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chapter 22

Metabolic Homeostasis

and development. If there is a net excess energy intake,

BMI increases, eventually leading to overweight and ul-

timately to obesity and morbid obesity. In a population

with stable genetic factors, increase in obesity is primar-

ily attributable to consumption of excess foods with high

fat content and decreased physical activity. Obesity is a

worldwide health problem. It is a risk factor for devel-

opment of diabetes mellitus, hypertension, and heart dis-

ease, all of which cause decreased quality of life and life

expectancy.

Feeding behavior and energy balance are regulated by

a complex set of short-term and long-term physiological

signals. Mechanisms that lead to obesity involve interac-

tions between genetic, environmental, and neuroendocrine

factors. The short-term regulators of hunger and satiety

may include plasma levels of glucose and amino acids,

cholecystokinin and other hormones, and body tempera-

ture. One of the long-term regulators of food intake and

energy expenditure is an adipocyte-derived hormone lep-

tin (Chapter 5). Leptin is a polypeptide of 167-amino acid

residues that functions in the afferent signal pathway of a

negative feedback loop in regulating the size of adipose

tissue and energy balance. The physiological role of lep-

tin was established by using

ob/ob

and

db/db

mice that

have identical phenotypes of obesity and diabetes mellitus.

In the

ob/ob

mice, leptin levels are low due to mutations

in the leptin gene, and in the

db/db

mice the leptin re-

ceptors are defective due to inactivating mutations. The

role of leptin and its receptor was investigated by joining

the circulatory systems (parabiosis) of

ob/ob

and

db/db

mice. In

ob/ob

mice, obesity, diabetes, and sterility are

corrected by leptin administration. These animal studies

have led to understanding of several aspects of obesity in

humans.

In humans, leptin is secreted in a pulsatile manner,

in a nyctohemeral rhythm, and in proportion to size

of the adipose tissue. The pathway of leptin’s action

involves the neuroendocrine system of the hypothala-

mus (Figure 22-27). When leptin levels are low, ap-

petite increases via the activation of the neuropeptide Y

Phosphorylation*

PPAR-/2

(Active)

Preadipocytes

Phosphorylated PPARy2

(Inactive)

Adipocytes

+

Leptin*

F I G U R E 2 2 - 2 7

A model for the regulation of human food consumption. Asterisks (*) indicate obesity-causing mutations. Abbreviations

are given in the text.