Energy homeostasis deregulation is attenuated by TUDCA treatment in streptozotocin‐induced Alzheimer’s disease mice model.

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common cause

of dementia. While cognitive defcits remain the major manifestation of AD, metabolic and non- cognitive abnormalities, such as alterations in food intake, body weight and energy balance are also

present, both in AD patients and animal models. In this sense, the tauroursodeoxycholic acid (TUDCA) has shown benefcial efects both in reducing the central and cognitive markers of AD, as well as in attenuating the metabolic disorders associated with it. We previously demonstrated that TUDCA

improves glucose homeostasis and decreases the main AD neuromarkers in the streptozotocin- induced AD mouse model (Stz). Besides that, TUDCA-treated Stz mice showed lower body weight

and adiposity. Here, we investigated the actions of TUDCA involved in the regulation of body weight and adiposity in Stz mice, since the efects of TUDCA in hypothalamic appetite control and energy homeostasis have not yet been explored in an AD mice model. The TUDCA-treated mice (Stz+TUDCA) displayed lower food intake, higher energy expenditure (EE) and respiratory quotient. In addition, we observed in the hypothalamus of the Stz+TUDCA mice reduced fuorescence and gene expression of infammatory markers, as well as normalization of the orexigenic neuropeptides AgRP and NPY expression. Moreover, leptin-induced p-JAK2 and p-STAT3 signaling in the hypothalamus of Stz +TUDCA mice was improved, accompanied by reduced acute food intake after leptin stimulation. Taken together, we demonstrate that TUDCA treatment restores energy metabolism in Stz mice, a phenomenon that is associated with reduced food intake, increased EE and improved hypothalamic leptin signaling. These fndings suggest treatment with TUDCA as a promising therapeutic intervention for the control of energy homeostasis in AD individuals.