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

• Published in: AGE Vol. 37; no. 3; p. 9765
• Main Authors: Hill, Cristal M., Arum, Oge, Boparai, Ravneet K., Wang, Feiya, Fang, Yimin, Sun, Liou Y., Masternak, Michal M., Bartke, Andrzej
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01-06-2015; Springer Nature B.V
• Subjects: Adiponectin - blood; Aging; Animals; Biomedical and Life Sciences; Calorimetry, Indirect; Cell Biology; Cytokines; Diet; Diet, High-Fat; Energy Metabolism - physiology; Females; Geriatrics/Gerontology; Growth hormones; Insulin - blood; Insulin resistance; Insulin-Like Growth Factor I - metabolism; Insulin-like growth factors; Interleukin-2 - blood; Interleukin-4 - blood; Interleukin-6 - blood; Laboratory animals; Life Sciences; Longevity; Medicine; Metabolic disorders; Mice; Mice, Knockout; Middle age; Molecular Medicine; Nutrition research; Obesity; Oxygen Consumption - physiology; Phenotype; Pregnancy; Pregnancy-Associated Plasma Protein-A - deficiency; Proteins; Respiratory Rate - physiology; Rodents; Sucrose; Sucrose - administration & dosage; Tumor Necrosis Factor-alpha - blood; Tumor necrosis factor-TNF; High-fat/high-sucrose diet; PAPP-A KO mice; Immune response; Longevity; Insulin/IGF-1 signaling; Metabolic flexibility
• ISSN: 0161-9152; 2509-2715; 1574-4647; 2509-2723
• DOI: 10.1007/s11357-015-9765-1

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 (VO
2
) 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.