Sepsis occurs when an infection surpasses local tissue containment and generates a series of dysregulated pathophysiological responses that result in systemic organic dysfunction [1], [2]. In this syndrome a hyper-dynamic evolution is observed, including periods of hyper- and hypoglycemia, with hypoglycemia commonly related to the worse prognosis and high mortality. Interestingly these changes are also observed in the lipopolysaccharide (LPS)-induced systemic inflammatory model of sepsis [3], [4], [5]. It is well established that systemic inflammation results in exaggerated consumption of energy in the form of adenosine triphosphate (ATP) by the cells of the immune system, resulting in an increased consumption of glucose [6], [7].

Moreover, it has also been demonstrated that LPS-induced hypoglycemia is triggered by a series of metabolic changes promoted by the synthesis of pro-inflammatory cytokines, such as TNF-α and IL-6. These cytokines reduce the gluconeogenesis pathway downregulating key protein content, such as phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) [8], [9]. It has also been reported that hypoglycemia observed during systemic inflammation can be a result of a decrease in corticosteroid response to stress, and the decreased response or failure of the sympathetic nervous system (SNS) and exacerbated production of nitric oxide (NOx) [10], [11], [12], [13].

Excessive recruitment of the immune system can be avoided by stimulating the brain-immune regulatory axis, which can modulate the immune response through humoral and neural pathways [14]. The stimulation of the hypothalamic–pituitary–adrenal axis culminates in the release of glucocorticoids that decreases the immune activity. Moreover, recent reports have sought to understand the participation of the cholinergic anti-inflammatory reflex in systemic inflammation [15]. The efferent arm of the anti-inflammatory reflex modulates immune organs such as the spleen, attenuating systemic cytokine production and consequently protecting from inflammatory disorders. This pathway can be stimulated by several drugs administered centrally, among them, Angiotensin-(1–7) (Ang-(1–7)) [16], [17].

Ang-(1–7) is a neuro heptapeptide derived from angiotensin with vasodilatory and anti-inflammatory actions [16], [17], [18]. Studies carried out by our research group have shown that central treatment of Ang-(1–7) can negatively regulate systemic inflammation induced by LPS, stimulating the efferent sympathetic pathway and attenuating the synthesis of TNF-α, IL-1β, IL-6, and NOx by the spleen and liver [17]. Furthermore, central Ang-(1–7) treatment attenuated LPS-induced glucocorticoid release, suggesting that the anti-inflammatory reflex and the hypothalamic-pituitary axis are involved in the central anti-inflammatory effects of Ang-(1–7). However, the central anti-inflammatory effect of Ang-(1–7) on glucose homeostasis is not known. Therefore, the aim of this study is to evaluate the effects of central administration of Ang-(1–7) on endotoxemia-induced hypoglycemia in rats.