Energy Balance and Body Mass

• Stability of the body's total mass and composition over long periods of time requires that energy intake matches energy expenditure.
• Only about 27% of the energy ingested normally reaches the functional systems of the cells.
• A significant portion of ingested energy is eventually converted to heat due to protein metabolism, muscle activity, and the activity of various organs and tissues.
• Excess energy intake is primarily stored as fat.
• A deficit of energy intake results in the loss of total body mass until energy expenditure equals energy intake, or death occurs.
• Maintaining an adequate energy supply is necessary for survival.
• The body has powerful physiologic control systems that help maintain adequate energy intake.
• Deficits in energy stores rapidly activate multiple mechanisms that cause hunger and drive a person to seek food.
• Large energy expenditure associated with physical work stimulates equally large increases in caloric intake.
• Maintaining an adequate energy supply is so critical that multiple short-term and long-term control systems regulate food intake, energy expenditure, and energy stores.
• Stability of body weight and composition over long periods requires that a person's energy intake and energy expenditure be balanced.
• The neuroendocrine system coordinates metabolism in mammals.
• Epinephrine and norepinephrine serve as neurotransmitters in certain synapses of the brain and smooth muscle, also function as hormones that regulate fuel metabolism in the liver and muscle.

Hunger, Appetite & Satiety

• Hunger is associated with a craving for food, rhythmical contractions of the stomach, and restlessness.
• Hunger causes a person to search for an adequate food supply.
• Appetite is a desire for food, often of a particular type, and is useful in helping to choose the quality of the food to be eaten.
• Satiety occurs when the quest for food is successful.

Hypothalamus

• Contains hunger and satiety centers.
• The lateral nuclei of the hypothalamus serve as a feeding center, stimulation causes an animal to eat voraciously (hyperphagia), destruction causes lack of desire for food and progressive inanition, characterized by marked weight loss, muscle weakness, and decreased metabolism.
• The lateral hypothalamic feeding center operates by exciting the motor drives to search for food.
• The ventromedial nuclei of the hypothalamus serve as the satiety center, which gives a sense of nutritional satisfaction that inhibits the feeding center.
• Electrical stimulation of the ventromedial nuclei can cause complete satiety, even in the presence of highly appetizing food (aphagia).
• Destruction of the ventromedial nuclei causes voracious and continued eating until the animal becomes extremely obese.
• The arcuate nuclei are sites in the hypothalamus where multiple hormones released from the gastrointestinal tract and adipose tissue converge to regulate food intake and energy expenditure.
• Lesions of the paraventricular nuclei often cause excessive eating.
• Lesions of the dorsomedial nuclei usually depress eating behavior.
• Chemical cross-talk occurs among neurons on the hypothalamus, and these centers coordinate the processes that control eating behavior and the perception of satiety.
• These nuclei influence the secretion of hormones that are important for regulating energy balance and modulating metabolism, including those from the thyroid, adrenal glands, and pancreatic islet cells.
• Feedback mechanisms control food intake, stretch receptors in the stomach activate sensory afferent pathways in the vagus nerve and inhibit food intake.
• Peptide YY (PYY), cholecystokinin (CCK), and insulin are gastrointestinal hormones released by the ingestion of food and suppress further feeding.
• Ghrelin is released by the stomach, especially during fasting, and stimulates appetite.
• Leptin inhibits food intake and is produced in increasing amounts by fat cells as they increase in size
• The hypothalamus receives neural signals from the GIT that provide sensory information about stomach filling, chemical signals from nutrients in the blood (glucose, amino acids, and fatty acids) that signify satiety, signals from gastrointestinal hormones, signals from hormones released by adipose tissue, and signals from the cerebral cortex (sight, smell, and taste).

