TY - JOUR
T1 - Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity
AU - Tam, Joseph
AU - Vemuri, V. Kiran
AU - Liu, Jie
AU - Bátkai, Sándor
AU - Mukhopadhyay, Bani
AU - Godlewski, Grzegorz
AU - Osei-Hyiaman, Douglas
AU - Ohnuma, Shinobu
AU - Ambudkar, Suresh V.
AU - Pickel, James
AU - Makriyannis, Alexandros
AU - Kunos, George
PY - 2010/8/2
Y1 - 2010/8/2
N2 - Obesity and its metabolic consequences are a major public health concern worldwide. Obesity is associated with overactivity of the endocannabinoid system, which is involved in the regulation of appetite, lipogenesis, and insulin resistance. Cannabinoid-1 receptor (CB1R) antagonists reduce body weight and improve cardiometabolic abnormalities in experimental and human obesity, but their therapeutic potential is limited by neuropsychiatric side effects. Here we have demonstrated that a CB1R neutral antagonist largely restricted to the periphery does not affect behavioral responses mediated by CB1R in the brains of mice with genetic or diet-induced obesity, but it does cause weight-independent improvements in glucose homeostasis, fatty liver, and plasma lipid profile. These effects were due to blockade of CB1R in peripheral tissues, including the liver, as verified through the use of CB1R-deficient mice with or without transgenic expression of CB1R in the liver. These results suggest that targeting peripheral CB1R has therapeutic potential for alleviating cardiometabolic risk in obese patients.
AB - Obesity and its metabolic consequences are a major public health concern worldwide. Obesity is associated with overactivity of the endocannabinoid system, which is involved in the regulation of appetite, lipogenesis, and insulin resistance. Cannabinoid-1 receptor (CB1R) antagonists reduce body weight and improve cardiometabolic abnormalities in experimental and human obesity, but their therapeutic potential is limited by neuropsychiatric side effects. Here we have demonstrated that a CB1R neutral antagonist largely restricted to the periphery does not affect behavioral responses mediated by CB1R in the brains of mice with genetic or diet-induced obesity, but it does cause weight-independent improvements in glucose homeostasis, fatty liver, and plasma lipid profile. These effects were due to blockade of CB1R in peripheral tissues, including the liver, as verified through the use of CB1R-deficient mice with or without transgenic expression of CB1R in the liver. These results suggest that targeting peripheral CB1R has therapeutic potential for alleviating cardiometabolic risk in obese patients.
UR - http://www.scopus.com/inward/record.url?scp=77955286305&partnerID=8YFLogxK
U2 - 10.1172/JCI42551
DO - 10.1172/JCI42551
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C2 - 20664173
AN - SCOPUS:77955286305
SN - 0021-9738
VL - 120
SP - 2953
EP - 2966
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 8
ER -
