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Food intake and energy expenditure must be balanced to maintain a healthy body weight. This balance is kept by the central nervous system, which controls feeding behavior and energy metabolism.
Several brain systems are involved, including the brainstem which receives neuronal inputs from the digestive tract, and the hypothalamus which picks up hormonal and nutritional signals from the circulation. These two systems collect information about the body’s nutrient status and respond accordingly. They also interact with the reward and motivation pathways, which drive food-seeking behavior.
The arcuate nucleus, ARC, of the hypothalamus, emerges as the major control center. There are two groups of neurons, with opposing functions, in the ARC: the appetite-stimulating neurons expressing NPY and AGRP peptides, and the appetite-suppressing neurons producing POMC peptide.
Appetite-stimulating neurons are activated by hunger, while appetite-suppressing neurons are stimulated by satiety, or fullness.
Neurons of the ARC project to other nuclei of the hypothalamus, of which the paraventricular nucleus, PVN, is most important. PVN neurons further process the information and project to other circuits outside the hypothalamus, thus coordinating a response that controls energy intake and expenditure.
Short-term regulation of feeding is based on how empty or how full the stomach is, and if there are nutrients in the intestine. In the fasting state, an empty stomach sends stretch information to the brainstem, signaling hunger. It also produces a peptide called ghrelin, which acts on the arcuate nucleus to stimulate feeding. Ghrelin also acts directly on the PVN to reduce energy expenditure.
Upon food ingestion, distension of the stomach is perceived by the brainstem as satiety. Ghrelin is no longer produced. Instead, several other gut peptides are released from the intestine and act on the hypothalamus and other brain areas to suppress appetite and increase energy expenditure.
Long-term regulation, on the other hand, takes cues from the amount of body fat: low body fat content encourages feeding and energy preservation, while high body fat suppresses appetite and promotes energy expenditure. Two hormones are involved: leptin and insulin.
Insulin is a hormone produced by the pancreas and is released into the bloodstream upon food ingestion, when blood glucose starts to rise. Leptin is a hormone secreted by adipose tissues in a process dependent on insulin. The amount of circulating leptin in the plasma is directly proportional to the body fat content. Increased leptin levels in the blood signal to the brain that the body has enough energy storage, and that it has to stop eating and burn more energy. Leptin and insulin seem to work together on hypothalamic nuclei, as well as other brain areas, to inhibit food intake and increase energy expenditure.
Obesity results from the dysregulation of feeding behaviors and energy metabolism. Obesity is most commonly associated with chronic low leptin activities, which trick the brain into thinking that the body is always starved. This leads to overeating and excessive energy storage as fats.
Both genetic and lifestyle factors contribute to low leptin signaling, but the contribution of each factor varies widely from person to person.
The major lifestyle factor is a high-fat, energy-rich diet. In an early stage of high-fat-diet–induced obesity, increased amounts of saturated fatty acids cross the blood brain barrier and provoke an inflammatory response in hypothalamic neurons. Inflammation induces stress in these neurons, blunting their response to leptin. This is known as leptin resistance. Leptin levels are high, but because the cells cannot react to leptin, the brain interprets it as low and triggers the starvation response.
Genetic factors include mutations in the leptin gene itself, or in one of the numerous downstream genes that are required for leptin action in various pathways. Leptin deficiency due to gene mutations is very rare. More common are mutations in the downstream genes, which render a certain pathway irresponsive to leptin.
A major risk factor for childhood obesity is maternal obesity and mother’s high-fat-diet during pregnancy and lactation. A maternal diet rich in saturated fats can cause inflammation in the infant’s hypothalamus. It may also prime the reward pathways in infants, influencing their food choice toward energy-rich foods.
