This study will test the hypothesis that leptin contributes to the regulation of the
dynamics of human endocrine function.
Three separate, but complementary, specific aims, will elucidate the role of leptin in the
regulation of (A) the human pituitary-adrenal axis, (B) the human pituitary-gonadal axis,
and (C) the human pituitary-thyroid axis. These aims will be approached by a carefully
designed, prospective clinical study of the rapidly-sampled dynamics of endocrine rhythms
during the course of leptin-replacement treatment in the only three adult individuals
identified in the world so far who are leptin-naive due to a functional leptin gene
mutation. A study of leptin-naive subjects avoids all confounding factors and pitfalls,
because the only bioactive leptin to which they will be exposed is the exogenously
administered recombinant protein. Thus, this proposal will permit us to ascertain the
endocrine effects of human leptin. The proposed studies will elucidate key aspects of human
endocrine function and will give new insights on the role of leptin in human endocrine
We also propose to perform structural MRI scans (on and off leptin replacement) to test the
association of the changes in brain tissue composition with leptin replacement, and to test
how leptin influences regional brain function during the presentation of food-related
stimuli (pictures of food), which we will present to the patients along with neutral
pictures (e.g., landscapes). We will test how this possible effect on brain function will
be related to food craving or hunger.
In yet another part of the study we will assess the kinetics of human recombinant leptin.
- Congenital leptin deficiency (these are only 3 adult individuals in the world that
have been identified as leptin-naïve thus far).
- Pregnant, trying to become pregnant, breast-feeding an infant or sexually active
women, not using contraception.
- Subjects with hemoglobin levels below 12 g/dl.
- Subjects whose body contains a ferromagnetic implanted device that might produce a
safety hazard during fMRI.