, 37:51 | Cite as

Female PAPP-A knockout mice are resistant to metabolic dysfunction induced by high-fat/high-sucrose feeding at middle age

  • Cristal M. HillEmail author
  • Oge Arum
  • Ravneet K. Boparai
  • Feiya Wang
  • Yimin Fang
  • Liou Y. Sun
  • Michal M. Masternak
  • Andrzej Bartke


Longevity and aging are influenced by common intracellular signals of the insulin/insulin-like growth factor (IGF)-1 pathway. Abnormally high levels of bioactive IGF-1 increase the development of various cancers and may contribute to metabolic diseases such as insulin resistance. Enhanced availability of IGF-1 is promoted by cleavage of IGF binding proteins (IGFBPs) by proteases, including the pregnancy-associated plasma protein-A (PAPPA). In vitro, PAPP-A is regulated by pro-inflammatory cytokines (PICs) such as interleukin (IL)-6 and tumor necrosis factor (TNF). Mice born with deficiency of the Papp-a gene (PAPP-A knockout (KO) mice) live ∼30–40 % longer than their normal littermates and have decreased bioactive IGF-1 on standard diets. Our objective was to elucidate how the effects of high-fat, high-sucrose diet (HFHS) promote obesity, induce metabolic dysfunction, and alter systemic cytokine expression in PAPP-A KO and normal mice. PAPP-A KO mice fed HFHS diet for 10 weeks were more glucose tolerant and had enhanced insulin sensitivity compared to normal mice fed HFHS diet. PAPP-A KO mice fed HFHS diet had lower levels of pro-inflammatory cytokines (IL-2, IL-6, and TNF-α) compared to normal mice fed the same diet. However, anti-inflammatory cytokine levels (IL-4 and adiponectin) were higher in PAPP-A KO mice fed HFHS diet compared to normal mice fed HFHS. Circulating PAPP-A levels were elevated in normal mice fed an HFHS diet compared to normal mice fed a standard, low-fat, low-sucrose (LFLS) diet. Indirect calorimetry showed, at 10 weeks of feeding HFHS diet, significantly increased oxygen consumption (VO2) in PAPP-A KO mice fed HFHS diet compared to normal mice fed the same diet. Furthermore, respiratory quotient (RQ) was significantly lower in PAPP-A KO mice fed HFHS diet compared to normal (N) mice fed HFHS diet indicating PAPP-A KO mice fed HFHS diet are able to rely on fat as their primary source of energy more so than normal controls. We conclude that PAPP-A KO mice are resistant to the HFHS diet induction of metabolic dysfunction associated with higher levels of anti-inflammatory cytokines and a remarkably metabolic flexible phenotype and that some of the effects of HFHS diet in normal animals may be due to increased levels of PAPP-A.


High-fat/high-sucrose diet Immune response Insulin/IGF-1 signaling Longevity Metabolic flexibility PAPP-A KO mice 



This work was supported by grants from the National Institute on Aging (AG032290 and PO1 AG031376). We gratefully acknowledge numerous colleagues’, students’, and lab members’ contributions to the progress of our work. We would also like to graciously thank Dr. Cheryl A. Conover for providing PAPP-A (−/+) breeding pairs to generate the colony for this study.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

11357_2015_9765_MOESM1_ESM.ppt (112 kb)
Supplementary Table 1 Fat and carbohydrate diet source (PPT 112 kb)
11357_2015_9765_MOESM2_ESM.ppt (63 kb)
Supplementary Fig. 1 Area under curve, insulin tolerance test (week 10) (PPT 63.0 kb)
11357_2015_9765_MOESM3_ESM.ppt (95 kb)
Supplementary Fig. 2 Absolute fat pad weight (final weight) (PPT 95.0 kb)
11357_2015_9765_MOESM4_ESM.ppt (92 kb)
Supplementary Fig. 3 Indirect calorimetry-carbon dioxide measurement (PPT 91.5 kb)


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Copyright information

© American Aging Association 2015

Authors and Affiliations

  • Cristal M. Hill
    • 1
    • 3
    Email author
  • Oge Arum
    • 3
    • 4
  • Ravneet K. Boparai
    • 3
  • Feiya Wang
    • 3
  • Yimin Fang
    • 3
  • Liou Y. Sun
    • 3
  • Michal M. Masternak
    • 2
  • Andrzej Bartke
    • 1
    • 3
  1. 1.Department of Medical Microbiology, Immunology, and Cell BiologySouthern Illinois University School of MedicineSpringfieldUSA
  2. 2.Burnett School of Biomedical Sciences, College of MedicineUniversity of Central FloridaOrlandoUSA
  3. 3.Geriatrics Research Laboratory, Department of Internal MedicineSouthern Illinois University School of MedicineSpringfieldUSA
  4. 4.SpringfieldUSA

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