Obesity is a complex disease of great public health significance worldwide. It involves complications including cardiovascular diseases, diabetes mellitus type 2, nonalcoholic fatty liver disease, and certain types of cancers. More recently, changes in the microbiota have been recognized as a key contribution to obesity and its complications (Zielinska-Blizniewska et al., 2019).

The gut microbiota is a complex community containing trillions of microorganisms, mainly bacterial species that affect the host's systems and organs and modulate the host's physiological functions. Gut microbiota composition is dynamic and changes throughout human life depending on environmental (e.g., diet) and host (e.g., genetics and age) factors (Dave et al., 2012; De La Cuesta-Zuluaga et al., 2019).

Obesity-associated microbiota alters host energy harvesting, inflammation, insulin resistance, and fat deposition (Sankararaman et al., 2023). Changes in microbiota diversity and composition are increasingly associated with several disease states, including obesity. Intestinal microbiota can regulate metabolism, homeostasis, adiposity, energy balance, central appetite, and food reward signaling, which are crucial in obesity (Torres-Fuentes et al., 2017).

The gut-microbiota-brain axis is a bidirectional communication between the brain and gut bacterial community through multiple systems forming a network. It has a significant role in maintaining the homeostasis of the central nervous system (CNS) and gastrointestinal system (Asadi et al., 2022; Zhu et al., 2017). Neuroendocrine factors complex network and their receptors centrally regulate appetite, food intake, and energy balance, which mediate the bidirectional communication between the gastrointestinal tract and the brain (Asadi et al., 2022; Cryan et al., 2019; Martin et al., 2018). The gut-microbiota-brain axis plays a fundamental role in obesity and other disorders. Therefore, targeting the gut microbiome represents a promising therapeutic strategy for obesity.

Given the emerging role of gut microbiota in obesity, dietary polyphenols have gained attention for their potential to modulate microbial composition and improve metabolic health (Osborn et al., 2022). Among these, açaí (Euterpe oleracea Mart.), widely found in the Amazon region of Brazil, has been proposed as a functional food due to its potential to mitigate obesity-related metabolic alterations (De Moraes Arnoso et al., 2022). We previously reported that the hydroalcoholic extract of the açaí seed (ASE), rich in polyphenols such as catechin, epicatechin, and polymeric proanthocyanidins (De Bem et al., 2014; De Oliveira et al., 2015) has beneficial effects as anti-obesity (Santos et al., 2020; Tavares et al., 2020), antidiabetic (Da Silva Cristino Cordeiro et al., 2018; De Bem et al., 2018) and antihypertensive (Vilhena et al., 2021) effects which could be attributed, in part, to antioxidant and anti-inflammatory effects (Da Silva Cristino Cordeiro et al., 2018; De Bem et al., 2018; De Moraes Arnoso et al., 2022; Quitete et al., 2021).

Additionally, a therapeutic agent widely used is Metformin (dimethyl biguanide) due to its well-documented effects on improving glycemic control as an oral blood-glucose-lowering agent for type 2 diabetes mellitus (T2DM). Studies have demonstrated that Metformin also plays a clinical role in obesity (Adeyemo et al., 2015; Bailey, 2017). More recently, studies have shown an important effect of Metformin in modulating the gut microbiota in obesity (Pascale et al., 2019; Zhang and Hu, 2020).

Metformin exerts part of its therapeutic effects through gut-mediated and central mechanisms, particularly involving the gut-brain axis. Moreover, this drug increases glucose utilization in the gut, alters bile acid metabolism, and modulates the gut microbiota composition effects that contribute to improved glucose homeostasis and insulin sensitivity (Napolitano et al., 2014; Wu et al., 2017). Notably, Metformin enhances the abundance of Akkermansia muciniphila, a mucin-degrading bacterium linked to improved metabolic profiles (Shin et al., 2014). Furthermore, Metformin influences intestinal GLP-1 secretion, which affects appetite regulation and insulin secretion. In the hypothalamus, Metformin has been shown to activate AMP-activated protein kinase (AMPK), particularly in the arcuate nucleus, leading to decreased hepatic glucose production and reduced food intake (Andrzejewski et al., 2014; Rena et al., 2017). Moreover, Metformin lowers blood glucose levels through these combined gut and central mechanisms, contributes to weight regulation, and improves energy homeostasis.

Despite its established efficacy and safety, Metformin presents limitations such as gastrointestinal side effects, contraindications in renal impairment, and variable individual response (Foretz et al., 2014; Rena et al., 2017). Additionally, it does not fully address the complex mechanisms underlying obesity, including neuroinflammation and gut microbiota alterations. Thus, complementary strategies such as natural bioactive compounds, like ASE, potentially offer metabolic benefits through alternative pathways such as modulation of the gut-brain axis, inflammation, and oxidative stress (Bahadoran et al., 2013; Cani et al., 2008). ASE, a natural compound, may offer metabolic benefits comparable to Metformin, potentially acting through distinct or complementary biological pathways.

Building on our previously published findings demonstrating the significant anti-obesity and hypoglycemic effects of ASE in a murine model of diet-induced obesity, in the present study, we hypothesized that ASE could modulate gut microbiota composition and hypothalamic alterations associated with obesity. Furthermore, we aimed to compare its effects with Metformin, a widely used pharmacological agent for treating metabolic disorders.