Page 318 - Robbins Basic Pathology by Vinay Kumar, Abul K. Abbas, Jon C. Aster

304 C H A P T E R 7 Environmental and Nutritional Diseases

CENTRAL PROCESSING

Inhibit
Anabolic circuits

Hypothalamus

Catabolic circuits
Activate

Pancreatic β cells Adiposity signals Energy expenditure Food intake
Stomach Insulin Leptin

Ghrelin

Intestines PYY Regulates Energy balance

Adipocytes
(energy stores)

AFFERENT SYSTEM EFFERENT SYSTEM

Figure 7–23 Energy balance regulatory circuitry. When sufficient energy is stored in adipose tissue and the individual is well fed, afferent adiposity
signals (insulin, leptin, ghrelin, peptide YY) are delivered to the central neuronal processing units, in the hypothalamus. Here the adiposity signals inhibit
anabolic circuits and activate catabolic circuits. The effector arms of these central circuits then influence energy balance by inhibiting food intake and
promoting energy expenditure. This in turn reduces the energy stores, and pro-adiposity signals are blunted. Conversely, when energy stores are low,
the available anabolic circuits take over, at the expense of catabolic circuits, to generate energy stores in the form of adipose tissue.

NPY (neuropeptide Y) and AgRP (agouti-related epinephrine from sympathetic nerve endings in adipose
peptide) neurons. tissue. Fat cells express β3-adrenergic receptors that, when
• The efferent system, which consists of hypothalamic stimulated by norepinephrine, cause fatty acid hydrolysis
neurons regulated by the arcuate nucleus. POMC/ and also uncouple energy production from storage.
CART neurons activate efferent neurons that enhance
energy expenditure and weight loss, while NPY/AgRP In rodents and humans, loss-of-function mutations
neurons activate efferent neurons that promote food affecting components of the leptin pathway give rise to
intake and weight gain. Signals transmitted by efferent massive obesity. Mice with mutations that disable the
neurons also communicate with forebrain and midbrain leptin gene or its receptor fail to sense the adequacy of fat
centers that control the autonomic nervous system. stores, so they behave as if they are undernourished, eating
Discussed next are three important components of the ravenously. As in mice, mutations of the leptin gene or
afferent system that regulate appetite and satiety: leptin, receptor in humans, although rare, may cause massive
adipose tissue, and gut hormones. obesity. More common are mutations in the melanocortin
receptor-4 gene (MC4R) gene, found in 4% to 5% of patients
Leptin with massive obesity. These monogenic traits underscore the
importance of the leptin pathway in the control of body
Through complex, incompletely understood mechanisms, weight, and it is possible that more common types of
the output of leptin is regulated by the adequacy of fat stores. defects in this pathway will be discovered in the obese. For
With abundant adipose tissue, leptin secretion is stimu- example, many obese persons have high blood leptin
lated, and the hormone travels to the hypothalamus, where levels, suggesting that leptin resistance is prevalent among
it reduces food intake by stimulating POMC/CART neurons and humans.
inhibiting NPY/AgRP neurons. The opposite sequence of
events occurs when there are inadequate stores of body fat: Adipose Tissue
Leptin secretion is diminished and food intake is increased.
In persons of stable weight, the activities of these pathways In addition to leptin, adipose tissue produces other media-
are balanced. Leptin also increases energy expenditure by tors, such as adiponectin, cytokines, chemokines, and
stimulating physical activity, energy expenditure, and steroid hormones, which allow adipose tissue to function
thermogenesis, which may be the most important catabolic as a link between lipid metabolism, nutrition, and inflam-
effects mediated by leptin through the hypo­thalamus. matory responses. The total number of adipocytes is established
Thermogenesis seems to be controlled in part by efferent by adolescence and is higher in people who were obese as
hypothalamic signals that increase the release of nor­ children, providing another reason for concern about child-
hood obesity. Although in adults about 10% of adipocytes
turn over annually, the number of adipocytes remains