E-Newsletter No. 66

However quaint this paraphrase of the hit song from My Fair Lady may be perceived, the metaphor is aptly valid. Many different metabolic and hormonal factors are required for maintenance of energy homeostasis in the body. The brain is the first responder to nutritional intake, and the center for control of energy metabolism.

Most people can lose weight. But few can maintain their new weight for long. Researchers are now tackling the problem, and what they have learned is disconcerting. The human body, it seems, is designed to sabotage weight loss at every turn --- once a body has been fatter, it wants to get back to the weight it used to be. Physiology is cruelly changed in two ways: The body needs fewer calories to maintain itself, but its craving for food is more intense.

Becoming overweight, in other words, is like being issued a credit card with an uncomfortably high balance that you’ll probably end up paying off forever. Making sure the pounds stay off means pitting one’s willpower against a swarm of biological processes involving the brain, hormones, metabolism and fat storage. 

Nutritional intake triggers a series of neurochemical signals in response to various hormones (insulin, leptin, ghrelin, amlyn, and corticosteroids), regulatory peptides (neuropeptides), and neurotransmitters (serotonin) (1, 9, 10). Circulating concentrations of insulin and leptin increase after nutrient intake of glucose and fatty acids. Subsequent delivery of these hormones to brain receptor sites signals the presence of energy stores in the rest of the body. This in turn inhibits food intake and increases energy metabolism through a negative feedback mechanism in which the brain sends signals to the liver to control production of glucose and food intake in response to both hormone levels and nutrient-related signals the brain has received(14,16).

The signaling pathways of the brain involve complex interactions of various hormones, neuropeptides, and other signaling molecules. New discoveries in neuroscience research indicate insulin from the pancreas, and leptin from fat stores are important neuromodulators in controlling levels of anorexigenic and orexigenic neuropeptides through brain pathways for regulation of body fat content.

The anorexigenic neuropeptides include pro-opiomelanocortin (POMC), α-melanocyte-stimulating hormone (α-MSH), and the cocaine- and amphetamine-regulated transcript (CART). The orexigenic neuropeptides include neuropeptide Y (NPY) and agouti-related peptide (AgRP) (1,2,9). In addition, the electrical potential of neurons may be affected, which may promote other peptide release or other downstream signaling events. In particular one study has shown that stimulation by means of the PI 3-kinase pathway of hypothalamic adenosine triphosphate-sensitive potassium channels is linked to reduced hepatic output of glucose (13).

The administration of insulin or leptin to the brain can reduce food intake and weight gain. However, when mice are bred to have no insulin receptors, or bred to have no leptin receptors, adding insulin or leptin to them, respectively, results in increased levels of food intake and obesity in conjunction with increases in body fat and plasma leptin levels, mild insulin resistance, elevated plasma insulin levels, and hypertriglyceridemia (19). Treatment of mice lacking the leptin receptor (ob/ob) leads to weight loss in these animals; however, mice with the leptin receptor-blocking gene mutation (db/db) are leptin resistant, further suggesting its role in satiety and feeding behavior (12).

The orexigenic neuropeptide NPY has been found to be positively associated with weight gain due to reduced energy expenditure (20, 21, 22). Expression of AgRP conveys similar effects, although it acts more indirectly by inhibiting signaling of various melanocortin receptors (16). The anorexigenic neuropeptides POMC, CART, and α-MSH oppose these mechanisms and are stimulated by the presence of insulin or leptin (1), while the expression of AgRP is reduced. Additionally, when this occurs, melanocortin receptor (MC3 and MC4) is freed to be released, which then acts to suppress food intake and increase energy expenditure (23).

The stress centers in the brain also respond to levels of food intake. These include the sympathetic and parasympathetic nervous systems which comprise the tightly interconnected central autonomic nervous system and are usually activated simultaneously. The autonomic nervous system along with the endocrine system is responsible for maintenance of energy homeostasis (24). The adrenal medulla and sympathetic nervous system form the sympatho-adrenal system. The adrenal system exerts its action through epinephrine secreted from the adrenal medulla, whereas the sympathetic acts by secretion of norepinephrine from sympathetic nerve endings.

Further, peripheral adipose tissue is no longer considered to be an inert organ of energy storage, but in fact possesses important endocrine and metabolic functions that are closely involved in energy homeostasis. Fat cells (adipose tissue) are metabolically active, continuously communicating with the brain and other organs through at least 25 hormones and other signaling mechanisms. For example, in addition to leptin, adipose tissue is known to secrete angiotensinogen resulting in increased activity of local and systemic rennin-angiotensen system (25); another mechanism is the action of an adipocyte-derived factor that enhances the release of a hepatic stimulator of aldosterone synthesis; and, finally, there are increased circulating renin levels, which might stimulate increased sympathetic nervous system activity(26).

In summary, obesity is associated with a wide variety of neuroendocrine and metabolic abnormalities initiated in the brain. These signals then are transmitted down to various endocrine and other organ systems of the body thus contributing to the development of heart and vascular disease. These alterations include activation of the renin-angiotensin system, stimulation of the sympathetic nervous system, the development of insulin resistance and hyperinsulinemia, elevated levels of free fatty acids, and increased circulating serum levels of leptin due to leptin resistance. Such pathophysiologic alterations alone or in combination may predispose to the development of hypertension, cardiovascular disease, myocardial and vascular smooth muscle hypertrophy, and congestive heart failure. Weight loss reverses many of these neuroendocrine and metabolic effects of obesity and may potentially attenuate the risk for their cardiac and vascular sequelae. 

This enhanced understanding of brain signaling pathways may provide answers not only about how to control weight gain, but also provide us with improved insights in controlling the increasing prevalence of in-born errors of metabolism such as insulin, and/or leptin resistance, obesity, cardiometabolic risk, diabetes and other diseases accelerating aging.

References 
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