Antagonism of T-type calcium channels inhibits high-fat diet-induced weight gain in mice.
The epidemics of obesity and metabolic disorders have well-recognized health and economic burdens. Pharmacologic treatments for these diseases remain unsatisfactory with respect to both efficacy and side-effect profiles. Here, we have identified a potential central role for T-type calcium channels in regulating body weight maintenance and sleep. Previously, it was shown that mice lacking CaV3.1 T-type calcium channels have altered sleep/wake activity. We found that these mice were also resistant to high-fat diet-induced weight gain, without changes in food intake or sensitivity to high-fat diet-induced disruptions of diurnal rhythm. Administration of a potent and selective antagonist of T-type calcium channels, TTA-A2, to normal-weight animals prior to the inactive phase acutely increased sleep, decreased body core temperature, and prevented high-fat diet-induced weight gain. Administration of TTA-A2 to obese rodents reduced body weight and fat mass while concurrently increasing lean muscle mass. These effects likely result from better alignment of diurnal feeding patterns with daily changes in circadian physiology and potentially an increased metabolic rate during the active phase. Together, these studies reveal what we believe to be a previously unknown role for T-type calcium channels in the regulation of sleep and weight maintenance and suggest the potential for a novel therapeutic approach to treating obesity.
Uebele
Victor N
VN
Department of Sleep Research, Merck Research Laboratories, West Point, Pennsylvania 19486-0004, USA. victor_uebele@merck.com
Gotter
Anthony L
AL
Nuss
Cindy E
CE
Kraus
Richard L
RL
Doran
Scott M
SM
Garson
Susan L
SL
Reiss
Duane R
DR
Li
Yuxing
Y
Barrow
James C
JC
Reger
Thomas S
TS
Yang
Zhi-Qiang
ZQ
Ballard
Jeanine E
JE
Tang
Cuyue
C
Metzger
Joseph M
JM
Wang
Sheng-Ping
SP
Koblan
Kenneth S
KS
Renger
John J
JJ
D000818:Animals; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D020747:Calcium Channels, T-Type / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004041:Dietary Fats / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015394:Molecular Structure; D051381:Rats; D015430:Weight Gain / Q000187:drug effects*
C498197:Cacna1g protein, mouse; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D004041:Dietary Fats