Abstract
The nuclear bile acid (BA) receptor farnesoid X receptor (FXR) is a major regulator of metabolic/energy homeostasis in peripheral organs. Indeed, enterohepatic-expressed FXR controls metabolic processes (BA, glucose and lipid metabolism, fat mass, body weight). The central nervous system (CNS) regulates energy homeostasis in close interaction with peripheral organs. While FXR has been reported to be expressed in the brain, its function has not been studied so far. We studied the role of FXR in brain control of energy homeostasis by treating wild-type and FXR-deficient mice by intracerebroventricular (ICV) injection with the reference FXR agonist GW4064. Here we show that pharmacological activation of brain FXR modifies energy homeostasis by affecting brown adipose tissue (BAT) function. Brain FXR activation decreases the rate-limiting enzyme in catecholamine synthesis, tyrosine hydroxylase (TH), and consequently the sympathetic tone. FXR activation acts by inhibiting hypothalamic PKA-CREB induction of TH expression. These findings identify a function of brain FXR in the control of energy homeostasis and shed new light on the complex control of energy homeostasis by BA through FXR.
Highlights
Proper energy homeostasis is crucial to maintain health and avoid the development of metabolic disorders such as obesity, dyslipidemia and type 2 diabetes
To assess if brain Farnesoid X Receptor (FXR) contributes to the regulation of energy homeostasis, we first fine-mapped the exact localization of FXR expression in the hypothalamus at mRNA and protein levels (Gofflot et al, 2007; Huang et al, 2016; Figures 1, 2)
To determine whether FXR plays a role in the brain control of energy homeostasis, we treated mice by ICV injection with the reference FXR agonist GW4064 (Maloney et al, 2000)
Summary
Proper energy homeostasis is crucial to maintain health and avoid the development of metabolic disorders such as obesity, dyslipidemia and type 2 diabetes. Studies evaluating BA-FXR signaling in the CNS mainly focused on its potential role in neurodegenerative conditions, such as Alzheimer’s disease (Lo et al, 2013; Bell et al, 2018; McMillin et al, 2018), Parkinson’s disease (Castro-Caldas et al, 2012; Abdelkader et al, 2016; Moreira et al, 2017; Rosa et al, 2018), Huntington’s disease (Keene et al, 2001, 2002) as well as amyotrophic lateral sclerosis (Vaz et al, 2015; Elia et al, 2016) In these models of neurodegeneration, BA-FXR activation appears rather protective by acting on its pathophysiological mechanisms. We identify an unexpected novel function of brain FXR in its ability to control BAT function via a mechanism involving modification of hypothalamic PKA-CREB signaling and, subsequently, the sympathetic tone
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