Molecular Mechanisms Behind Appetite Suppression Drugs Discovered

Researchers in a new study discovered an ion channel necessary for brain cells to use in order to properly respond to the leptin hormone or obesity drug lorcaserin.

When the hormone or drug is detected by brain cells, eating is suppressed, which makes it a treatment target for obesity. Ion channels are passageways on the surface of neurons that transport ions in and out of the cells.

A better understanding of this relationship could lead to targeted treatments for obesity or even diabetes, according to the study published by Cell Reports.

"We found that an ion channel made up of TrpC5 (transient receptor potential cation 5) protein subunits is required for the proper regulation of basal metabolism and body weight," said senior study author Kevin Williams, PhD.

In a preclinical study involving mice, depletion of TrpC5 resulted in Pomc neurons becoming unresponsive to leptin or lorcaserin. This resulted in increased body weight over time.

A beneficial effect of improved blood sugar control resulting from lorcaserin treatment was not observed in TrpC5-deficient mice, according to the study.

“As researchers, we are trying to understand the cellular and molecular mechanisms that contribute to changes in body weight and blood-sugar balance,” Dr Williams said. “There is a possibility that this ion channel may someday be directly targeted for therapeutic regulation of eating and blood-sugar balance.”

Both leptin and lorcaserin control eating and metabolism by binding to receptors on the surface of the Pomc neurons located in the hypothalamus. Ion channels, which are formed by the gathering of TrpC proteins, are also located at the surface of the neurons.

While leptin and lorcaserin bind with different receptors, binding is ineffective unless TrpC5 ion channels are opened, according to the study.

In the current mouse study, the researchers compared normal animals to those who could not make the protein. The investigators took into account factors such as energy balance, eating, and activity levels.

A lack of TrpC5 in Pomc neurons was observed to block the appetite-suppressing affects of the hormone and drug, and it also seemed to downgrade the electrophysiological response, according to the study.

These findings also may explain previous findings that showed TrpC1, TrpC4, and TrpC5 were found in Pomc neurons, according to the authors. While it was understood that the TrpC family of proteins were able to create ion channels, the effects of the channels on metabolism were unknown.

Previously, the mechanisms behind appetite suppression in response to the activation of receptors for leptin or lorcaserin were also unknown. These findings may provide a new treatment option for patients with obesity in the future.

"Our results link TrpC5 subunits in the brain with leptin- and lorcaserin-dependent changes in nerve activity as well as energy balance, eating behavior, and blood-sugar levels," Dr Williams concluded.