The obesity is characterized by both an increased number of adipocytes and an increase in their size (J:7702); this is in contrast to other genetic obesities in the mouse in which increase in fat depots is due entirely to cell enlargement (J:5253, J:5765).

Hyperphagia may contribute tothe obesity. However, homozygotes gain excess weight and deposit excess fat even when restricted to a diet sufficient for normal lean mice, thus demonstrating an increased metabolic efficiency (J:6236). In parabiosis with normal mice, Lep^ob homozygotes eat less and lose weight; in parabiosis with Lepr^db homozygotes, they cease eating completely and die of starvation. This is taken to mean that they have a normal response to a 'satiety' factor, presumably the leptin protein, but are unable to produce enough of it to maintain normal food intake (J:5401).

Hyperinsulinemia does not develop until after the increase in food intake and is probably the result of it (J:5759). It has been shown, however, that homozygous Lep^ob mice have an abnormally low threshold for stimulation of pancreatic islet insulin secretion (J:14402), even in very young animals before obesity develops (J:22634). As is the case with the diabetes mutant Lepr^db, manifestation of the diabetic syndrome is strikingly dependent on genetic background. On a C57BL/6 background, Lep^ob homozygotes develop a well compensated diabetes with only temporary and moderate hyperglycemia, marked hyperinsulinemia, and enlarged islets of Langerhans. Onthe C57BLKS background, however, they become severely diabetic with regression of the islets and early death (J:5400).

Lep^ob homozygous mice have an impaired capacity for non-shivering thermogenesis which can be demonstrated at low temperatures as early as 10 days of age (J:12010). At 4 degrees C they rapidly become hypothermic and die within a few hours (J:5958). It has been suggested that a reduction in the energy requirement normally used for thermoregulatory heat production could be responsible for the increased metabolic efficiency noted above. That is unlikely to be the major cause of the thermoregulatory problems, however, since brief exposure of obese mice to 10 degrees C produces cold adaptation and allows indefinite survival at 4degrees C with maintenance of nearly normal body temperature (J:6756).

Coleman has suggested that the hyperinsulinemia of obese mice, which increases synthetic processes and decreases degradation, might spare the energy normally spent on tissue turnover and account at least in part for the increased efficiency (J:6756). Some contribution to the effect may also come from a low basal Na+,K+ATPase activity, shown to occur in muscle of 14-day old mutants (J:6182).

Heterozygotes (Lep^ob/+) have normal body weight, blood glucose, and plasma insulin, but can survive a prolonged fast longer than congenic wild type controls, suggesting that increased metabolic efficiency is expressed to some extent in heterozygotes (J:159).

Female homozygotes are always sterile, although their ovaries respond to exogenous pituitary hormones. About 20% of male homozygotes may be transiently fertile, particularly if maintained on a restricted diet (J:7702).

Cloning of the Lep gene has made possible the production of recombinant leptin. Injection of this protein into Lep^ob homozygotes sharply reduces body weight, decreases food intake, and increases energy expenditure. There is no effect in diabetic Lepr^db homozygotes, who are resistant to effects of the Lep^ob mutation. Normal mice also decrease food consumption and lose weight, with an accompanying loss in body fat (J:29161). Other investigators have obtained congruent results in normal and in Lep^ob mice (J:29162, J:29075); leptin also reduces food intake in fasted normal mice (J:28578). Leptin treatment effects on behavior of Lep^ob mice suggest a direct effect on neuronal networks (J:29160). Interactions of leptin with effects of hypothalamic lesions and of the Lepr gene indicate that Lep is upstream in the pathway of adipose tissue mass regulation (J:27422). Mutant leptin produced by the Lep^ob mutation fails to self-regulate production of leptin mRNA, which rises to a level 4 times that in normal mice. Lean mice when fasted decrease in leptin mRNA levels, but obese animals do not (J:29081).

There is a vast literature on the biochemical and physiological changes in Lep^ob mice, which has been reviewed by Herberg and Coleman (J:5759) and more recently by Charlton (J:7702). Many of the studies performed in adult mice may involve secondary effects of obesity rather than primary causes of it.

Increased blood levels of corticosterone occur in Lep^ob/Lep^ob mice, and most of the symptoms of the obese syndrome are ameliorated by excision of the adrenal glands. The hypothalamus-pituitary-adrenal axis is dysregulated, with hyperactivity of pituitary synthesis and secretion of adrenocorticotropic hormone (ACTH), as well as hyperresponsiveness of the adrenal cortex to ACTH (J:13151). Adrenal medullary activity, on the other hand, may be decreased; a diminished urinary excretion of epinephrine in obese homozygous mice indicates reduced medullary production, although this may be a secondary effect of the obesity (J:4033). A low serum level of the thyroid hormone triiodothyronine (T3) is also characteristic of obese homozygotes. Early treatment of these mice with T3 increases oxygen consumption and temperature while reducing body fat (J:22025). T3 treatment increases oxidative metabolism in muscle, but not in brown adipose tissue or in liver (J:22377).

Plasma triglyceride levels are elevated in mouse mutants considered models of non-insulin-dependent diabetes,including Lep^ob mutants. Cholesterol is also elevated, but the increase is primarily in high-density lipoprotein cholesterol (J:18161), so that atherosclerotic lesions are not increased (J:19043).