1. Introduction
Obesity is highly prevalent, with 1.9 billion overweighted adults, being 650 million obese. It represents a major worldwide public health challenge that reduces life expectancy by 0.9 to 4.2 years and causes the death of 3.4 million adults per year (WHO, 2019).
Obesity is typically associated with ‘poor’ diets, high in fat and low in dietary fibre. Mechanistically, this is related to insulin resistance, resulting in dysregulation of glucose and lipid metabolisms, together with development of low-grade systemic inflammation. Infiltration of activated immune cells in metabolic tissues, including liver and fat, leads to proinflammatory cytokine secretion and re-programming of immunoregulatory cells. These alterations raise the risk of comorbidities, like metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), type 2 diabetes and/or cardiovascular diseases(Targher, Byrne, Lonardo, Zoppini, & Barbui, 2016).
The gut microbiome is also involved in the pathogenesis of obesity. Development of obesity and the associated inflammation and insulin resistance have been related to dysbiosis, modifications in the composition and/or function of the intestinal microbiota. This has also been linked to the impairment of energy homeostasis and gut permeability(Shen et al., 2013). Therefore, alleviating gut dysbiosis in experimental models has shown to effectively prevent and treat obesity and its related disorders(Muscogiuri et al., 2019).
In addition, the circadian rhythm and the lipid metabolism are nowadays accepted to cross-regulate through different mechanisms that include hormones like melatonin, leptin or glucocorticoids, intestinal microbiome and energy metabolism. Its dysregulation may be also associated with the risk of obesity, which may subsequently worsen circadian clocks(Li et al., 2020).
In this regard, melatonin, which is an important regulator of the circadian rhythm(Reiter, Tamura, Tan, & Xu, 2014), oxidative stress(Zhang & Zhang, 2014), immune function(Liu et al., 2017), and glucose and lipid metabolism(Cipolla-Neto, Amaral, Afeche, Tan, & Reiter, 2014), has been described to also prevent obesity in high fat diet-fed mice, thus leading to gut microbiota modulation, by restoring Firmicutes /Bacteroidetes ratio and raisingAkkermansia abundance(Abuqwider, Mauriello, & Altamimi, 2021). Moreover, melatonin has been reported to improve lipid metabolism and reduce hepatic lipid accumulation and steatosis, maybe through gut microbiota reprogramming, as well(Yin et al., 2018). However, melatonin displays an extremely short half-life (under 30 min), which hinders its clinical application, but it provides new insights for the melatoninergic pathway-based therapeutics. Hence, different melatonin agonists, with better pharmacokinetics and longer half-times, have been developed. Among these, agomelatine is an agonist of the melatonin receptors MT1 and MT2, but also an antagonist of 5-HT2B and 5-HT2C serotonin receptors(Hickie & Rogers, 2011). Agomelatine shows potent antidepressant and anxiolytic properties and is licensed for the management of major depressive disorders in adults(Gorwood et al., 2020). Recently, it has been reported its anxiolytic/antidepressant effect in obese rats, maybe due to an amelioration of the high fat diet (HFD)-associated inflammation and oxidative stress(Rebai, Jasmin, & Boudah, 2021). Therefore, a comprehensive study of the effects of agomelatine would be necessary to consider its therapeutic value in these conditions. With this aim, agomelatine was assayed in an experimental model of obesity induced by a HFD in mice. Its effect was compared to that of melatonin and metformin, which has been used as a weight loss drug(Pu et al., 2020) and their impact on metabolic profile, inflammatory response, vascular dysfunction and gut microbiota composition was evaluated.