Dynamics of Leptin and Endocrine Function
Dynamics of Leptin and Endocrine Function
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
 hypothalamus.

 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 depression.
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
 effective contraception.

 No patients with HIV infection.

 No subjects who cannot discontinue use of alcohol/tobacco.