Biphasic suppression of appetite by cannabinoid CB1 receptor antagonists with distinct functional activities

Lin, Ying‐Ting; Shia, Kak‐Shan; Hsiao, Wen-Chi; Hsieh, W.C.; Yeh, Teng‐Kuang; Tseng, Shi-Liang; Hsu, Chia‐Yu; Chao, Yu‐Sheng; Hung, Ming‐Shiu

doi:10.1016/j.phrs.2010.06.001

Cited by 10 publications

(4 citation statements)

References 31 publications

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“…22. In brief, compounds dissolved in ethanol/PEG 300/Tween 80/Cremophor EL (12/56/11/21 by weight) were administered orally to individually housed male Wistar rats (230--280 g) before lights were turned off.…”

Section: Hypothermia and Analgesia Responsesmentioning

confidence: 99%

Induction of fatty acid oxidation resists weight gain, ameliorates hepatic steatosis and reduces cardiometabolic risk factors

Lin

Shia

et al. 2011

Int J Obes

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OBJECTIVE: Fatty acid oxidation has been implicated in amelioration of obesity by burning off excessive accumulated lipid. BPR697, a peripheral cannabinoid receptor 1 (CB1) antagonist, elevated fat oxidation without added energy expenditure. Its impact on food intake, body weight changes and metabolic alterations were examined in rats fed standard chow and in diet-induced obesity (DIO) mice. MATERIALS AND METHODS: CB1 agonist-induced hypothermia and analgesia responses were measured to examine the brain activity of BPR697. The acute effects of BPR697 on food intake, body weight change and post-absorptive metabolic profiles were investigated in rats. Energy utilization with BPR697 was examined by indirect calorimetry. Chronic treatment of DIO mice was used to evaluate the long-term effects of BPR697. RESULTS: Distribution of BPR697 was significantly biased in favor of the periphery instead of the brain, as shown by its low brain/plasma concentration ratio and confirmed by the negative response of BPR697 in CB1 agonist-induced hypothermia and analgesia. When administered to rats at 20 mg kg À1 , BPR697 showed a unique spectrum of effects with significant weight loss without altered food intake. Furthermore, BPR697 increased serum levels of free fatty acids and ketone bodies and reduced hepatic lipid accumulation with preservation of liver glycogen in postprandial rats. Indirect calorimetric profiling of BPR697 revealed a similar trend, shifting whole-body energy catabolism toward fat oxidation, but without elevated energy expenditure. In DIO mice with chronic treatment, animals treated with BPR697 at 20 mg kg À1 resisted weight gain and showed a reduction of high-fat-induced cardiometabolic abnormalities such as hyperglycemia, abdominal fat and liver steatosis. CONCLUSION: The induction of fatty acid oxidation without concomitant elevation of energy expenditure by the peripheral CB1 antagonist BPR697 is sufficient to cause substantial weight loss in chow-fed rats. In the presence of high-dietary fat intake, BPR697 resists weight gain and alleviates obesity-related cardiometabolic risk factors. Keywords: fatty acid oxidation; peripheral CB1 antagonist; food intake; body weight; cardiometabolic risk factors INTRODUCTION Energy homeostasis, the balance between energy intake and energy expenditure, is regulated by coordinated interaction between the central nervous system and peripheral tissues. Elucidation of the metabolic factors influencing energy balance, and lipid and glucose metabolism has been a major focus of research interest, and many studies of the underlying mechanisms have revealed the importance of communication between the central nervous system and the periphery. 1--3 Among various factors involved in energy balance, endocannabinoids (for example, anandamide and 2-arachidonoylglycerol) mediate a positive energy balance via activation of their receptor, cannabinoid receptor 1 (CB1). The brain CB1 receptor, a G proteincoupled receptor, is present at a high level in brain tissue, and enhances appetite a...

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Section: Hypothermia and Analgesia Responsesmentioning

confidence: 99%

Induction of fatty acid oxidation resists weight gain, ameliorates hepatic steatosis and reduces cardiometabolic risk factors

Lin

Shia

et al. 2011

Int J Obes

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“…This increased potency may result from the elevation of endocannabinoid levels induced in response to obesity or fat intake, and/or the more sustainable suppressive effect that occurs in animals fed energy‐dense diets (e.g. HFD) compared with animals on SD ; however, BPR0912 treatment did not acutely decrease food intake by mice on either an SD or a HFD. Our data stand in contrast to previous studies of two peripheral CB1R antagonists, JD5037 and AM6545, which demonstrated acute food intake suppression in DIO mice compared with their central CB1R templates SLV319 and rimonabant, respectively .…”

Section: Discussionmentioning

confidence: 99%

A novel peripheral cannabinoid receptor 1 antagonist, BPR0912, reduces weight independently of food intake and modulates thermogenesis

Hsiao

Shia

Wang

et al. 2015

Diabetes Obesity Metabolism

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BPR0912 exhibits significant in vivo efficacy in inducing food intake-independent weight loss in DIO mice, while tending to reduce their hepatic steatosis. The thermogenic effects of BPR0912, as well as its modulation of protein and gene expression patterns in WAT and BAT, may enhance its efficacy as an anti-obesity agent. The results of the present study support the benefits of the use of peripheral CB1R antagonists to combat metabolic disorders.

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“…Also reported by Hung et al [33][34], a novel class of aryl alkynylthiophenes has been designed to target peripheral CB1R to eliminate/minimize CNS side effects as observed with 1. As shown in Scheme 2, several compounds of the series exhibited low B/P ratio with potent CB1R activity (IC 50 = 1.1~25.8 nM).…”

Section: Peripheral Chemical Modifications Based On Pyrazole Corementioning

confidence: 99%

A New Perspective of Cannabinoid 1 Receptor Antagonists: Approaches Toward Peripheral CB1R Blockers without Crossing the Blood-Brain Barrier

Wu¹,

Yeh²,

Ly³

et al. 2011

CTMC

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Since Rimonabant was withdrawn in Europe in 2008 because of its substantial CNS risk factors including depression and anxiety, the development of anti-obesity drugs targeting CB1R in the brain has been suspended and/or terminated globally. Instead, developing peripherally restricted CB1R antagonists is actively pursued in the hope that not only could they eliminate any CNS adverse effects observed with Rimonabant, but also maintain therapeutic benefits in metabolic syndrome, including obesity, type 2 diabetes, and non-alcoholic fatty liver diseases. In this review, we summarized the most recent advances that have been made on this area, with particular emphasis on various synthetic approaches, whereby the increase in polarity, water solubility and polar surface area were centralized on, toward potential peripheral-acting CB1 antagonists.

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Biphasic suppression of appetite by cannabinoid CB1 receptor antagonists with distinct functional activities

Cited by 10 publications

References 31 publications

Induction of fatty acid oxidation resists weight gain, ameliorates hepatic steatosis and reduces cardiometabolic risk factors

Induction of fatty acid oxidation resists weight gain, ameliorates hepatic steatosis and reduces cardiometabolic risk factors

A novel peripheral cannabinoid receptor 1 antagonist, BPR0912, reduces weight independently of food intake and modulates thermogenesis

A New Perspective of Cannabinoid 1 Receptor Antagonists: Approaches Toward Peripheral CB1R Blockers without Crossing the Blood-Brain Barrier

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