title: Nrf2 deficiency in myeloid cells is not sufficient to protect mice from high-fat diet-induced adipose tissue inflammation and insulin resistance.
abstract: Activation of the transcription factor NF-E2-related factor 2 (Nrf2) by oxidative stress induces the expression of a variety of antioxidant and anti-inflammatory genes. Yet, genetic ablation of Nrf2 was shown to protect mice from high-fat diet (HFD)-induced obesity and insulin resistance. The mechanisms that underlie this seemingly paradoxical finding remain largely unexplored. Here we examined whether Nrf2 deficiency in myeloid cells contributes to protection against HFD-induced metabolic changes by decreasing adipose tissue inflammation. In vitro, induction of IL-1β by inflammatory stimuli was significantly reduced in Nrf2-deficient macrophages. Whereas inflammatory gene expression in the stromal vascular fraction was reduced in both global and chimeric Nrf2 KO mice, only global Nrf2-deficient, and not bone marrow-transplanted Nrf2 chimeric, mice were protected against HFD-induced adipose tissue inflammation. Whereas global Nrf2 deficiency resulted in significantly decreased expression of inflammatory genes and PPARγ2, there was no difference when Nrf2 was absent only from myeloid cells. In vitro coculture with adipocytes demonstrated that macrophage Nrf2 regulated inflammatory gene expression in macrophages; however, it was not required to induce inflammatory gene expression in adipocytes. Finally, in contrast to global Nrf2 knockout, Nrf2 deficiency in myeloid cells did not protect against HFD-induced insulin resistance. Together, our data demonstrate a dominant role for nonmyeloid Nrf2 in controlling HFD-induced adipose tissue inflammation and the development of insulin resistance.
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Akshaya K
authors.initials: AK
authors.lastname: Meher
authors.forename: Poonam R
authors.initials: PR
authors.lastname: Sharma
authors.forename: Vitor A
authors.initials: VA
authors.lastname: Lira
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Kensler
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yan
authors.forename: Norbert
authors.initials: N
authors.lastname: Leitinger
mesh_terms: D041721:3T3-L1 Cells; D000273:Adipose Tissue / Q000473:pathology*; D000818:Animals; D004041:Dietary Fats / Q000008:administration & dosage*; D015870:Gene Expression; D005951:Glucose Tolerance Test; D007150:Immunohistochemistry; D007249:Inflammation / Q000473:pathology*; D007333:Insulin Resistance; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D004041:Dietary Fats; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse