Abstract
LH-21 is a triazol derivative that has been described as a low-permeant neutral CB1 antagonist, though its pharmacology is still unclear. It has been associated with anti-obesity actions in obese rats. However, its role in preventing type 2 diabetes (T2D) onset have not been studied yet. Given CB1 receptors remain as potential pharmacological targets to fight against obesity and T2D, we wanted to explore the metabolic impact of this compound in an animal model of obesity and pre-diabetes as well as the lack of relevant actions in related central processes such as anxiety. C57BL/6J mice were rendered obese and pre-diabetic by feeding a high-fat diet for 15 weeks and then treated with LH-21 or vehicle for two weeks. Food intake, body weight and glucose handling were assessed, together with other relevant parameters. Behavioural performance was evaluated by the open field test and the elevated plus maze. LH-21 did not affect food intake nor body weight but it improved glucose handling, displaying tissue-specific beneficial actions. Unexpectedly, LH-21 induced anxiolysis and reverted obesity-induced anxiety, apparently through GPR55 receptor. These results suggest that LH-21 can be a new candidate to fight against diabetes onset. Indeed, this compound shows potential in counteracting obesity-related anxiety.
Highlights
Obesity and related co-morbidities are reaching pandemic proportions worldwide
According the literature a mouse model of diet-induced obesity[14] was used to assess the effects of subchronic treatment with LH-21 (3 mg/Kg/day for two weeks) on body weight, food intake, glucose homeostasis and inflammatory status, and a behavioural study was performed on these animals
Obese pre-diabetic mice treated daily for up to 2-weeks with LH-21 (3 mg/Kg b.w.) did not display weight loss nor decreased food intake as compared to vehicle treated mice (Fig. 2A,B). They remained glucose intolerant when compared to vehicle-injected mice as assessed by glucose area-under-the-curve (AUC) calculation (ANOVA analysis for the entire time frame, Fig. 2C insert), though decreased glucose values were found at time point 30 min after glucose overload (Student’s t test), i.e. there was a lower plateau in glucose excursion (Fig. 2C)
Summary
Obesity and related co-morbidities are reaching pandemic proportions worldwide. In 2014, 11% of men and 15% of women age 18 and older were obese, while more than 42 million children under the age of five years were overweight in 20131. Its pharmacology isn’t clear and other authors have reported extra-CB1 effects of LH-21 and its ability in crossing the blood-brain-barrier (BBB)[11]. This compound has been found to decrease feeding behaviour in food-deprived rats and to reduce food intake and body weight gain in a genetic model of obesity, the obese Zucker rat[12]. The beneficial actions of this compound in diabetes onset as well as the putative mechanisms involved have yet to be clarified Despite this compound being able to cross the BBB to some extent, its putative modulatory actions of obesity-related anxiety are unknown
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