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

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.

Keywords: BDNF; CREB; CRTC1; circadian rhythms; major depressive disorder; neuroplasticity; obesity.

FIGURE 1

Activity-dependent synapse-to-nucleus translocation of CRTC1 mediates the activation of neuroplasticity gene transcription. CRTC1 is sequestered in dendritic spines under basal conditions via a phosphorylation-dependent association with 14-3-3 proteins. Simultaneous activation of calcium and cAMP pathways (by L-VGCC or NMDAR, and GPCR-activated AC) triggers release from 14-3-3 proteins by, respectively, activating the phosphatase calcineurin (CaN) and inhibiting kinases of the AMPK family (SIK). Dephosphorylated CRTC1 migrates into the nucleus and is recruited to the promoter via an interaction with the bZIP domain of CREB, thus promoting expression of Bdnf and other neuroplasticity genes. AC, adenylate cyclase; AMPK, AMP-activated protein kinase; CaN, calcineurin; CBP, CREB-binding protein; CREB, cAMP response-element binding protein; CRTC1, CREB-regulated transcription coactivator 1; GPCR, G protein-coupled receptor; L-VGCC, L-type voltage-gated calcium channels; NMDAR, N-methyl-D-aspartate receptor; PKA, protein kinase A; SIK, salt-inducible kinase.

FIGURE 2

Possible role of CRTC1 in the pathogenesis of depression and associated disorders. Preclinical animal models of depression suggest that life stressors decrease CRTC1 levels in the prefrontal cortex and hippocampus, which triggers an altered neuroplasticity and functional connectivity related to the pathogenesis of depression and associated metabolic syndrome and chronodisruption.