Emotional regulatory function of receptor interacting protein 140 revealed in the ventromedial hypothalamus

Abstract

Receptor-interacting protein (RIP140) is a transcription co-regulator highly expressed in macrophages to regulate inflammatory and metabolic processes. However, its implication in neurological, cognitive and emotional conditions, and the cellular systems relevant to its biological activity within the central nervous system are currently less clear. A transgenic mouse line with macrophage-specific knockdown of RIP140 was generated (MΦRIPKD mice) and brain-region specific RIP140 knockdown efficiency evaluated. Mice were subjected to a battery of tests, designed to evaluate multiple behavioral domains at naïve or following site-specific RIP140 re-expression. Gene expression analysis assessed TNF-α, IL-1β, TGF-1β, IL1-RA and Neuropeptide Y (NPY) expression, and in-vitro studies examined the effects of macrophage’s RIP140 on astrocytes’ NPY production. We found RIP140 expression was dramatically reduced in macrophages within the ventromedial hypothalamus (VMH) and the cingulate cortex of MΦRIPKD mice. These animals exhibited increased anxiety- and depressive-like behaviors. VMH-targeted RIP140 re-expression in MΦRIPKD mice reversed its depressive- but not its anxiety-like phenotype. Analysis of specific neurochemical changes revealed reduced astrocytic-NPY expression within the hypothalamus of MΦRIPKD mice, and in-vitro analysis confirmed that conditioned medium of RIP140-silnenced macrophage culture could no longer stimulate NPY production from astrocytes. The current study revealed an emotional regulatory function of macrophage-derived RIP140 in the VMH, and secondary dysregulation of NPY within hypothalamic astrocyte population, which might be associated with the observed behavioral phenotype of MΦRIPKD mice. This study highlights RIP140 as a novel target for the development of potential therapeutic and intervention strategies for emotional regulation disorders.

Retinoic Acid Induces Ubiquitination-Resistant RIP140/LSD1 Complex to Fine-Tune P ax6 Gene in Neuronal Differentiation

“…Therefore, RIP140 seems to be able to adopt various mechanisms to provide a feedback control for multiple critical physiological processes. Gene knockout/silencing studies in animals reveal numerous abnormal phenotypes in the mouse . Most interestingly, behavior phenotypes are commonly observed in these studies.…”

“…For most transcription factors, RIP140 acts as a corepressor by recruiting various repressive enzymes/factors such as HDACs, CtBP, and G9a, and so forth . Animal studies have revealed its diverse functions in various biological/physiological processes including energy expenditure, behavior, immunity, lipid metabolism, insulin signaling, and neuron stress, and so forth . In the RA‐induced ESC differentiation process, RIP140 is required for the Brg/Brm switch on the Nanog and Oct4 gene promoters when they are silenced in differentiating cells .…”

Behavioral stress reduces RIP140 expression in astrocyte and increases brain lipid accumulation

“…1306A30679). All behavioral assessments were performed as previously described (Flaisher-Grinberg et al, 2012, Flaisher-Grinberg et al, 2014). The general activity was assessed by the automated open field environments.…”

“…Receptor-interacting protein 140 (RIP140), a transcriptional co-regulator for numerous transcription factors and a signal transduction regulator, is recently implicated in the regulation of cognitive function, emotional response and neuron health via its activities in microglia and neurons (Feng et al, 2014, Flaisher-Grinberg et al, 2014). RIP140 is first known to co-regulate the activities of many nuclear receptors/transcription factors that regulate lipid metabolism.…”

“…Whole body RIP140 knockout mice are lean and exhibit memory deficits and increased stress responses, in addition to numerous defects particularly in reproduction (Duclot et al, 2012). Macrophage specific RIP140 knockdown mice have decreased microglia RIP140 level in ventromedial hypothalamus and the cingulate cortex, and exhibit increased anxiety- and depressive-like behaviors (Flaisher-Grinberg et al, 2014). More recently, we found that loss of RIP140 in hippocampal neurons can result in increased vulnerability to ER stress-induced death (Feng et al, 2014).…”