Obesity Class BMI (kg/m2 ) Risk

Underweight <18.5 Increased

Normal 18.5–24.9 Normal

Overweight 25.0–29.9 Increased

Obesity I 30.0–34.9 High

II 35.0–39.9 Very high

Extreme Obesity III ³40.0 Extremely high

Data from National Institutes of Health, National Heart, Lung, and Blood Institute. Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults

—The evidence report. Obes Res 6 (suppl 2):515, 1998.

These three components are described next.[80] Not shown in Figure 9-32 is that energy expenditure occurs through a variety of hormonal (e.g., thyrotropin-releasing hormone) and

autonomic intermediaries.

Among the afferent signals, insulin and leptin exert long-term control over the energy cycle by activating catabolic circuits and inhibiting anabolic pathways, as discussed in greater detail

below. By contrast, ghrelin is predominately a short-term mediator. Produced in the stomach, ghrelin levels rise sharply before every meal and fall promptly when the stomach is "filled."

In fact, it is thought that the success of gastric bypass surgery in massively obese individuals may relate more to the associated suppression of ghrelin levels than to an anatomic reduction

in stomach capacity.

Whereas both insulin and leptin influence the energy cycle, available data suggest that leptin has a more important role than insulin in the central nervous system control of energy

homeostasis.[81] [81A] Hence, our discussion will be focused on leptin, recognizing that leptin and insulin share some of their actions.

It is now established that adipocytes communicate with the hypothalamic centers that control appetite and energy expenditure by secreting leptin, a member of the cytokine family. When

there is an abundance of stored energy in the form of adipose tissue, the resultant high levels of leptin cross the blood-brain barrier, binding to leptin receptors. Leptin receptor signaling has

two effects: it inhibits anabolic circuits that normally promote food intake and inhibit energy expenditure, and, through a distinct set of neurons, leptin triggers catabolic circuits ( Fig. 9-

32 ). The net effect of leptin, therefore, is to reduce food intake and promote energy expenditure. Hence, over a period of time, energy stores (adipocytes) are reduced, and weight is lost.

This in turn reduces the circulating levels of leptin, and a new equilibrium is reached. This cycle is reversed when adipose tissue is lost and leptin levels are reduced below a threshold.

Equilibrium is again reached, since with low leptin levels, the anabolic circuits are relieved of inhibition and catabolic circuits are not activated, resulting in net gain of weight.

The molecular basis of leptin action is extremely complex and not yet fully unraveled. For the most part, leptin exerts its function through a series of integrated neural pathways referred to

as the leptin-melanocortin circuit, described in Box 9-1 and illustrated in Figure 9-33 . The understanding of this circuitry is important since obesity is a serious public health problem, and

development of antiobesity drugs will depend on a full understanding of these pathways.

Obesity, particularly central obesity, increases the risk for a number of conditions,[79] including diabetes, hypertension, osteoarthritis, pancreatitis, and many others, listed in Table 9-26 .

Only some of these complications are discussed here. The mechanisms underlying these associations are complex and likely to be interrelated. Obesity, for instance, is associated with

insulin resistance and hyperinsulinemia, important features of non-insulin-dependent, or type II, diabetes, and weight loss is associated with improvement. It has been speculated that

excess insulin, in turn, may play a role in the retention of sodium, expansion of blood volume, production of

Figure 9-32 A simplified schema of the circuitry that regulates energy balance. When sufficient energy is stored in adipose tissue and the individual is well fed, afferent adiposity signals

(insulin, leptin, ghrelin) 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 impact on energy balance by inhibiting food intake and promoting energy expenditure. This in turn reduces the energy stores and the adiposity

signals are obtunded. 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, thus generating an equilibrium.

Figure 9-33The neurohumoral circuits in the hypothalamus that regulate energy balance. Details are in the text.

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