Short-term regulation of food intake primarily involves neural signals from the gastrointestinal (GI) tract, blood nutrient levels, and GI tract hormones. Communication between the gut and brain via vagal nerve fibers plays a significant role in evaluating the contents of the gut. Clinical studies have shown that protein ingestion produces a more prolonged response in these nerve fibers compared to an equivalent amount of glucose. Additionally, the activation of stretch receptors caused by GI tract distension sends signals along vagus nerve afferents, suppressing the hunger center and reducing appetite.

Nutrient signals related to energy stores are also critical in short-term regulation. Blood levels of glucose, amino acids, and fatty acids provide essential information to the brain, enabling it to adjust energy intake to match energy expenditure. Rising blood glucose levels and elevated levels of amino acids suppress appetite, although the exact mechanism for the latter remains unclear. Similarly, higher concentrations of circulating fatty acids can inhibit eating, but this response depends on factors such as the type of fatty acid and the individual's metabolic state.

Hormones also play a vital role in regulating short-term food intake. Gut hormones, such as cholecystokinin (CCK), released during food absorption, act as satiety signals that reduce hunger. Conversely, ghrelin, a hormone produced by the stomach, is a potent appetite stimulant, increasing food intake.

Long-term regulation of food intake involves the hormone leptin, primarily secreted by adipose cells in proportion to fat stores. Rising leptin levels signal the hypothalamus to reduce appetite by suppressing the activity of neurons that produce neuropeptide Y (NPY) and agouti-related peptide (AgRP), both potent appetite stimulants while stimulating pro-opiomelanocortin (POMC) neurons that promote satiety. When fat stores decrease, leptin levels drop, reducing this inhibitory signal and increasing appetite. When fat stores decrease, leptin levels drop, leading to increased appetite and food intake. However, weight gain occurs only when calorie intake consistently exceeds energy expenditure.