OR15-4 Preferential Expression of Pregnancy Associated Plasma Protein-A in Human Preadipocytes from Omental Fat: Regulation by Cytokines and Resveratrol

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR15-Adipokine Action
Sunday, June 16, 2013: 11:15 AM-12:45 PM
Presentation Start Time: 12:00 PM
Room 303 (Moscone Center)
Caroline J Davidge-Pitts*, Carlos J Escande and Cheryl A Conover
Mayo Clinic, Rochester, MN
Background and Aims:  Obesity is a proinflammatory state with attendant metabolic disturbances, including diabetes and atherosclerosis.  Excess visceral fat, rather than subcutaneous fat, is associated with these adverse effects.  Thus, a better understanding of the regulatory factors leading to depot-specific adipogenesis is critical.  The insulin-like growth factor (IGF) system plays an important role in the development of adipose tissue including proliferation, differentiation and cell survival.  Pregnancy associated plasma protein A (PAPP-A) is a zinc metalloproteinase that enhances local IGF bioavailability by proteolysis of inhibitory IGF binding proteins. Genome-wide expression profiles of primary preadipocytes from human fat identified PAPP-A as one of the most distinctive genes expressed, with levels in preadipocytes from omental (Om) fat greatly exceeding those from subcutaneous (Sc) fat.  The aims of this study were (1) to follow-up on the initial microarray data and characterize PAPP-A mRNA and protein expression in primary cultures of human preadipocytes isolated from Om and Sc depots and (2) to investigate factors regulating PAPP-A expression, focusing on proinflammatory cytokines and resveratrol that have been shown to have negative and positive effects, respectively, on metabolism and diet-induced obesity.

Results: Expression of PAPP-A mRNA and protein was significantly higher in human preadipocytes from Om compared to Sc fat depots.  Proinflammatory cytokines, interleukin-1β (IL-1β) and tumor necrosis factor -α (TNF-α), significantly stimulated PAPP-A mRNA and protein expression in preadipocytes through nuclear factor (NF) kB, c-Jun N-terminal kinase (JNK) and p38 pathways. IL-1β appeared to stimulate PAPP-A expression through the JNK pathway more effectively than TNF-α. No effect on phosphatidylinositol 3-kinase or Erk1/2 pathways was seen with these cytokines. Pretreatment of preadipocytes with resveratrol markedly inhibited cytokine-stimulated PAPP-A expression. This down-regulation of PAPP-A by resveratrol did not occur through known targets of resveratrol, i.e., AMP kinase or SIRT1.

Summary and Conclusions:  PAPP-A is preferentially expressed in human preadipocytes from visceral fat and is up-regulated by inflammatory cytokines. The intracellular pathways mediating PAPP-A up-regulation are commonly associated with stress, including JNK, p38 and NFkB, although IL-1β and TNF-α seem to have differing effects. Resveratrol down-regulates cytokine-induced PAPP-A expression through a pathway that appears to be independent of SIRT1 and AMPK.  These data position PAPP-A as an important regulator of depot-specific adipogenesis with implications for potential treatment and/or prevention strategies for obesity and obesity-related disease.

Nothing to Disclose: CJD, CJE, CAC

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