title: Female PAPP-A knockout mice are resistant to metabolic dysfunction induced by high-fat/high-sucrose feeding at middle age.
abstract: 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.
authors.affiliation: Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, USA, chill@siumed.edu.
authors.forename: Cristal M
authors.initials: CM
authors.lastname: Hill
authors.forename: Oge
authors.initials: O
authors.lastname: Arum
authors.forename: Ravneet K
authors.initials: RK
authors.lastname: Boparai
authors.forename: Feiya
authors.initials: F
authors.lastname: Wang
authors.forename: Yimin
authors.initials: Y
authors.lastname: Fang
authors.forename: Liou Y
authors.initials: LY
authors.lastname: Sun
authors.forename: Michal M
authors.initials: MM
authors.lastname: Masternak
authors.forename: Andrzej
authors.initials: A
authors.lastname: Bartke
mesh_terms: D052242:Adiponectin / Q000097:blood; D000818:Animals; D002153:Calorimetry, Indirect; D059305:Diet, High-Fat; D004734:Energy Metabolism / Q000502:physiology*; D007328:Insulin / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007376:Interleukin-2 / Q000097:blood; D015847:Interleukin-4 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008136:Longevity; D051379:Mice; D018345:Mice, Knockout; D010101:Oxygen Consumption / Q000502:physiology; D010641:Phenotype; D011266:Pregnancy-Associated Plasma Protein-A / Q000172:deficiency*; D056152:Respiratory Rate / Q000502:physiology; D013395:Sucrose / Q000008:administration & dosage*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D052242:Adiponectin; D007328:Insulin; D007376:Interleukin-2; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D013395:Sucrose; D007334:Insulin-Like Growth Factor I; D011266:Pregnancy-Associated Plasma Protein-A