Chronic circadian shift leads to adipose tissue inflammation and fibrosis. (5th February 2021)

• Record Type: Journal Article
• Authors: Xiong, Xuekai; Lin, Yayu; Lee, Jeongkyung; Paul, Antonio; Yechoor, Vijay; Figueiro, Mariana; Ma, Ke
• Is Part Of: Molecular and cellular endocrinology. Volume 521(2021)
• Publication Date: 2021-02-05
• Subjects: Circadian clock -- Adipose tissue -- Inflammation -- Shiftwork -- Insulin resistance; Bmal1 Brain and Muscle Arnt-like Protein 1 -- CLOCK Circadian Locomotor Output Cycle -- ECM extracellular matrix -- eWAT epidydimal white adipose tissue -- iWAT inguinal white adipose tissue; Endocrinology -- Periodicals; Molecular biology -- Periodicals; Cytology -- Periodicals; Endocrinology -- Periodicals; Hormones -- Periodicals; Endocrinologie -- Périodiques; Cytology; Endocrinology; Molecular biology; Periodicals; 573.4
• DOI: 10.1016/j.mce.2020.111110
• Languages: English
• ISSNs: 0303-7207

Abstract

Abstract: The circadian clock exerts temporal coordination of metabolic pathways. Clock disruption is intimately linked with the development of obesity and insulin resistance, and our previous studies found that the essential clock transcription activator, Brain and Muscle Arnt-like 1 (Bmal1), is a key regulator of adipogenesis. However, the metabolic consequences of chronic shiftwork on adipose tissues have not been clearly defined. Here, using an environmental lighting-induced clock disruption that mimics rotating shiftwork schedule, we show that chronic clock dysregulation for 6 months in mice resulted in striking adipocyte hypertrophy with adipose tissue inflammation and fibrosis. Both visceral and subcutaneous depots display enlarged adipocyte with prominent crown-like structures indicative of macrophage infiltration together with evidence of extracellular matrix remodeling. Global transcriptomic analyses of these fat depots revealed that shiftwork resulted in up-regulations of inflammatory, adipogenic and angiogenic pathways with disruption of normal time-of-the-day-dependent regulation. These changes in adipose tissues are associated with impaired insulin signaling in mice subjected to shiftwork, together with suppression of the mTOR signaling pathway. Taken together, our study identified the significant adipose depot dysfunctions induced by chronic shiftwork regimen that may underlie the link between circadian misalignment and insulin resistance. Highlights: Chronic shiftwork in mice induced marked adipocyte hypertrophy of visceral and subcutaneous depots. Chronic shift led to macrophage infiltration with up-regulated inflammatory pathways. Transcriptomic profiling revealed enriched processes characteristic of obesity in chronic shiftwork. Diurnal regulation of adipogenic and lipid metabolic pathways were altered in shift-induced adipose expansion. Chronic shiftwork impaired insulin signaling and suppressed mTOR pathway in adipose depots.