Dallas: UT Southwestern Medical Center researchers have identified an ion channel required for brain cells to suppress eating behavior in response to the hormone leptin or to the anti-obesity drug lorcaserin. Ion channels are tunnel-shaped passageways on the surface of neurons through which charged particles, or ions, can travel in and out of the cell. A deeper understanding of this brain-metabolism relationship could someday lead to new, better targeted treatments for obesity or diabetes, said lead author Dr. Kevin Williams, Assistant Professor of Internal Medicine at UT Southwestern and senior author of the study, published recently in 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,” Dr. Williams said.
In the mouse study, loss of TrpC5 caused types of nerve cells in the
brain called Pomc neurons to become unresponsive to leptin or
lorcaserin, resulting in increased body weight over time. The normally
beneficial effect of lorcaserin on blood-sugar levels was also lost in
mice deficient for TrpC5, the study showed.
“As researchers, we are trying to understand the cellular and
molecular mechanisms that contribute to changes in body weight and
blood-sugar balance. There is a possibility that this ion channel may
someday be directly targeted for therapeutic regulation of eating and
blood-sugar balance,” Dr. Williams said.
Leptin and lorcaserin exert their effects on eating and other aspects
of metabolism by binding to different types of receptors that sit on
the surface of Pomc neurons in the hypothalamus, the part of the brain
that helps govern metabolism and other involuntary bodily functions such
as breathing and sleeping. The ion channels, formed when TrpC proteins
gather together to form a channel, or tube-like structure, are also on
the surface of Pomc neurons.
Although leptin and lorcaserin bind to different receptors, binding
is ineffective unless nearby TrpC5 ion channels are opened to allow the
passage of ions in and out of the cell.
The researchers conducted experiments comparing normal mice and mice genetically unable to make TrpC5. Energy
balance, eating behavior, and activity levels were measured. The
researchers found that a lack of TrpC5 in Pomc neurons was enough to
block the usual appetite-suppressing effects of leptin and lorcaserin.
Lack of TrpC5 also seemed to blunt the cell’s electrophysiological
response to leptin and lorcaserin.
The research helps explain some intriguing observations previously
made by researchers at UT Southwestern and elsewhere. Studying the seven
proteins in the TrpC family, earlier studies determined that TrpC1,
TrpC4, and TrpC5 (and to a lesser extent TrpC6 and TrpC7) were detected
in Pomc neurons. Although it was known that these TrpC family members
could form ion channels, the effects or relative importance of TrpC5
proteins in particular to regulate metabolism were unknown, Dr. Williams
said. Moreover, the molecular mechanisms underlying appetite
suppression in response to activation of receptors for leptin or
lorcaserin were unclear, he added.
“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 said.
Lead authors of the study from UT Southwestern’s Division of Hypothalamic Research
were former postdoctoral fellow Dr. Jong-Woo Sohn and current or former
visiting graduate students Yong Gao, Ting Yao, and Zhuo Deng.
Instructor of Internal Medicine Dr. Tiemin Liu
and visiting researchers Dr. Jia Sun and Dr. Yiru Huang also
contributed to the work, as did researchers from Harvard University; the
University of Texas Medical Branch in Galveston, Texas; and several
institutions in China.
This study was supported by the National Institutes of Health, the
China Scholarship Council, the National Research Foundation of Korea,
the Korean Ministry of Health and Welfare, and the National Natural
Science Foundation of China.
About UT Southwestern Medical Center
UT Southwestern, one of the premier academic medical centers in the
nation, integrates pioneering biomedical research with exceptional
clinical care and education. The institution’s faculty includes many
distinguished members, including six who have been awarded Nobel Prizes
since 1985. The faculty of almost 2,800 is responsible for
groundbreaking medical advances and is committed to translating
science-driven research quickly to new clinical treatments.
UT Southwestern physicians provide medical care in about 80 specialties
to more than 100,000 hospitalized patients and oversee approximately 2.2
million outpatient visits a year.