Biology of Disease

NUTRITIONAL DISORDERS

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In 1994, the *obese gene was discovered in mice. Its expression
in adipocytes produces the hormone leptin, a polypeptide of 146
amino acid residues (Figure 10.23), which is secreted in amounts
that are proportional to the mass of body fat. Among the effects
of leptin are to decrease adiposity or total body fat and to pass
through the blood–brain barrier and act on the hypothalamus
to inhibit eating. It also stimulates the oxidation of fatty stores
and prevents lipid accumulating in nonadipose tissues and so
protects the individual against some of the adverse effects of
fat accumulation, for example coronary artery disease. During
periods when more energy is used than ingested, that is the
starved state, adipose tissue is metabolized and the amount of
leptin secreted declines. Hence, the mouse is stimulated to eat
more. When more energy is consumed than used, the converse
holds. Mutations to the gene or its absence in mice can lead
to excessive overeating and morbid obesity (Figure 10.24 (A)
and(B)). Injections of synthetic leptin to obese mice cause a
weight loss. These findings led to great excitement that obesity

in humans could be a genetic phenomenon and controllable

by leptin therapy. However, although the physiological effects

of leptin are similar in humans and mice, mutations in the

*OBESE gene have been discovered in only a handful of obese

humans. Two of these patients were members of the same

highly consanguineous family and weighed 29 and 86 kg at the

ages of two and eight years respectively. TheirOBESE genes had

a deletion mutation of a single guanine nucleotide at codon

133 leading to a biologically inactive leptin. Injections of leptin

relieved their symptoms. However, most obese people, in fact,

secrete leptin in amounts that exceed its production in thinner

people because they have a greater mass of fat. Unfortunately,

they appear to be less sensitive to its effects.

*The convention is to write mice genes in lower case italic letters and

humans in upper case italics.

BOX 10.2 Leptin and obese/OBESE

Figure 10.23 Molecular model of a leptin molecule. PDB file 1AX8.

Figure 10.24 (A) Normal and (B) genetically obese mice.