title: Angiotensinogen gene silencing reduces markers of lipid accumulation and inflammation in cultured adipocytes.
abstract: Inflammatory adipokines secreted from adipose tissue are major contributors to obesity-associated inflammation and other metabolic dysfunctions. We and others have recently documented the contribution of adipose tissue renin-angiotensin system to the pathogenesis of obesity, inflammation, and insulin resistance. We hypothesized that adipocyte-derived angiotensinogen (Agt) plays a critical role in adipogenesis and/or lipogenesis as well as inflammation. This was tested using 3T3-L1 adipocytes, stably transfected with Agt-shRNA or scrambled Sc-shRNA as a control. Transfected preadipocytes were differentiated and used to investigate the role of adipose Agt through microarray and PCR analyses and adipokine profiling. As expected, Agt gene silencing significantly reduced the expression of Agt and its hormone product angiotensin II (Ang II), as well as lipid accumulation in 3T3-L1 adipocytes. Microarray studies identified several genes involved in lipid metabolism and inflammatory pathways which were down-regulated by Agt gene inactivation, such as glycerol-3-phosphate dehydrogenase 1 (Gpd1), serum amyloid A 3 (Saa3), nucleotide-binding oligomerization domain containing 1 (Nod1), and signal transducer and activator of transcription 1 (Stat1). Mouse adipogenesis PCR arrays revealed lower expression levels of adipogenic/lipogenic genes such as peroxisome proliferator activated receptor gamma (PPARγ), sterol regulatory element binding transcription factor 1 (Srebf1), adipogenin (Adig), and fatty acid binding protein 4 (Fabp4). Further, silencing of Agt gene significantly lowered expression of pro-inflammatory adipokines including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and monocyte chemotactic protein-1 (MCP-1). In conclusion, this study directly demonstrates critical effects of Agt in adipocyte metabolism and inflammation and further support a potential role for adipose Agt in the pathogenesis of obesity-associated metabolic alterations.
authors.affiliation: Department of Animal Science, University of Tennessee Knoxville, TN, USA ; Obesity Research Center, University of Tennessee Knoxville, TN, USA.
authors.forename: Wenting X
authors.initials: WX
authors.lastname: Carroll
authors.forename: Nishan S
authors.initials: NS
authors.lastname: Kalupahana
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Booker
authors.forename: Nalin
authors.initials: N
authors.lastname: Siriwardhana
authors.forename: Monique
authors.initials: M
authors.lastname: Lemieux
authors.forename: Arnold M
authors.initials: AM
authors.lastname: Saxton
authors.forename: Naima
authors.initials: N
authors.lastname: Moustaid-Moussa
keywords: adipocytes; adipogenesis; adipokines; angiotensinogen; gene silencing; inflammation