Inflammation-activated C/EBPβ mediates high-fat diet-induced depression-like behaviors in mice

Abstract

Depression, one of the most common causes of disability, has a high prevalence rate in patients with metabolic syndrome. Type 2 diabetes patients are at an increased risk for depression. However, the molecular mechanism coupling diabetes to depressive disorder remains largely unknown. Here we found that the neuroinflammation, associated with high-fat diet (HFD)-induced diabetes and obesity, activated the transcription factor CCAAT/enhancer binding protein β (C/EBPβ) in hippocampal neurons. This factor repressed brain-derived neurotrophic factor (BDNF) expression and caused depression-like behaviors in male mice. Besides, the loss of C/EBPβ expression in C/EBPβ heterozygous knockout male mice attenuated HFD-induced depression-like behaviors, whereas Thy1-C/EBPβ transgenic male mice (overexpressing C/EBPβ) showed depressive behaviors after a short-term HFD. Furthermore, HFD impaired synaptic plasticity and decreased surface expression of glutamate receptors in the hippocampus of wild-type (WT) mice, but not in C/EBPβ heterozygous knockout mice. Remarkably, the anti-inflammatory drug aspirin strongly alleviated HFD-elicited depression-like behaviors in neuronal C/EBPβ transgenic mice. Finally, the genetic delivery of BDNF or the pharmacological activation of the BDNF/TrkB signaling pathway by 7,8-dihydroxyflavone reversed anhedonia in a series of behavioral tests on HFD-fed C/EBPβ transgenic mice. Therefore, our findings aim to demonstrate that the inflammation-activated neuronal C/EBPβ promotes HFD-induced depression by diminishing BDNF expression.

7,8-Dihydroxyflavone is a direct inhibitor of pyridoxal phosphatase

“…The discovery of 7,8-DHF as a direct PDXP inhibitor was unexpected. Interestingly, numerous in vivo studies have reported the effectiveness of 7,8-DHF in brain disorder models, including rodent models of Alzheimer's disease (49)(50)(51)(52)(53)(54)(55)(56), depression (57)(58)(59)(60)(61)(62), schizophrenia (63)(64)(65)(66)(67), or epilepsy (68,69), as well as in rodent models of autism (70)(71)(72)(73).…”

“…The discovery of 7,8-DHF as a direct PDXP inhibitor was unexpected. Interestingly, numerous in vivo studies have reported the effectiveness of 7,8-DHF in brain disorder models, including rodent models of Alzheimer's disease (50)(51)(52)(53)(54)(55)(56)(57), depression (58)(59)(60)(61)(62)(63), schizophrenia (64)(65)(66)(67)(68), epilepsy (69,70) and autism (71)(72)(73)(74). Although PLP deficiency is thought to contribute to the respective human conditions (3,75,76), PLP-dependent processes have not yet been considered in the context of 7,8-DHF-induced effects.…”

Transcutaneous vagus nerve stimulation modulates depression‐like phenotype induced by high‐fat diet via P2X7R/NLRP3/IL‐1β in the prefrontal cortex

“…Twenty ZDF rats were randomly divided into the ZDF + Purina group (32% fat, 13% protein, 55% carbohydrate; N = 10) and ZDF + KK group (17.9% fat, 17.5% protein, 48.5% carbohydrate; N = 10) compared with the ZL group (general maintenance diet #1022, N = 10). Behavioral tests, forced swimming test (FST) and open field test (OFT), were, respectively, measured every 2 weeks to evaluate the depressive‐like phenotype 3,26–29 . Gut microbiota composition and metabolome characteristics were measured at the end of this experiment (Figure 1A).…”

The Genetic Basis of Future Pharmacological Strategies for the Management of Comorbid Obesity and Depression: A Scoping Review

“…Attempts should also be made to elucidate the cellular and tissue-level mechanisms through which these gene products are associated with obesity or depression. Such research would not only place future drug development on a firmer footing, but lead to the elucidation of further novel molecular targets, as well as interactions between those identified in current research [125][126][127][128]. Based on these results, both existing natural and synthetic compounds, as well as "leads" derived from such compounds, could be tested in animal models of obesity with associated depressive-like behaviors or symptoms [129,130].…”