Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity
Joseph Tam, V. Kiran Vemuri, Jie Liu, Sándor Bátkai, Bani Mukhopadhyay, Grzegorz Godlewski, Douglas Osei-Hyiaman, Shinobu Ohnuma, Suresh V. Ambudkar, James Pickel, Alexandros Makriyannis, George Kunos
Joseph Tam, V. Kiran Vemuri, Jie Liu, Sándor Bátkai, Bani Mukhopadhyay, Grzegorz Godlewski, Douglas Osei-Hyiaman, Shinobu Ohnuma, Suresh V. Ambudkar, James Pickel, Alexandros Makriyannis, George Kunos
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Research Article

Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity

Abstract

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.

Authors

Joseph Tam, V. Kiran Vemuri, Jie Liu, Sándor Bátkai, Bani Mukhopadhyay, Grzegorz Godlewski, Douglas Osei-Hyiaman, Shinobu Ohnuma, Suresh V. Ambudkar, James Pickel, Alexandros Makriyannis, George Kunos

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Figure 8

Effects of short-term CB1R blockade on hormonal and metabolic parameters in ob/ob mice.

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Effects of short-term CB1R blockade on hormonal and metabolic parameters...
Treatment of ob/ob mice with 10 mg/kg/d, i.p., of rimonabant or AM6545 for 7 days does not affect body weight and adiposity (A), but improves glucose tolerance and insulin resistance (B) and reduces plasma glucose and insulin levels (C). AM6545, but not rimonabant, reduces liver TG content and plasma ALT levels (D). Effects of rimonabant and AM6545 on plasma TG and on HDL and LDL cholesterol levels (E). Data represent mean ± SEM from 6 mice per group. *P < 0.05 relative to corresponding vehicle value.