MicroRNAs and downstream Adipokines regulated by Adiponectin in vivo are novel targets for controlling adipose tissue inflammation
(2012)
Files
thesispublicnew.pdf
Open Access - Adobe PDF
- 5.72 MB
Details
- Authors
- Supervisors
- Brichard, Sonia
- Abstract
- (en) Adipose tissue (AT) has been recognized as an active secretory organ, which releases a number of bioactive peptides, collectively named adipokines. They play a central role in energy and vascular homeostasis as well as in immunity. Dysregulation of adipokines triggers the development of a low-grade pro-inflammatory state, which is considered to build the common soil for the development of obesity-linked disorders. Thus, resetting the immunological balance in obese AT is a fundamental therapeutic strategy for the metabolic syndrome. ApN has emerged as a master regulator of immune/inflammatory homeostasis. Yet, the autocrine/paracrine effects of ApN on AT inflammation have been poorly investigated. We have previously generated a transgenic mouse model allowing persistent and moderate overexpression of ApN (ApN-Overex) specifically in white AT. I therefore took advantage of this unique model to unravel the effects of ApN on AT secretory function. I confirmed that ApN regulated in vivo the secretion of downstream adipokines, decreasing those with pro-inflammatory properties, while enhancing those with anti-inflammatory effects. These changes were specific: they occurred before the emergence of any metabolic confounding factors (such as improvement of insulin action or decrease of fat mass). Moreover, a reverse profile of expression was observed for most adipokines in ApN-knockout (ApN-KO) mice. Thus ApN induced in vivo a shift of the immune balance in AT toward a less inflammatory phenotype. Moreover, this shift induced by ApN was associated with reduced activity of NF-κB and Extracellular Signal-Regulated kinases (ERK1/2), as well as increased activity/expression of AMPK in AT. MicroRNAs (miRNAs) are small non-coding RNAs that control gene expression by inducing target mRNA degradation or blocking translation. Deregulation of miRNAs is closely associated with obesity-related metabolic disorders. I therefore used the same ApN-Overex mice to investigate whether miRNAs regulated by ApN contribute to the anti-inflammatory effects of ApN in AT and whether these miRNAs represent novel mechanisms for controlling AT inflammation. Four miRNAs were modified in AT of ApN-Overex mice. Expression of miR532-5p and miR1983 was down-regulated, while that of miR883b-5p and miR1934 was up-regulated. miR883b-5p was identified by computational analysis as being involved in inflammatory pathways. By using gain-of or loss-of function approaches, I further validated that miR883b-5p repressed the lipopolysaccharide (LPS) facilitator, LPS-binding protein (LBP) in 3T3-F442A cells. miR883b-5p blockade also abolished the protective effects of ApN on induction of pro-inflammatory adipokines. These data were recapitulated in de novo AT (formed from engineered 3T3-F442A preadipocytes transplanted in nude mice) where miR883b-5p silencing induced LBP production and tissue inflammation. Eventually, miR883b-5p expression was down-regulated in AT of obese subjects, concomitantly with reduced ApN expression. Altogether, these data suggest that miR883b-5p may be an important mediator of the anti-inflammatory action of ApN in adipocytes. These newly identified downstream adipokines and miRNAs may open new therapeutic perspectives for the management of metabolic syndrome.
- Affiliations
Citations
Ge, Q. (2012). MicroRNAs and downstream Adipokines regulated by Adiponectin in vivo are novel targets for controlling adipose tissue inflammation. https://hdl.handle.net/2078.5/161569