This is a study investigating the hormones and substances important to the stress response.
The hormone that is most directly responsible for stress response is called
corticotropin-releasing hormone (CRH). CRH is produced in the hypothalamus of the brain and
causes the pituitary gland to produce another hormone called ACTH. The hormone ACTH then
acts on the adrenal glands causing them to produce the hormone cortisol.
Unfortunately, CRH levels are unable to be measured in simple blood samples. However,
substances like cortisol and leptin can provide information as to the activity of the
The hormone leptin is associated with the regulation of body weight and the normal
maintenance of bodily functions (homeostasis). It is found in fat cell (adipocyes) and
communicates the nutritional status of the body to the brain (central nervous system).
Research using animals has shown that defects in the communication between leptin and the
brain causes obesity (the state of being overweight). It has also been noted that obese
humans tend to have high levels of leptin.
By studying patients with abnormal genes responsible for leptin production, researchers have
found that a least one leptin gene must be intact for the normal secretion of hormones to
proceed. These results show that the hormone leptin is produced outside of the brain in fat
cells and acts directly on the function of the hypothalamus within the brain. Researchers
believe that leptin plays a key role in the normal release of hormones from the HPA axis.
Researchers intend on continuing to study the role of leptin in fat distribution, and the
activity of the HPA axis in normal volunteers. In addition, this study will focus on the
role of leptin in depression, because depression is characterized by changes in food intake,
body weight, and neuroendocrine function. Data gathered from this study will provide a
better understanding of the causes and medical consequences of major depression.
Our group has tested the hypothesis that the molecules involved in the neurobiology of the
stress response are key elements in the pathophysiology, treatment, and medical consequences
of major depressive disorder. Leptin is implicated in the regulation of adipose tissue,
body weight and homeostasis. In the first three years of this protocol we accomplished the
following: (1) discovered leptin pulsatility; (2) showed that is secreted in a highly
organized manner in men and women; (3) showed for the first time in humans an inverse
relation between rapid fluctuations in plasma leptin concentrations in healthy volunteers
and those of adrenocorticotropic hormone (ACTH) and cortisol; (4) demonstrated a complex
relation between the minute-to-minute dynamics of leptin and those of luteinizing hormone
and estradiol; (5) showed a striking correlation between the 24-h dynamics of leptin and
those of TSH and GH; (6) demonstrated highly significant correlation between hourly
fluctuations of leptin levels and those of psychometric variables such as sadness, social
withdrawal, and carbohydrate craving, and (7) showed that women produce twice as much leptin
per secretory event than men. By studying patients with a leptin gene mutation we showed
that at least one intact copy of the leptin gene is required for the regulation of TSH
function and GH architecture in humans. These results indicate that leptin, a peripherally
secreted molecule, appears to modulate the secretion of hypothalamic hormones. We have
therefore proposed that hypothalamic neuroendocrine transduction, a key function of the CNS,
may be regulated by leptin, a peripheral pulsatile signal of nutritional status. We would
like to continue and expand our studies on the interactions of leptin, fat distribution, and
the pituitary-adrenal axis in normal volunteers and also in patients with depression,
because depression is characterized by alterations in food intake, body weight, and
neuroendocrine function. Leptin profoundly affects the regulation of these three
parameters. Leptin also increases insulin resistance, being therefore a risk factor for
coronary artery disease, which is more prevalent and associated with higher mortality in
depressed patients than in the general population. The data to be generated by this study
will provide a better understanding of pathophysiology and medical consequences of major
Depressed patients must have a history of past major depression of at least four months
duration, or a history of two or more briefer episodes. Must be overweight.
Must not need a hospital admission as part of their treatment.
Overweight normal volunteers.
No subjects on chronic medication which cannot be washed out for one month.
No subjects with any serious medical illness.
No women who are pregnant, trying to become pregnant, or sexually active and not using
No patients with HIV infection.
No subjects who cannot discontinue use of alcohol/tobacco.