A Blog Around The Clock

First 'encyclopedia' of nuclear receptors reveals organisms' focus on sex, food:

Organisms thrive on sex and food, and so do their cells' receptors.

In creating the first "encyclopedia" of an entire superfamily of nuclear receptors - proteins that turn genes on and off throughout the body - UT Southwestern Medical Center researchers found that certain receptors form networks and interact to regulate disease states and physiology in two main areas, reproduction and nutrient metabolism.

Receptor networks also have key roles in metabolism's biological clock, researchers found.

The findings, published today in two studies in the journal Cell, chart the anatomy and timing of nuclear receptor expression throughout the body in hopes that researchers can uncover global receptor functions to improve prediction, diagnosis and treatment of diseases, from hypertension to diabetes.

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In the circadian study, researchers used mice to see how daily circadian rhythms influence the activity of the nuclear receptor superfamily in key metabolic tissues.

They found that the activity of more than half of receptors follow rhythmic cycles, so coordinated changes in receptor activity helps explain the cyclic behavior of metabolism. This also suggests that the superfamily acts as a mega-network to influence metabolism, rather than in a series of independent signaling pathways.

"Understanding timing patterns of receptors might help explain aspects of the out-of-rhythm states linked to many metabolic diseases," Dr. Mangelsdorf said.

Expression of receptors and expression of genes that are involved in synthesis and secretion of ligands that activate those receptors are synchronized by the circadian clock. This is sometimes called "internal coincidence".

When you are jet-lagged, some organs reset their timing to the new time-zone much faster than the others, leading to internal desynchronizaton. Thus, ligands (e.g., hormones) are secreted at times when their receptors are not around, and the receptors are expressed when there are no ligands in the system. Everything goes out of whack.

That is why jet-lag makes you feel sick, and a permanent state of being jet-lagged caused by shift-work (so called "shift-lag") can make you seriously ill.

It is not just nuclear receptors that are expressed in a rhythmic fashion. If a gene is important for the function of that cell, i.e., not housekeeping genes (e.g., actin or ribosome subunits) but genes that define that cell's "job" in the body (e.g., liver enzymes in liver cell, neurotransmitters in neurons, etc.), than that gene will be expressed in a circadian pattern.

The map of nuclear receptors will be a great aid for future research in circadian regulation of body functions.