Peroxisome proliferator-activated receptor-γ (PPARγ) modulates hypothalamic Trh regulation in vivo

Abstract Thyroid hormone receptor (TR) and peroxisome proliferator-activated receptor γ (PPARγ) co-regulate numerous peripheral metabolic responses. To examine potential crosstalk between PPARγ and TRβ in the hypothalamus, thyrotropin-releasing hormone ( Trh ) regulation in the newborn mouse hypothalamus was followed. QPCR showed PPARγ to be expressed in the hypothalamus at this developmental stage. Intracerebral injection of PPARγ agonists modified transcription from a TRH-luc construct introduced into the hypothalamus and increased serum thyroxine levels. Furthermore, shRNA-based in vivo PPARγ knockdown amplified T 3 -independent transcription and PPARγ overexpression dose-dependently abrogated T 3 -dependent Trh repression. Overexpression of retinoid X receptor-α (RXRα), the common heterodimeric partner of PPARγ and TRβ, rescued PPARγ abrogation of T 3 -dependent repression. Thus, competition for RXR could represent one mechanism underlying this hypothalamic crosstalk between PPARγ and TRβ. These demonstrations of PPARγ effects on hypothalamic Trh transcription in vivo consolidate the role of the TRH neuron as a central integrator of energy homeostasis.