Neurons & Neurotransmitters in the Hypothalamus

• Two distinct types of neurons exist in the arcuate nuclei of the hypothalamus.
• These neurons are especially important as controllers of both appetite and energy expenditure.
• Proopiomelanocortin (POMC) neurons produce α-melanocyte-stimulating hormone (α-MSH) in conjunction with cocaine- and amphetamine-related transcript (CART).
• Neuropeptide Y (NPY) and agouti-related protein (AGRP) neurons that produce the orexigenic substances.
• Activation of POMC neurons decreases food intake and increases energy expenditure.
• Activation of NPY-AGRP neurons increases food intake and reduces energy expenditure.
• POMC neurons release α-MSH, which then acts on melanocortin receptors found especially in neurons of the paraventricular nuclei.
• There are at least five subtypes of melanocortin receptor (MCR).
• MCR-3 and MCR-4 are especially important in regulating food intake and energy balance.
• Activation of MCR-3 and MCR-4 reduces food intake while increasing energy expenditure.
• Inhibition of MCR-3 and MCR-4 leads to the opposite effect.
• The effect of MCR is mediated, at least in part, by activation of neuronal pathways that project from the paraventricular nuclei to the nucleus tractus solitarius and stimulate sympathetic nervous system activity.
• Mutations of MCR-4 represent the most common known monogenic (single-gene) cause of human obesity.
• Some studies suggest that MCR-4 mutations may account for as much as 5 to 6% of early-onset severe obesity in children.
• Excessive activation of the melanocortin system reduces appetite.
• Some studies suggest that this activation may play a role in causing the anorexia associated with severe infections or cancer tumors.
• AGRP is a natural antagonist of MCR-3 and MCR-4 that is released from the orexigenic neurons of the hypothalamus, which increases feeding by inhibiting the effects of α-MSH to stimulate melanocortin receptors.
• Excessive formation of AGRP in mice and humans due to gene mutations is associated with excessive feeding and obesity

NPY

• NPY is also released from orexigenic neurons of the arcuate nuclei.
• When energy stores of the body are low, orexigenic neurons are activated to release NPY, which stimulates appetite.
• At the same time, firing of the POMC neurons is reduced, thereby decreasing the activity of the melanocortin pathway and further stimulating appetite.
• Orexigenic substances stimulate feeding.
• Anorexigenic substances inhibit feeding.

Neural Centres That Influence the Mechanical Process of Feeding

• If the brain is sectioned below the hypothalamus but above the mesencephalon, the animal can still perform the basic mechanical features of the feeding process.
• The animal can salivate, lick its lips, chew food, and swallow.
• The actual mechanics of feeding are controlled by centers in the brainstem.
• Other centers control the quantity of food intake and excite these centers of feeding mechanics to activity.
• Neural centers higher than the hypothalamus also play important roles in the control of appetite.
• These centers include the amygdala and the prefrontal cortex, which are closely coupled with the hypothalamus.
• Destructive lesions in the amygdala have demonstrated that some of its areas increase feeding, whereas others inhibit feeding.
• Stimulation of some areas of the amygdala elicits the mechanical act of feeding.
• An important effect of destruction of the amygdala on both sides of the brain is a "psychic blindness" in the choice of foods.
• The animal loses the appetite control that determines the type and quality of food it eats.

Factors That Regulate Quantity of Food Intake:

• Regulation can be divided into short-term regulation, which is concerned primarily with preventing overeating at each meal, and long-term regulation, which is concerned primarily with the maintenance of normal quantities of energy stores in the body.
• Stretch inhibitory signals are transmitted mainly by way of the vagus nerve to suppress the feeding center and reduce the desire for food when the stomach and duodenum become distended.
• Cholecystokinin is released mainly in response to fat entering the duodenum and has a direct effect on the feeding centers to reduce subsequent eating.
• CCK may decrease feeding by activating the melanocortin pathway in the hypothalamus.
• Food intake stimulates the release of PYY, with blood concentrations rising to peak levels 1 to 2 hours after ingesting a meal.
• The peak levels of PYY are influenced by the number of calories ingested and the composition of the food.
• Higher levels of PYY are observed after meals with a high-fat content.
• The importance of this GIT hormone in regulating appetite in humans is still unclear.
• The presence of food in the intestines stimulates them to secrete glucagon-like peptide, which in turn enhances glucose-dependent insulin production and secretion from the pancreas.
• Glucagon-like peptide and insulin both tend to suppress appetite.
• Eating a meal stimulates the release of several gastrointestinal hormones that may induce satiety and reduce further intake of food.
• Leptin is a peptide hormone (146 amino acids) thought to serve as an indicator (lipostat) of energy stores, as well as a modulator of energy balance.

Leptin effects on Fat Metabolism:

• Decrease in fat storage.
• Increase in sympathetic-mediated energy expenditure.
• Increase in the expression of uncoupling proteins.
• Decrease in triglyceride content by increasing fatty acid oxidation.
• Decrease in activity and expression of esterification and lipogenic enzymes.
• Decrease in lipogenic activity of insulin, favoring lipolysis.