Myeloid Cell-specific Disruption of Period1 and Period2 Exacerbates Diet-induced Inflammation and Insulin Resistance

Xu, Huaxi; Li, Honggui; Woo, Sung Oh; Kim, Sam-Moon; Shende, Vikram R.; Neuendorff, Nichole; Guo, Xin; Guo, Ting; Qi, Ting; Pei, Ya; Zhao, Yan; Hu, Xiang; Zhao, Jiajia; Chen, Lili; Chen, Lulu; Ji, Jun-Yuan; Alaniz, Robert C.; Earnest, David J.; Wu, Chaodong

doi:10.1074/jbc.m113.539601

Cited by 79 publications

(99 citation statements)

References 55 publications

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“…40,41 Furthermore, disruption of a circadian gene led to the disruption of hepatic lipid homeostasis in mice, 42 whereas myeloid cell-specific disruption of Per1 and Per2 expression in mice exacerbated both diet-induced inflammation and insulin resistance. 43 A recent study found that mistimed sleep disrupted the daily regulation of global gene expression in humans. 44 As social jetlag disrupts sleep timing, it is thus possible that social jetlag has similar effects on gene expression.…”

Section: Discussionmentioning

confidence: 99%

Social jetlag, obesity and metabolic disorder: investigation in a cohort study

et al. 2014

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BACKGROUND Obesity is one of the leading causes of preventable death worldwide. Circadian rhythms are known to control both sleep timing and energy homeostasis, and disruptions in circadian rhythms have been linked with metabolic dysfunction and obesity-associated disease. In previous research, social jetlag, a measure of chronic circadian disruption caused by the discrepancy between our internal versus social clocks, was associated with elevated self-reported body mass index, possibly indicative of a more generalized association with obesity and metabolic dysfunction. METHODS We studied participants from the population-representative Dunedin Longitudinal Study (N = 1037) to determine whether social jetlag was associated with clinically assessed measurements of metabolic phenotypes and disease indicators for obesity-related disease, specifically, indicators of inflammation and diabetes. RESULTS Our analysis was restricted to N = 815 non-shift workers in our cohort. Among these participants, we found that social jetlag was associated with numerous clinically assessed measures of metabolic dysfunction and obesity. We distinguished between obese individuals who were metabolically healthy versus unhealthy, and found higher social jetlag levels in metabolically unhealthy obese individuals. Among metabolically unhealthy obese individuals, social jetlag was additionally associated with elevated glycated hemoglobin and an indicator of inflammation. CONCLUSIONS The findings are consistent with the possibility that ‘living against our internal clock’ may contribute to metabolic dysfunction and its consequences. Further research aimed at understanding that the physiology and social features of social jetlag may inform obesity prevention and have ramifications for policies and practices that contribute to increased social jetlag, such as work schedules and daylight savings time.

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Section: Discussionmentioning

confidence: 99%

Social jetlag, obesity and metabolic disorder: investigation in a cohort study

et al. 2014

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“…After digestion and centrifugation, the pelleted adipose tissue SVCs were cultured for 7 d, and cultures were then harvested separately at the same time of day (9:00 AM). Adipose tissue SVC samples were independently subjected to fluorescence‐activated cell sorting (FACS) analysis, real‐time PCR analysis of inflammatory cytokines, and bioluminescence analysis of clock gene rhythms by using established methods (9, 20).…”

Section: Methodsmentioning

confidence: 99%

“…Specifically how circadian clock disruption contributes to metabolic disorders is unclear, but the activation of proinflammatory macrophages and inflammatory signaling have been identified as key processes in the physiologic cascade linking clock‐and metabolic‐dysregulated phenotypes. In this regard, global and myeloid cell–specific clock disruption ( Per1 ldc / Per2 ldc ) exacerbates macrophage proinflammatory activation, leading to adipose tissue inflammation and further potentiation of high‐fat diet (HFD)‐induced increases in body weight, systemic insulin resistance, and hyperglycemia (9). Collectively, these observations suggest that macrophage proinflammatory activation and adipose tissue inflammation are critical factors in the mechanism by which circadian clock disruption potentiates diet‐induced metabolic phenotypes.…”

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confidence: 99%

Shift work cycle‐induced alterations of circadian rhythms potentiate the effects of high‐fat diet on inflammation and metabolism

