Preferential impact of pregnancy-associated plasma protein-A deficiency on visceral fat in mice on high-fat diet

Conover, Cheryl A.; Harstad, Sara L.; Tchkonia, Tamar; Kirkland, James L.

doi:10.1152/ajpendo.00405.2013

Cited by 30 publications

(41 citation statements)

References 35 publications

(44 reference statements)

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“…It was also noted that PAPP-A was highly expressed in human preadipocytes obtained from visceral fat depots compared to those from subcutaneous fat depots (9). Similar findings were reported for mice (10). These studies suggest not only diagnostic and prognostic value, but also potential therapeutic value for PAPP-A.…”

Section: Introductionsupporting

confidence: 90%

Tissue-specific changes in pregnancy associated plasma protein-A expression with age in mice

Harstad

Conover

2014

Experimental Gerontology

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Pregnancy-associated plasma protein-A (PAPP-A) is a novel zinc metalloproteinase that functions in many systems outside of pregnancy. Data in both humans and mice suggest a role for PAPP-A in aging and age-related diseases. However, our knowledge of tissue-specific PAPP-A expression and possible changes in this expression with age is limited. Thus, the aim of this study was to determine PAPP-A mRNA expression in multiple tissues with age in both male and female mice using real-time PCR. These included heart, liver, kidney, bone, fat, skeletal muscle, gonads, brain, thymus and spleen. In young mice, PAPP-A mRNA was expressed at relatively high levels in all tissues examined except for liver. The only difference in expression between males and females was seen in kidney, subcutaneous fat and gonads. The highest PAPP-A mRNA expression levels were found in visceral fat and these were 10-fold higher than in subcutaneous fat. PAPP-A expression significantly increased with age in kidney, brain and gonads. PAPP-A expression significantly deceased with age in bone and skeletal muscle. In the thymus, PAPP-A mRNA showed a biphasic response with age. There were no age-related changes in PAPP-A expression seen in any of the other tissues examined. Expression of IGFBP-5 mRNA, a marker of insulin-like growth factorI (IGF-I) bioactivity known to be regulated by PAPP-A, paralleled the changes in PAPP-A expression with age in kidney, bone, skeletal muscle and thymus. Thus, tissue-specific PAPP-A expression in mice is differentially affected during aging, and may regulate local IGF-I bioactivity in certain tissues.

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Section: Introductionsupporting

confidence: 90%

Tissue-specific changes in pregnancy associated plasma protein-A expression with age in mice

Harstad

Conover

2014

Experimental Gerontology

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“…Thus, reduction in PAPP-A expression may be another mechanism responsible for resveratrol’s beneficial effects. Further evaluation of the specific role of PAPP-A in depot-specific adipogenesis is needed, as these findings in human preadipocytes in conjunction with the work in mice (Conover et al 2013) suggest the potential for PAPP-A to be a therapeutic target in the treatment of visceral obesity.…”

Section: Resultsmentioning

confidence: 99%

“…This is similar to a model proposed for PAPP-A in atherosclerotic plaque progression (Conover 2010). A recent study in mice suggests a novel interactive in vivo setting whereby PAPP-A regulates visceral adipose tissue response to insulin (Conover et al , 2013). …”

Section: Discussionmentioning

confidence: 99%

“…PAPP-A is a zinc metalloproteinase that enhances local IGF action through cleavage of inhibitory proteins that bind IGFs with high affinity, thereby freeing the IGFs in the pericellular environment to bind and activate receptors (Conover 2012). Elevated PAPP-A has been implicated in aging and age-related disease, while PAPP-A knockout mice have a 30% longer lifespan than wild type mice, with resistance to atherosclerotic plaque development (Boldt et al 2013, Conover et al 2010, Harrington et al 2007) and to visceral fat accumulation on high fat diet (Conover et al . 2013).…”

Section: Introductionmentioning

confidence: 99%

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Preferential expression of PAPPA in human preadipocytes from omental fat

