Despite daily fluctuations in energy intake, energy balance is maintained in humans such that body weight can remain constant for long periods of time. The maintenance of a constant body weight occurs because the body has a sensitive homeostatic feedback mechanism that uses hormonal signals to regulate appetite, energy output and metabolism. Evidence is accumulating that these homeostatic mechanisms can become dysfunctional with certain environmental triggers, and this can lead to weight gain and obesity. Regulation of body weight is thought to occur primarily though the action of insulin and leptin, which are both released in proportion to the amount of adipose tissue. In turn insulin, leptin regulate the release of effectors of energy balance in the central nervous system, and these then modify feeding behaviour. In addition a number of gut derived peptides such as ghrelin and peptide YY contribute to energy regulation.
Leptin is secreted by adipocytes and plasma levels relate to the fat mass of the individual. The Brain responds to changes in leptin levels with alterations in the feeding behaviour and the metabolism of the individual. As leptin levels increase the brain up regulates weight loss and down regulates feeding. Information about changes in the fat stores are therefore relayed to the central nervous system using leptin. The leptin receptor (Ob-R) is present in various areas of the brain including the hypothalamus. Leptin acts in the hypothalamus to inhibit a number of chemicals that stimulating food intake and weight gain including neuropeptide Y (NPY), melanin concentrating hormone (MCH), agouti related peptide (AgRP) and orexins. At the same time leptin stimulates a number of chemicals that increase satiety and weight loss, including the melanocortins, cocaine and amphetamine related transcript (CART), thyrotropin releasing hormone and corticotrophin releasing hormone.
Plasma concentrations of insulin also vary with the degree of adiposity in the same way as leptin. Insulin is needed for glucose entry to the cells, but insulin also has receptors in the hypothalamus which affect food intake and appetite. Insulin acts on the hypothalamus to promote a state of negative energy balance perhaps by inhibition of neuropeptide Y and by increasing the sensitivity of the hypothalamus to external satiety signals such as from cholecystokinin. However, insulin also has potent anabolic actions in peripheral tissues that can cause weight gain. Type I diabetics given insulin infusions to stabilise blood glucose levels gain weight despite a reduced food intake. Because insulin release is related to adiposity, as weight gain becomes evident it would be expected that individuals insulin levels would rise and this may cause further weight gain due to peripheral anabolism despite a decrease in appetite.
Ghrelin is an orexigenic peptide hormone released from the endocrine cells of the gut. Plasma concentrations of ghrelin rise during fasting and fall post prandially. In contrast, the anorexigenic peptide YY is released from the L cells of the intestinal mucosa in relation to the energy content of the food, and levels fall during fasting. Maximum stimulation of peptide YY and maximum inhibition of ghrelin occurs within 1 hour of feeding, and levels return to normal within 90 minutes. Ghrelin bind to its receptor in the hypothalamus where it causes the release of the hunger stimulating peptides NPY and AgRP. Ghrelin also binds to receptors in the anterior pituitary gland where it causes the release of growth hormone. Peptide YY binds to neuropeptide Y receptors and inhibits gut motility, as well as gallbladder and pancreatic secretion. Protein is able to stimulate the release of Peptide YY which may explain the appetite suppressing weight loss effects of protein.
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