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

Abstract

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...

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

“…The biased biodistribution of BPR0912 was also evident in the food intake experiments of the present study. Our previous examination of a different peripheral CB1R antagonist, BPR0697, suggested that acute blockade of peripheral CB1R was not involved in the food intake suppression observed in animals that were on a SD and treated with this agent . This result has been further supported by investigations of JD5037 , a peripheral CB1R antagonist, and also by our examination of BPR0912 in the present study.…”

“…Kits to measure serum concentrations of glucose, triglycerides (both from Randox, Crumlin, UK), insulin (Mercodia, Uppsala, Sweden), leptin (R&D Systems, Minneapolis, MN, USA), and non‐esterified fatty acids (Wako, Osaka, Japan) were used according to the manufacturers' instructions. Liver triglycerides were determined as previously described and as detailed in File S1.…”

Grape seed procyanidins administered at physiological doses to rats during pregnancy and lactation promote lipid oxidation and up-regulate AMPK in the muscle of male offspring in adulthood

“…Thus, in an experiment performed with mice fed a HFD, Lagouge et al demonstrated that chronic treatment with resveratrol did not affect either the RQ or energy intake but resulted in an increased EE that could be, at least in part, responsible for the lower body weight gain and adiposity observed in these animals compared with mice that did not receive this polyphenol [45]. In another study, acute treatment of chow-fed rats with the peripheral cannabinoid receptor 1 (CB1) antagonist BPR697 enhanced fatty acid oxidation and produced a substantial body weight loss without affecting EE and energy intake [46]. Similar results were obtained by Attane and collaborators, whose partially associated the drop in RQ observed in HFD apelin-treated mice with decreased adiposity, although no changes in EE were observed [47].…”

Studies on Mechanistic Role of Natural Bioactive Compounds in the Management of Obesity An Overview

“…The latter effect should not be neglected, although this aspect is beyond the scope of this work. It is known that the metabolic changes that occur in the liver as a result of obesity are important mechanisms that underlie development of metabolic syndrome and insulin resistance [120].…”