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

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Abstract

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.

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

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