New Insights Into the Pivotal Role of CREB-Regulated Transcription Coactivator 1 in Depression and Comorbid Obesity.

Clara Rossetti,Jean-René Cardinaux,Antoine Cherix,Laetitia F Guiraud

doi:10.3389/fnmol.2022.810641

Abstract

Depression and obesity are major public health concerns, and there is mounting evidence that they share etiopathophysiological mechanisms. The neurobiological pathways involved in both mood and energy balance regulation are complex, multifactorial and still incompletely understood. As a coactivator of the pleiotropic transcription factor cAMP response element-binding protein (CREB), CREB-regulated transcription coactivator 1 (CRTC1) has recently emerged as a novel regulator of neuronal plasticity and brain functions, while CRTC1 dysfunction has been associated with neurodegenerative and psychiatric diseases. This review focuses on recent evidence emphasizing the critical role of CRTC1 in the neurobiology of depression and comorbid obesity. We discuss the role of CRTC1 downregulation in mediating chronic stress-induced depressive-like behaviors, and antidepressant response in the light of the previously characterized Crtc1 knockout mouse model of depression. The putative role of CRTC1 in the alteration of brain energy homeostasis observed in depression is also discussed. Finally, we highlight rodent and human studies supporting the critical involvement of CRTC1 in depression-associated obesity.

Highlights

According to the World Health Organization, more than 300 million people suffer from depression worldwide (World Health Organization, 2017)
Mice lacking CREB-regulated transcription coactivator 1 (CRTC1) exhibit depressivelike endophenotypes (Breuillaud et al, 2012; Meylan et al, 2016a,b) and an altered regulation of feeding behavior resulting in hyperphagic obesity only in males (Rossetti et al, 2017)
More research is needed to understand why Crtc1−/− female mice are less affected and whether the altered circadian activity of the males correlates, for instance, with a reduced average duration of sleep and modified sleep patterns. Related to these metabolic and circadian alterations, magnetic resonance spectroscopy (MRS) studies with Crtc1−/− male mice suggest that CRTC1 plays a critical role in regulating brain neuroenergetics

Summary

Introduction

According to the World Health Organization, more than 300 million people suffer from depression worldwide (World Health Organization, 2017). AAV-shRNA-mediated knockdown of hippocampal SIK2 or genetic knockout of Sik2 protected mice in CSDS and CUMS models of depression with antidepressant-like effects depending on the CRTC1-CREB-BDNF pathway.

Results

Conclusion