Leptin is produced primarily in the white adipose tissue; the circulating level of leptin is determined by the total amount of fat in the body. Leptin produced by the adipocytes gene is released into the general circulatory system (see the red line in the summary Figure 1) and is delivered to the brain via the circulatory system, where it crosses the blood-brain barrier (BBB) by a receptor-mediated transport process. Leptin acts through the leptin receptor (LEP-R), a single-trans membrane-domain receptor of the cytokine receptor family. The LEP-R is present in the neuropeptide Y (NPY) neurons in the arcuate nucleus and can respond to leptin in such a way as to decrease the activity of these neurons. Thus leptin orchestrates signals in the ventromedial hypothalamic region of the brain where a group of cells in the satiety center suppresses a desire to eat food. The hypothalamus also receives energy signals from ghrelin and insulin which complement the leptin message. Thus, leptin can function as a satiety factor as long as there is a functional diabetes Db/ Db gene which codes for the leptin receptor present in the hypothalamus. In summary, leptin signals the brain that the body has had enough food to eat.
Fig1. Adipocyte produced leptin delivers a message to the hypothalamus related to amount of food intake. Leptin, which is produced by adipose cells, is the lead regulator of a neuroendocrine supported energy homeostasis process mediated by integrated actions on the adipose-gut-brain axis. Leptin is released into the general circulatory system and is delivered to the brain via the circulatory system where it crosses the blood-brain barrier (BBB) by a receptor-mediated transport process (see the red line). Leptin acts through the leptin receptor (LEP-R), a single-transmembrane-domain receptor of the cytokine receptor family. The LEP-R is present in the neuropeptide Y (NPY) neurons in the arcuate nucleus in such a way as to decrease the activity of these neurons. Thus leptin orchestrates signals in the ventromedial hypothalamic region of the brain where a group of cells in the satiety center suppresses a desire to eat food, thereby producing a feeling of satiety.
The hypothalamus also receives neuronal inputs (autonomic afferents) concerning the external environment including light status and blood glucose levels. This then results in multiple central nervous system actions in the hypothalamus which generate both auto nomic outputs and also endocrine outputs from the pituitary which feedback to adipose and muscle which collectively results in imposing a decreased food intake. The hypothalamus has responsibility for determining the state of the body’s hunger status, fatigue, temperature, thirst, and sleep and circadian cycles. Thus the hypothalamus is essential for life. Besides containing receptors for leptin, the hypo thalamus has receptors for other hormones including insulin, CCK (cholecystokinin), ghrelin, PPY (peptide YY), and GLP-1 (glucagon-like peptide); these will be discussed in Chapter 7.
A number of unexpected actions of leptin have been identified. Leptin inhibits bone formation through a hypothalamic relay which controls bone mass. In rodents, leptin is required for female and male fertility. It has a lesser effect on human fertility. In humans, ovulatory cycles in females are believed to be linked to energy balance (positive or negative) depending on whether a female is gaining or losing weight. The placenta has been shown to secrete leptin.
In summary, the essential physiological role of leptin is to signal the presence of a caloric deficiency which mediates changes in metabolism rather than signaling an excess of calories. Also it should be appreciated that much research remains to clearly define the complexity of how energy expenditure contributes to obesity and the details of how hormones may modulate energy expenditure.
