Ghrelin is a peptide hormone known for its role in the stimulation of appetite and feeding behavior (hunger hormone), energy homeostasis, and carbohydrate metabolism.
Ghrelin is produced mainly by the PD/D1 cells of the stomach but is also present in other tissues, including the small intestine, hypothalamus, pancreas, pituitary, and adrenal gland.
Functions
Ghrelin contributes to a large number of bodily functions, including appetite regulation and fat storage, inhibition of insulin secretion, stimulation of growth hormone release, reward processing, increased gastric acid secretion, intestinal motility, and other potential effects.
Ghrelin’s notable effects of appetite stimulation increased food intake, and increased fat storage have dubbed it the “hunger hormone.” Ghrelin acts on the hypothalamus, an area of the brain which contains the satiety center which is responsible for appetite regulation. Ghrelin is thought to be part of a neural network that is involved in feeding regulation, modulating the appetitive response to food cues as well as increasing brain response in areas responsible for visual processing, attention, and memory associated with images of food. Ghrelin has been shown to increase food intake by up to 30% when administered to humans. Ghrelin also has involvement in the regulation of lipid metabolism, promoting fat storage by activation of hypothalamic orexigenic neurons and the stimulation of fat storage-related protein expression in adipocytes in addition to exerting direct peripheral effects on lipid metabolism including the stimulation of liver lipogenesis, modulation of taste sensitivity, and increasing white adipose tissue mass.
Ghrelin is also known to inhibit insulin secretion in both humans and animals, thereby increasing blood glucose levels. In clinical studies, the administration of ghrelin in humans has resulted in increased glucose levels with little change in insulin levels.
Another function of ghrelin is the stimulation of growth hormone (GH) released from the pituitary gland. Exogenous ghrelin has been found to stimulate growth hormone release from the pituitary via a mechanism involving endogenous GH-releasing hormone. Notably, growth hormone breaks down fat (lipolysis) and builds muscle while ghrelin promotes lipogenesis.
Ghrelin is also known to act on reward-processing regions of the brain such as the amygdala; its binding activates the reward link, potentially contributing to food and alcohol addiction.
Additionally, ghrelin has been found to stimulate gastric motility as well as gastric acid secretion via a mechanism involving the vagal nerve. Studies demonstrate that ghrelin acts on acid secretion at a capacity rivaling that of histamine and gastrin and that both are synergistically involved in the process. Like motilin, it also promotes intestinal motility.
Ghrelin is also thought to be involved in sleep-wake cycle regulation. Studies have shown that shorter sleep duration is associated with elevated levels of ghrelin and reduced leptin.
Mechanism
Ghrelin levels in the body are regulated primarily by the intake of food; its secretion becomes activated when the stomach is empty (during fasting) and inhibited when it is stretched (after a meal). Different types of nutrients have varying effects on ghrelin release; carbohydrates and proteins reduce ghrelin release more than fats. Reduced ghrelin release is also associated with somatostatin and numerous other hormones released from the digestive tract.
Clinical significance
Given its functions in appetite regulation, the role of ghrelin in obesity is of great interest. Multiple studies have demonstrated that, in obese individuals, there is inadequate postprandial suppression of ghrelin, leading to a continued sense of hunger and difficulty losing weight. This factor is especially relevant with regard to dieting, which causes an increase in ghrelin levels; this may explain challenges in maintaining weight loss via dieting. Other studies have shown significant decreases in serum ghrelin levels following bariatric surgery, which may explain their effective weight loss results. Ghrelin is also thought to be involved in Prader-Willi syndrome, a genetic condition characterized by severe obesity, hyperphagia, cognitive impairment, and hypothyroidism. Levels of ghrelin increase in Prader-Willi syndrome. High ghrelin levels also appear in patients with cachexia and anorexia nervosa, and this is thought to be the body’s mechanism for responding to weight loss by increasing food intake and fat storage. In anorexia nervosa, while ghrelin levels rise, the patient's appetite does not, so a plausible explanation for elevated ghrelin levels is possible ghrelin resistance. Ghrelin levels correlate inversely with BMI.
