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.