The excessive consumption of high sugar-fat diets is one the main responsible for obesity development, a condition considered a major health problem worldwide. Increased body fat mass is a risk factor for the manifestation of several diseases, including type II diabetes, cardiovascular diseases, immunological disorders and even some types of cancer (1). Under positive energy balance conditions, the inappropriate expansion of adipose tissue results in adipokines production imbalance, oxidative stress and inflammation, all considered pathogenic pillars for disease development (2). Among the several consequences of adipose tissue dysfunction, hyperleptinemia is one of the most relevant for obesity, associated with inflammation, insulin resistance and cardiovascular diseases (1).

Leptin is a hormone produced mainly by adipocytes and its secretion is stimulated by insulin and other gastric peptides such as ghrelin, for example, shortly after food intake (3). After being produced by adipose tissue, leptin circulates through the bloodstream, crosses the blood-brain barrier and reaches the hypothalamus, where it binds to specific long-chain receptors, ObRb or LEPR-B (Leptin Receptor Long Isoform) (4). After extracellular domain binding, the leptin pathway involves JAK2 (Janus kinase 2) activation and phosphorylation of tyrosine residues (Tyr985, Tyr 1077, and Tyr1138) leading to STAT3 (signal transducers and activators of transcription 3) activation, with consequently nucleus translocation that results in transcription of target genes responsible for appetite inhibition and increased energy expenditure. Also, the nuclear translocation of STAT3 stimulates SOCS3 (suppressor of cytokine signaling 3) transcription, that inhibits LEPR-B receptors, acting as feedback negative for leptin action, controlling this hormone action (3).

For some years, it has been observed that obese individuals present, concomitantly, increased leptin levels and impaired hormone action, a condition named leptin resistance. Among the several mechanisms associated with leptin resistance, chronic inflammation commonly present in obesity condition is one of them (4). At the hypothalamus, inflammation stimulates SOCS3 production, blocking both JAK2 activation and leptin binding with ObRb receptor, resulting in hyperleptinemia (5).

Several studies have investigated bioactive compounds and their role as antioxidant and anti-inflammatory agents over the pathological damage caused by obesity, inflammation, and redox imbalance (6,7). Bergamot (Citrus bergamia) is a fruit commonly used in cosmetic and food industry; however, since it presents a composition rich in flavonoids, the interest in the antioxidant and anti-inflammatory potential has been emerged (3). The literature has been demonstrated hypoglycemic and hypolipidemic effects of bergamot fruit (8). However, Baron et al. (2021) demonstrated that bergamot leaves extract has a wider variety of polyphenolic compounds and a greater antioxidant and anti-inflammatory capacity compared to the fruit (9). A review study published by Aragonès et al. (2016) shows that leptin resistance modulation by some bioactive compounds as soon as presents some pathways involved (Aragonès et al., 2016). Therefore, due to the lack of studies with the bergamot leaves extract effect in vivo, mainly addressing the leptin pathway, the aim of this study was to test the hypothesis that the treatment with bergamot leaves extract can improve the leptin resistance by attenuating inflammation and oxidative stress in the hypothalamus, recovering the leptin pathway in obese rats.