New signaling pathway provides clues to obesity

The discovery of this novel cell signaling pathway, reported today in the journal Nature, revises the previous "on-off" switch model of appetite control, said Roger Cone, Ph.D., who led the research team with Masoud Ghamari-Langroudi, M.D., Ph.D.

The discovery centers on a receptor in the brain's appetite control center, the melanocortin-4 receptor, or MC4R, a G-protein coupled receptor (GPCR) embedded in the membranes of nerve cells.

"This is a whole new way of understanding how some GPCRs signal," said Cone, chair of the Department of Molecular Physiology and Biophysics and Joe C. Davis Professor of Biomedical Science.

"Most GPCRs act like on-off switches, signaling over short time frames, but this finding identifies a molecular mechanism for converting an on-off switch into a rheostat," Cone said. "This could help explain slow, sustained biological processes that also are mediated by GPCRs, such as tanning or weight regain after dieting."

For years, MC4R has been characterized as a classic "on-off" switch typical of GPCRs. Alpha-melanocyte stimulating hormone (alpha-MSH) and agouti-related peptide (AgRP) compete for the same binding site on the receptor. Activation of the receptor by alpha-MSH turns appetite off, whereas inhibition by AgRP stimulates appetite.

In this common mode, GPCRs can only take so much stimulation before they shut down, a phenomenon called "desensitization." GPCR desensitization often happens rapidly and is essential for the function of many physiological systems, such as vision or smell.

But desensitization does not explain the return to homeostasis, the set point for body weight, which often occurs over the course of months once the dieter stops dieting.

The answer may be "hypersensitization," the reverse of desensitization, which occurs when MC4R "couples" to a potassium channel called Kir7.1. This process is independent of G protein signaling.

Studies in animals have shown that "a single dose of the peptide AgRP can stimulate daily food intake for up to 10 days. This observation simply didn't fit with traditional GPCR signaling," Cone said.

The current study found that AgRP not only competes with alpha-MSH for binding to the receptor, but also is a "biased agonist" that induces the MC4R to open Kir7.1. Opening the potassium channel "hyperpolarizes" and inhibits neurons involved in blocking appetite, and thus increases the sensation of hunger.

This finding may lead to new approaches for treating obesity. "The challenge now is to develop small molecule biased agonists of the MC4R," Cone said.

Kir7.1 is expressed in many other tissues, including kidney, uterine muscle, and intestine. Elsewhere, other candidate GPCRs that may signal directly through ion channels like Kir7.1 are also being investigated, he said.