Regulation of adipogenic differentiation and adipose tissue inflammation by interferon regulatory factor 3

Abstract

Dysfunction of adipocytes and adipose tissue is a primary defect in obesity and obesity-associated metabolic diseases. Interferon regulatory factor 3 (IRF3) has been implicated in adipogenesis. However, the role of IRF3 in obesity and obesity-associated disorders remains unclear. Here, we show that IRF3 expression in human adipose tissues is positively associated with insulin sensitivity and negatively associated with type 2 diabetes. In mouse pre-adipocytes, deficiency of IRF3 results in increased expression of PPARγ and PPARγ-mediated adipogenic genes, leading to increased adipogenesis and altered adipocyte functionality. The IRF3 knockout (KO) mice develop obesity, insulin resistance, glucose intolerance, and eventually type 2 diabetes with aging, which is associated with the development of white adipose tissue (WAT) inflammation. Increased macrophage accumulation with M1 phenotype which is due to the loss of IFNβ-mediated IL-10 expression is observed in WAT of the KO mice compared to that in wild-type mice. Bone-marrow reconstitution experiments demonstrate that the nonhematopoietic cells are the primary contributors to the development of obesity and both hematopoietic and nonhematopoietic cells contribute to the development of obesity-related complications in IRF3 KO mice. This study demonstrates that IRF3 regulates the biology of multiple cell types including adipocytes and macrophages to prevent the development of obesity and obesity-related complications and hence, could be a potential target for therapeutic interventions for the prevention and treatment of obesity-associated metabolic disorders.

STING orchestrates the crosstalk between polyunsaturated fatty acid metabolism and inflammatory responses

“…Indeed, STING-associated cytokine production can be induced by high-fat diets (HFDs) and alter metabolic homeostasis ( Bai et al., 2017 ). In addition, TBK1 and IRF3 activation, both downstream effectors of STING, also regulate central metabolic pathways ( Kumari et al., 2016 ; Zhao et al., 2018 ), including fatty acid metabolism ( Tang et al., 2021 ). Conversely, fatty acid biosynthesis pathways have been proposed to participate in controlling antiviral responses through modulation of the expression of interferon-stimulated genes (Isg) ( Kanno et al., 2021 ).…”

Signaling pathways and intervention for therapy of type 2 diabetes mellitus

“…PPARγ mainly functions as a core regulator of adipogenesis, improving insulin sensitivity and glucose metabolism. In terms of mechanisms, deletion of IRF3 can increase the expression of PPARγ, leading to severe IR and glucose intolerance 470 . As opposed to IRF3, TAZ could protect mice from HFD‐induced IR and glucose intolerance through upregulating the expression of PPARγ 471 .…”

Link between sterile inflammation and cardiovascular diseases: Focus on cGAS-STING pathway in the pathogenesis and therapeutic prospect

“…Thus, reticulum STING which promotes the recruitment and activation of TBK1 is transported to the Golgi apparatus via the ERGIC, where palmitoylation of its Cys88 and Cys91 sites further promotes the recruitment and activation of TBK1, thereby activating IRF3 and NF-κB ( 36 , 37 ). Nuclear transcription of IRF3 or NF-κB promotes the expression of downstream inflammatory factors such as TNF-α, IL-6, IL-1β, MCP-1, and IFNs, eventually leading to the inflammatory response, suggesting activation of IRF3 or NF-κB play an important role in sterile inflammatory diseases ( 9 , 12 , 22 , 24 , 38 – 40 ). Furthermore, the C- terminal tail (CTT) is necessary for STING to activate TBK1 and IRF3, and there is a conservative consensus motif in the CTT (pLxIS; p is hydrophilic and x is any residue), which is phosphorylated at Ser366 in human STING (Ser365 in mice) ( 41 , 42 ).…”