et al. 2018

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Based on genetic models with mutation or deletion of core clock genes, circadian disruption has been implicated in the pathophysiology of metabolic disorders. Thus, we examined whether circadian desynchronization in response to shift work-type schedules is sufficient to compromise metabolic homeostasis and whether inflammatory mediators provide a key link in the mechanism by which alterations of circadian timekeeping contribute to diet-induced metabolic dysregulation. In high-fat diet (HFD)-fed mice, exposure to chronic shifts of the light-dark cycle (12 h advance every 5 d): 1) disrupts photoentrainment of circadian behavior and modulates the period of spleen and macrophage clock gene rhythms; 2) potentiates HFD-induced adipose tissue infiltration and activation of proinflammatory M1 macrophages; 3) amplifies macrophage proinflammatory cytokine expression in adipose tissue and bone marrow-derived macrophages; and 4) exacerbates diet-induced increases in body weight, insulin resistance, and glucose intolerance in the absence of changes in total daily food intake. Thus, complete disruption of circadian rhythmicity or clock gene function as transcription factors is not requisite to the link between circadian and metabolic phenotypes. These findings suggest that macrophage proinflammatory activation and inflammatory signaling are key processes in the physiologic cascade by which dysregulation of circadian rhythmicity exacerbates diet-induced systemic insulin resistance and glucose intolerance.-Kim, S.-M., Neuendorff, N., Alaniz, R. C., Sun, Y., Chapkin, R. S., Earnest, D. J. Shift work cycle-induced alterations of circadian rhythms potentiate the effects of high-fat diet on inflammation and metabolism.

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“…Abnormal regulation of circadian clocks in peripheral tissues is suggested to cause cell dysfunction and chronic diseases (8,30). It has been shown that the clock machinery including nuclear receptors controls inflammatory immune responses (5,17,19,(23)(24)(25)(31)(32)(33). We found that the level and expression of clock proteins (BMAL1 and PER2) and associated nuclear receptors (REV-ERBa) were reduced in PBMCs and sputum cells (mainly inflammatory cells [i.e., macrophages and neutrophils]) and in lungs from smokers and patients with COPD.…”

Section: Original Researchmentioning

confidence: 99%

Disruption of Sirtuin 1–Mediated Control of Circadian Molecular Clock and Inflammation in Chronic Obstructive Pulmonary Disease

Yao¹,

Sundar²,

Huang³

et al. 2015

Am J Respir Cell Mol Biol

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Chronic obstructive pulmonary disease (COPD) is the fourth most common cause of death, and it is characterized by abnormal inflammation and lung function decline. Although the circadian molecular clock regulates inflammatory responses, there is no information available regarding the impact of COPD on lung molecular clock function and its regulation by sirtuin 1 (SIRT1). We hypothesize that the molecular clock in the lungs is disrupted, leading to increased inflammatory responses in smokers and patients with COPD and its regulation by SIRT1. Lung tissues, peripheral blood mononuclear cells (PBMCs), and sputum cells were obtained from nonsmokers, smokers, and patients with COPD for measurement of core molecular clock proteins (BMAL1, CLOCK, PER1, PER2, and CRY1), clock-associated nuclear receptors (REV-ERBa, REV-ERBb, and RORa), and SIRT1 by immunohistochemistry, immunofluorescence, and immunoblot. PBMCs were treated with the SIRT1 activator SRT1720 followed by LPS treatment, and supernatant was collected at 6-hour intervals. Levels of IL-8, IL-6, and TNF-a released from PBMCs were determined by ELISA. Expression of BMAL1, PER2, CRY1, and REV-ERBa was reduced in PBMCs, sputum cells, and lung tissues from smokers and patients with COPD when compared with nonsmokers. SRT1720 treatment attenuated LPS-mediated reduction of BMAL1 and REV-ERBa in PBMCs from nonsmokers. Additionally, LPS differentially affected the timing and amplitude of cytokine (IL-8, IL-6, and TNF-a) release from PBMCs in nonsmokers, smokers, and patients with COPD. Moreover, SRT1720 was able to inhibit LPS-induced cytokine release from cultured PBMCs. In conclusion, disruption of the molecular clock due to SIRT1 reduction contributes to abnormal inflammatory response in smokers and patients with COPD.Keywords: circadian rhythm; SIRT1; REV-ERBa; BMAL1; smokers Clinical RelevanceAlthough the circadian clock regulates the inflammatory response, there is no information available regarding the impact of chronic obstructive pulmonary disease (COPD) on molecular clock function in peripheral tissues and its modulation by sirtuin 1 (SIRT1). We report here that clock proteins, including BMAL1 and REV-ERBa, are reduced in peripheral tissues from patients with COPD in part owing to SIRT1 reduction. LPS differently affects the timing and amplitude of cytokine release from peripheral blood mononuclear cells among nonsmokers, smokers, and patients with COPD. The SIRT1 activator SRT1720 is able to inhibit LPS-induced cytokine release in peripheral blood mononuclear cells. This has implications in the pathogenesis and pharmacological chronotherapy of COPD.

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Myeloid Cell-specific Disruption of Period1 and Period2 Exacerbates Diet-induced Inflammation and Insulin Resistance

Cited by 79 publications

References 55 publications

Social jetlag, obesity and metabolic disorder: investigation in a cohort study

Social jetlag, obesity and metabolic disorder: investigation in a cohort study

Shift work cycle‐induced alterations of circadian rhythms potentiate the effects of high‐fat diet on inflammation and metabolism

Disruption of Sirtuin 1–Mediated Control of Circadian Molecular Clock and Inflammation in Chronic Obstructive Pulmonary Disease

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