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.

Testosterone reduces hippocampal synaptic damage in an androgen receptor-independent manner

“…Consistent with our results, Guo et al (2020) also confirmed that Erk1/2 inhibitor blocked the structural synaptic plasticity of testosterone on primary rat hippocampal neurons. Phospho-CREB may bind to the promoters of susceptibility genes associated with synaptic plasticity to enhance their transcription and then regulate brain functions ( Rossetti et al 2022 ). However, whether Erk1/2–CREB mediates the effect of testosterone on cognitive function and neuroprotection in vivo needs to be further demonstrated.…”

Deletion of Crtc1 leads to hippocampal neuroenergetic impairments associated with depressive-like behavior

“…Even though Crtc1 is predominantly expressed in the brain [ 30 , 50 ] deleting this gene in mice induces a systemic metabolic deregulation [ 22 ], such as insulin resistance and obesity, together with a depressive-like phenotype [ 30 , 31 ]. As male Crtc1 −/− mice show a stronger depressive-like phenotype with a more severe comorbid obesity than females [ 21 , 23 , 29 ], we decided to capitalize on the former to focus on mechanistic aspects rather than sex differences in our neuroimaging study. While the association of MeS and behavioral alterations is likely to be complex and multifactorial, we report a clear link between brain glucose uptake and depressive-like behavior.…”

“…Importantly, CRTC1 has been implicated in rodent depressive-like behavior [23][24][25][26], which can be triggered by excessive CRTC1 phosphorylation and cytoplasmic sequestration as a response to chronic stress [27]. Thus, the Crtc1 knock-out (Crtc1 −/− ) mouse was shown to be a useful model to study the pathways and mechanisms linking metabolic diseases with depression [21,22,28,29] and to understand associated resistance to classic antidepressants, in particular to fluoxetine [30,31].…”

The unbroken Krebs cycle. Hormonal‐like regulation and mitochondrial signaling to control mitophagy and prevent cell death

“…[54] In addition, proteins phosphorylated by protein kinase A and/or C may enter the nucleus and regulate gene transcription. One relevant example is the cAMP response element-binding protein (CREB), a transcription factor of interest in diseases of the central nervous system, [55][56][57][58][59] that can translocate from the cytoplasm to the nucleus.…”