MicroRNAs Regulated by Adiponectin as Novel Targets for Controlling Adipose Tissue Inflammation

Abstract

A low-grade proinflammatory state contributes to the metabolic syndrome (MS). Adiponectin (ApN), which is reduced in the MS, has emerged as a master regulator of inflammation/immunity. We wanted to identify whether microRNAs (miRNAs) may mediate the antiinflammatory action of ApN on adipose tissue (AT). miRNA expression profiling was performed in mice overexpressing ApN specifically in AT and in wild-type controls. The role of specific miRNAs was analyzed by gain- or loss-of function approaches in 3T3-F442A (pre)-adipocytes and in de novo AT formed from engineered 3T3-F442A preadipocytes transplanted in nude mice. miRNA expression was compared in the omental AT of lean and obese subjects. The expression of miR532-5p and miR1983 was down-regulated, whereas that of miR883b-5p and miR1934 was up-regulated in AT of mice overexpressing ApN specifically in AT. We focused on miR883b-5p identified by computational analysis as being involved in inflammatory pathways. miR883b-5p overexpression down-regulated the lipopolysaccharide-binding protein (LBP) in 3T3-F442A cells, whereas miR883b-5p blockade had reverse effects. LBP aids in lipopolysaccharide binding to Toll-like receptor-4. miR883b-5p blockade also abolished the protective effects of ApN on proinflammatory adipokine induction. These data were recapitulated in the de novo AT in which miR883b-5p silencing induced LBP production and tissue inflammation. Eventually miR883b-5p expression was down-regulated in AT of obese subjects. We identified several novel miRNAs that are regulated by ApN in AT in vivo. miR883b-5p, which is up-regulated by ApN represses LBP and Toll-like receptor-4 signaling, acting therefore as a major mediator of the antiinflammatory action of ApN. These novel miRNAs may open new therapeutic perspectives for the MS.

Lipopolysaccharide binding protein is an adipokine involved in the resilience of the mouse adipocyte to inflammation

“…Supporting previous in vivo findings [3,5], increased LBP may cause metabolic stress and contribute to a vicious cycle that prevents further AT expansion and exacerbates the inflammatory response in AT. Consequently, LBP constitutes an important target to reverse these effects and restore AT physiology.…”

“…We found that levels of LBP expression were low when AT was physiologically functional and adipocyte differentiation was viable in an insulin-sensitive environment [5]. Conversely, LBP levels were increased under conditions of impaired adipose differentiation in association with insulin resistance [3,5,6]. However, these previous correlative studies do not allow a causative link to be defined for LBP and these two variables.…”

“…Adipocyte-secreted factors are known to be important in the modulation of a variety of processes, including energy balance, adipogenesis and systemic inflammation. Lipopolysaccharide (LPS) binding protein (LBP) is a well-known liver acute-phase reactant that has recently been identified as an adipokine [3,4]. The highest levels of LBP occur in fully differentiated human adipocytes from obese individuals [5].…”

A role for adipocyte-derived lipopolysaccharide-binding protein in inflammation- and obesity-associated adipose tissue dysfunction

“…Although circulating LBP is thought to derive from the liver [13,32], the close relationship between circulating LBP and obesity led us to investigate the possible contribution of AT to circulating LBP levels. In support of this relationship, a recent study reported increased LBP gene and protein expression in AT formed de novo using 3T3-F442A-transfected cells with a plasmid containing antagomirs against miR883b-5p [20]. Expression of LBP occurred in human AT and was substantially increased in SAT vs VAT, and in obese vs nonobese individuals.…”

“…A recent study described LBP secretion by 3T3-L1 adipocytes [19] and increased serum LBP levels in genetically and diet-induced obese mice after LPS injection, but AT LBP production was not investigated [19]. Supporting this novel finding, Ge et al found Lbp gene expression and LBP protein secretion in 3T3-F442A cells and in de novo AT formed from 3T3-F442A cells, showing that its regulation was mediated by microRNA 883b (miR883b)-5p [20]. However, they did not study Lbp gene expression in mice adipocytes or mice AT.…”