C. elegans weight loss circuitry

Scripps Resraech Institute News Release, LA JOLLA, CA—October 10, 2013 - from work published in Cell Metabolism

Principal Investigator Dr.Supriya Srinivasan

Scientists at The Scripps Research Institute (TSRI) have discovered key details of a brain-to-body signaling circuit that enables roundworms to lose weight independently of food intake. The weight-loss circuit is activated by combined signals from the worm versions of the neurotransmitters serotonin and adrenaline, and there are reasons to suspect that it exists in a similar form in humans and other mammals.

Experiments were conducted on C. elegans, whose short lifespans and well-characterized nervous systems make them a preferred species for quick-turnaround lab studies.

Their most surprising discovery was that serotonin isn't the sole driver of this weight-loss pathway, but works in concert with another neurotransmitter, octopamine whih is the C. elegans version of adrenaline (also called epinephrine) in mammals.

The team mapped out a self-reinforcing network of serotonin and octopamine-producing neurons in the worms that send the lose-weight signal to the body. This network includes a set of serotonin-sensitive neurons known as URX neurons, which have access to the worm circulatory system and apparently release a still-to-be-identified signaling molecule. The downstream result of this signal, the researchers found, is a boost in the production of a key enzyme in the worm intestine. The enzyme, known as adipocyte triglyceride lipase 1 (ATGL-1), literally cuts fat molecules in a way that leads to their further metabolic breakdown. ATGL-1 also has a very similar counterpart in mammals.

However, Srinivasan noted that the human experience with weight-loss drugs already hints that mammals may have such a fat-loss circuit. Serotonin-plus-adrenaline boosting therapies, the most prominent of which was fenfluramine-phentermine ("fen-phen"), have tended to do better at cutting weight than serotonin-boosting therapies alone. Unfortunately, the serotonin-boosting elements of these compounds have often been blamed for cardiovascular side effects—fenfluramine, for example, was banned by the FDA in 1997—but in principle, future combination therapies could be designed to avoid producing such side effects.