Davidge‐Pitts¹,

Escande²,

Conover³

2014

Journal of Endocrinology

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Fat distribution differs between individuals, and those with visceral fat predominance develop metabolic profiles that increase risk of adverse cardiovascular events. This is due, in part, to the proinflammatory state associated with visceral obesity as well as depot-specific adipogenesis. The insulin-like growth factor (IGF) system is important in adipose tissue development and metabolic function. Pregnancy associated plasma protein-A (PAPP-A) is a novel zinc metalloproteinase that regulates local IGF availability. The first aim of this study was to characterize PAPP-A mRNA and protein expression in primary cultures of human preadipocytes isolated from omental, mesenteric and subcutaneous depots. PAPP-A expression was significantly increased in omental preadipocytes compared to mesenteric and subcutaneous preadipocytes. The second aim was 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. Treatment of cultured primary human preadipocytes with tumor necrosis factor (TNF)-α and interleukin (IL) 1-β led to significant increases in PAPP-A expression. Activated pathways mediating cytokine-induced PAPP-A expression include the nuclear factor (NF) κB pathway and the mitogen activated protein kinase (MAPK) family, particularly c-Jun NH2-terminal kinase (JNK) and p38 mitogen-activated kinase. Resveratrol, a polyphenol with beneficial cardiometabolic effects, significantly down-regulated PAPP-A expression under basal and stimulated conditions. Resveratrol appeared to mediate its effects on PAPP-A through pathways independent of silent mating type information regulation 2 homolog 1 (SIRT1) and AMP kinase (AMPK) activation. Depot-specific PAPP-A expression in human preadipocytes may contribute to depot-specific function.

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“…Like IGF-I, PAPP-A displays antagonistic pleiotropy [2], i.e., expression is important early in life for optimal fetal growth and reproductive function but is associated in the adult with aging and age-related diseases [3,4]. We have shown that mice deficient in PAPP-A are resistant to the development of experimentally-induced atherosclerosis, diabetic nephropathy, and visceral obesity [4–6]. Moreover, these PAPP-A knock-out (KO) mice live 30–40% longer than their wild-type (WT) littermates with delayed occurrence of spontaneous cancers and reduced incidence and severity of many degenerative diseases of age [7].…”

Section: Introductionmentioning

confidence: 99%

Motor and memory testing of long-lived pregnancy-associated plasma protein—A knock-out mice

Mason

Grell

West

et al. 2014

Growth Hormone & IGF Research

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Mice deficient in pregnancy-associated plasma protein-A (PAPP-A), an IGF binding protein protease, have been shown to be resistant to experimentally-induced atherosclerosis and diabetic nephropathy, and, in the laboratory environment, live 30–40% longer than wild-type littermates in association with delayed incidence and occurrence of age-related neoplasms and degenerative diseases. OBJECTIVE PAPP-A is highly expressed in the cerebellum and hippocampus of the mouse brain. Therefore, the studies presented here were aimed at determining motor behavior, learning and retention in PAPP-A knock-out (KO) mice compared to wild-type (WT) littermates with age. DESIGN Balance and coordination were assessed using an accelerating rotarod; learning and memory were assessed in a Stone T-maze. RESULTS Time on the rotarod decreased with age but there was no significant difference between PAPP-A KO and WT mice at any of the testing ages. Latency to reach the goal box and number of errors committed in the Stone T-maze did not change with age and there were no significant differences between PAPP-A KO and WT mice. CONCLUSION Lack of PAPP-A in mice did not impact central regulation of coordination, learning or memory.

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Preferential impact of pregnancy-associated plasma protein-A deficiency on visceral fat in mice on high-fat diet

Cited by 30 publications

References 35 publications

Tissue-specific changes in pregnancy associated plasma protein-A expression with age in mice

Tissue-specific changes in pregnancy associated plasma protein-A expression with age in mice

Preferential expression of PAPPA in human preadipocytes from omental fat

Motor and memory testing of long-lived pregnancy-associated plasma protein—A knock-out mice

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