Task Force and “globesity”
Obes. Surg.
Neuroimaging and obesity: mapping the brain responses to hunger and satiation in humans using positron emission tomography
Ann. N.Y. Acad. Sci.
Persistence of abnormal neural responses to a meal in postobese individuals
Int. J. Obes. Relat. Metab. Disord.
Endocannabinoid control of food intake and energy balance
Nat. Neurosci.
Ghrelin increases food intake in obese as well as lean subjects
Int. J. Obes. Relat. Metab. Disord.
Associative processes in addiction and reward. The role of amygdala-ventral striatal subsystems
Ann. N.Y. Acad. Sci.
Food intake in Prader–Willi syndrome and controls with obesity after administration of a benzodiazepine-receptor agonist
Obes. Res.
Overweight children
Circulation
The number of hypothalamic hypocretin (orexin) neurons is not affected in Prader–Willi syndrome
J. Clin. Endocrinol. Metab.
Modulation of brain reward circuitry by leptin
Science
Fasting and post-prandial hyperghrelinemia in Prader–Willi syndrome is partially explained by hypoinsulinemia, and is not due to peptide YY 3-36 deficiency or seen in hypothalamic obesity due to craniopharyngioma
J. Clin. Endocrinol. Metab.
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Endocrine disorders in Prader-Willi syndrome: a model to understand and treat hypothalamic dysfunction
2021, The Lancet Diabetes and EndocrinologyCitation Excerpt :Total and free leptin concentrations are increased in individuals with Prader-Willi syndrome, similarly to what is observed in weight-matched controls and without relation to the different eating phases.84 The concentrations of neuropeptide Y, agouti-related protein, and hypocretins in individuals with Prader-Willi syndrome have been reported to be similar to healthy controls.86 Fasting cholecystokinin concentrations are reported to be either normal or increased in Prader-Willi syndrome, and similar concentrations are reported in response to a meal.87
Lack of response to disgusting food in the hypothalamus and related structures in Prader Willi syndrome
2019, NeuroImage: ClinicalCitation Excerpt :Therefore, it appears that PWS patients are to some extent capable of processing disgusting stimuli at the cortical, conscious level, but their limbic brain systems are notably insensitive to this sort of stimulation. The lack of limbic brain response may be relevant to the extent it could explain altered eating behavior and subsequent obesity in PWS, which is considered to be a failure of satiety (McAllister et al., 2011; Tauber et al., 2014) potentially related to hypothalamic dysfunction (Goldstone, 2006). The hypothalamus and the amygdala are strongly connected to each other and both to the basal ganglia/orbitofrontal loops that process satiety signals.
GHRH plus arginine and arginine administration evokes the same ratio of GH isoforms levels in young patients with Prader-Willi syndrome
2018, Growth Hormone and IGF ResearchCitation Excerpt :For these considerations, the pathogenesis of the impaired GH secretion in PWS still remains to be elucidated. Alternatively, we can suppose that the hypothalamic dysfunction in PWS does impair GH secretion, without affecting the biochemical mechanisms implicated in the generation of GH isoforms (e.g., gene expression, alternative splicing, posttranslational modifications and metabolism in the pituitary or circulation) [13], forcing us to search other potential causes (e.g. neuroendocrine [25,26] and/or nutritional factors [27]). This conclusion is similar to that drawn in one of our previous studies [14], but is now supported by the comparison of two different pharmacological tests acting at different levels in the GH hypothalamic-pituitary axis.
Influence of neuropeptide Y and pancreatic polypeptide on islet function and beta-cell survival
2017, Biochimica et Biophysica Acta - General SubjectsDisorders of glucose metabolism in Prader–Willi syndrome: Results of a multicenter Italian cohort study
2016, Nutrition, Metabolism and Cardiovascular DiseasesUnaltered ratio of circulating levels of growth hormone/GH isoforms in adults with Prader-Willi syndrome after GHRH plus arginine administration
2015, Growth Hormone and IGF ResearchCitation Excerpt :The occurrence of reduced GH secretion and hypogonadism in the majority of PWS patients, together with central adrenal insufficiency, hyperphagia, temperature instability and high pain threshold, suggest the presence of a hypothalamic–pituitary dysfunction [6]. Some sophisticated neuroimaging techniques have shown alterations of blood flow and metabolism in several regions of the cerebral cortex, while some cases have also revealed reduced perfusion in peri- and intra-hypothalamic areas [28]. Moreover, a reduction in GHRH-releasing neurons in the nucleus arcuatus, a down-regulation of neuropeptide Y, and a deficiency in vasopressin were previously described [29].