Farnesoid X Receptor activation in brain alters brown adipose tissue
function via the sympathetic system
Abstract
Background and Prupose: 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.
Experimental Approach: 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. Key Results: 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. Conclusions and Implication: 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.