Modulation of adipose inflammation by cellular retinoic acid-binding protein 1

Abstract

Objectives Obesity, a metabolic syndrome, is known to be related to inflammation, especially adipose tissue inflammation. Cellular interactions within the expanded white adipose tissue (WAT) in obesity contribute to inflammation and studies have suggested that inflammation is triggered by inflamed adipocytes that recruit M1 macrophages into WAT. What causes accumulation of unhealthy adipocytes is an important topic of investigation. This study aims to understand the action of Cellular Retinoic Acid Binding Protein 1 (CRABP1) in WAT inflammation. Methods Eight weeks-old wild type (WT) and Crabp1 knockout (CKO) mice were fed with a normal diet (ND) or high-fat diet (HFD) for 8 weeks. Body weight and food intake were monitored. WATs and serum were collected for cellular and molecular analyses to determine affected signaling pathways. In cell culture studies, primary adipocyte differentiation and bone marrow-derived macrophages (BMDM) were used to examine adipocytes’ effects, mediated by CRABP1, in macrophage polarization. The 3T3L1-adipocyte was used to validate relevant signaling pathways. Results CKO mice developed an obese phenotype, more severely under high-fat diet (HFD) feeding. Further, CKO’s WAT exhibited a more severe inflammatory state as compared to wild type (WT) WAT, with a significantly expanded M1-like macrophage population. However, this was not caused by intrinsic defects of CKO macrophages. Rather, CKO adipocytes produced a significantly reduced level of adiponectin and had significantly lowered mitochondrial DNA content. CKO adipocyte-conditioned medium, compared to WT control, inhibited M2-like (CD206+) macrophage polarization. Mechanistically, defects in CKO adipocytes involved the ERK1/2 signaling pathway that could be modulated by CRABP1. Conclusions This study shows that CRABP1 plays a protective role against HFD-induced WAT inflammation through, in part, its regulation of adiponectin production and mitochondrial homeostasis in adipocytes, thereby modulating macrophage polarization in WAT to control its inflammatory potential.

Molecular basis for cellular retinoic acid-binding protein 1 in modulating CaMKII activation

“…This view centers on the well-known genomic activities of RA, mediated by nuclear RA receptors (RARs) that regulate gene expression, generally referred to as the canonical activities of RA ( Wei, 2003 ; Cunningham and Duester, 2015 ). An increasing number of studies have identified rapid cytosolic (without involving nuclear RARs) activities of RA, which could modulate cytosolic signaling pathways as demonstrated in multiple cell types, including adipocytes ( Lin, 2020a ; Wei et al, 2022 ), cardiomyocytes ( Park et al, 2018 ; Park et al, 2019 ), stem cells ( Persaud et al, 2013 ; Lin et al, 2017 ), and neurons ( Lin, 2020b ; Lin et al, 2022 ). Recently, it has been established that CRABP1 acts as a direct mediator of these rapid cytosolic activities of RA in a cell context-dependent manner, referred to as non-canonical RA activities reviewed in Nagpal and Wei (2019) .…”

“…In embryonic stem cells, adipocytes, and neural stem cells that are extremely sensitive to growth factor-elicited signaling pathways such as the mitogen-activated protein kinase (MAPK) pathway ( Zhang et al, 2002 ; Wei, 2013 ), CRABP1 is important for stem cell proliferation ( Persaud et al, 2013 ; Lin et al, 2017 ), exosome secretion ( Lin et al, 2021 ), and adipokine production ( Wei et al, 2022 ). The MAPK pathway is initiated by the membrane-bound Ras GTPase, which serves as a molecular switch to activate the Raf-MEK-ERK kinase cascade upon growth factor stimulation ( Cargnello and Roux, 2011 ).…”

“…identified rapid cytosolic (without involving nuclear RARs) activities of RA, which could modulate cytosolic signaling pathways as demonstrated in multiple cell types, including adipocytes (Lin, 2020a;Wei et al, 2022), cardiomyocytes (Park et al, 2018;Park et al, 2019), stem cells (Persaud et al, 2013;Lin et al, 2017), and neurons (Lin, 2020b;Lin et al, 2022). Recently, it has been established that CRABP1 acts as a direct mediator of these rapid cytosolic activities of RA in a cell context-dependent manner, referred to as non-canonical RA activities reviewed in Nagpal and Wei (2019).…”

Depleting Cellular Retinoic Acid Binding Protein 1 Impairs UPRmt

“…These recently uncovered CRABP1mediated cytosolic activities are referred to as non-canonical activities of RA, in contrast to widely known canonical activities of RA mediated by nuclear RA receptors (RARs) that typically act to regulate gene expression [3,4]. Using Crabp1 gene knockout (CKO) mice and cell models, we have demonstrated that CRABP1 plays roles in multiple cellular processes and disease conditions [5], such as neuron stem cell proliferation [6], motor neuron (MN) function [7], endocrine homeostasis [8,9], exosome secretion [10] and adipocyte hypertrophy [11,12]. Most of these processes involve the modulation of either the ERK or the CaMKII pathway by CRABP1.…”

“…It is known that mitochondrial dysfunction underlines numerous diseases including cardiovascular diseases, metabolic disorders, and neurodegenerative diseases, such as ALS. Interestingly, in CKO embryonic stem cells (unpublished) and adipocytes [11], there is a significant reduction in mitochondrial DNA (mtDNA) content. Additionally, our unpublished preliminary studies have detected increased abnormality in mitochondrial function in CKO spinal cord tissues.…”