Microglia-specific knock-down of Bmal1 improves memory and protects mice from high fat diet-induced obesity

Abstract

Microglia play a critical role in maintaining neural function. While microglial activity follows a circadian rhythm, it is not clear how this intrinsic clock relates to their function, especially in stimulated conditions such as in the control of systemic energy homeostasis or memory formation. In this study, we found that microglia-specific knock-down of the core clock gene, Bmal1, resulted in increased microglial phagocytosis in mice subjected to high-fat diet (HFD)-induced metabolic stress and likewise among mice engaged in critical cognitive processes. Enhanced microglial phagocytosis was associated with significant retention of pro-opiomelanocortin (POMC)-immunoreactivity in the mediobasal hypothalamus in mice on a HFD as well as the formation of mature spines in the hippocampus during the learning process. This response ultimately protected mice from HFD-induced obesity and resulted in improved performance on memory tests. We conclude that loss of the rigorous control implemented by the intrinsic clock machinery increases the extent to which microglial phagocytosis can be triggered by neighboring neurons under metabolic stress or during memory formation. Taken together, microglial responses associated with loss of Bmal1 serve to ensure a healthier microenvironment for neighboring neurons in the setting of an adaptive response. Thus, microglial Bmal1 may be an important therapeutic target for metabolic and cognitive disorders with relevance to psychiatric disease.

Circadian Clock Regulates Inflammation and the Development of Neurodegeneration

“…Circadian clock is associated with microglial immune activity. It has been shown that the circadian clock genes are rhythmically expressed in microglial cells isolated from rodents housed under light/dark conditions (Hayashi et al, 2013;Fonken et al, 2015;Wang et al, 2021). Transcripts of pro-inflammatory cytokines-Il1b, Il6, and Tnfa, also show a time-of-day difference in microglia, with elevated expression during the light phase (Fonken et al, 2015;.…”

“…In microglial BV-2 cells, Bmal1 knockdown decreases the expression of pro-inflammatory cytokines (Il1b, Tnfa, and Il6) and increases the expression of anti-inflammatory cytokine-Il10 upon LPS stimulation . Moreover, lacking Bmal1 increases the microglial phagocytosis in mice on a high-fat diet as well as during the learning process (Wang et al, 2021). Rev-erba deficient microglia reveal proinflammatory phenotypes and elevated NF-kB activation via binding to the promoter regions of related genes; global deletion of Rev-erba leads to hippocampal microgliosis and neuronal damage in mice (Griffin et al, 2019a).…”

Mechanisms Driving Palmitate-Mediated Neuronal Dysregulation in the Hypothalamus

“…Microglial-specific BMAL1-KO also prevented diet-induced obesity due to increased microglial phagocytic capacity [207]. This ability led to increased retention of POMC neurons in the hypothalamus, which are typically selectively lost with exposure to an HFD [207,208]. Thus, brain-specific BMAL1 and circadian control are implicated as mediators of the effects of HFD-exposure.…”

“…For instance, mice with BMAL1-KO in skeletal muscle resisted HFD-induced obesity due to increased oxidative capacity [206]. Microglial-specific BMAL1-KO also prevented diet-induced obesity due to increased microglial phagocytic capacity [207]. This ability led to increased retention of POMC neurons in the hypothalamus, which are typically selectively lost with exposure to an HFD [207,208].…”

Multi-omics landscape of circadian rhythm pathway alterations in Glioma

“…Alteration of clock genes has long reported biological influence on aging, metabolism, immunity, DNA repair, and cell-cycle processes [2][3][4][5][6][7]. Therefore, aberrant circadian rhythms demonstrated pathogenetic correlations with various diseases, including cancer [8].…”