Female Papp-A Knockout Mice Are Resistant To Metabolic Dysfunction Induced By High-Fat/High-Sucrose Feeding At Middle Age

Keywords

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

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.

Publication Date

6-1-2015

Publication Title

Age

Volume

37

Issue

3

Number of Pages

1-14

Document Type

Article

Personal Identifier

scopus

DOI Link

https://doi.org/10.1007/s11357-015-9765-1

Socpus ID

84928998042 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/84928998042

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