Leptin is a 16-kDa hormone that is secreted by and in proportion to white fat cells. Leptin signals nutrient stores to neurons in the hypothalamus, which transduce this signal to modify food intake and energy expenditure. Leptin is also produced in the brain, the stomach, skeletal muscle, ovary, placenta, and pituitary. Our laboratory has previously shown the importance of the leptin signal to the maintenance of somatotropes, the secretion of growth hormone, and the onset of obesity in adulthood. What was not known, however, was the source of leptin responsible for this maintenance. We have created two tissue-specific leptin knockout animal lines to study the importance of the pituitary (specifically, somatotropes, lactotropes, and thyrotropes) versus the adipocyte as a pituitary-regulating source of leptin. The Adipocyte- Lep-null mutant animals have no circulating leptin, proving for the first time that the adipocyte is the only source of leptin that contributes to the circulating leptin pool. These animals have significant changes in pituitary and hypothalamic mRNA levels, as well as circulating pituitary hormone levels. Differences between this line and reported results in the ob/ob line, as well as our own global knockout model, indicate that pituitary leptin (and other extra-adipocyte sources of leptin) may retain some local and metabolic functions in the absence of circulating leptin. The Pit1-Lep-null mutants have no change in serum leptin, but male animals fail to maintain weight in adulthood. Mutant females have significantly decreased prolactin but maintain reproductive ability. Subtle metabolic changes may indicate a role for pituitary leptin, as well as prolactin, in the activity and oxidation of fats/carbohydrates in these animals.

We have created two new tissue-specific leptin knockout animal models using our floxed leptin mouse. Studies of these animals show, for the first time, that adipocyte leptin is the only source of circulating leptin in the body. Additionally, pituitary leptin and adipocyte leptin appear to work in concert to regulate pituitary hormone production and release. These studies contribute new information on isolated sources of leptin in the mouse.