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 pregnancyassociated 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 AGE (2015) 37: 51

Circulating IGF-1 deficiency exacerbates hypertension-induced microvascular rarefaction in the mouse hippocampus and retrosplenial cortex: implications for cerebromicrovascular and brain aging

“…To understand the effects of IGF-1 deficiency on the cerebral microcirculation in the present study, we used a novel mouse model of adult-onset isolated endocrine IGF-1 deficiency, which phenotypically better mimics age-related IGF-1 deficiency observed in humans that most other available rodent models of GH/IGF-1 deficiency (Arum et al 2014a;Hill et al 2015;Rojanathammanee et al 2014;Wiesenborn et al 2014;Arum et al 2014b;Schneider et al 2014). Serum IGF-1 levels and physiological parameters obtained in the same experimental cohorts of animals used for the present study have been recently reported (Toth et al 2014a).…”

GH and ageing: Pitfalls and new insights

“…Analysis of local, tissue-specific IGF-1 expression and activity is important in deciphering the phenotypic consequences of altered GH signaling, including its effects on healthspan and lifespan. Studies in animals with deletion of pregnancy associated plasma A (PAPP-A), a protease that degrades IGF-1 binding proteins, provided important evidence for the role of local (tissue) availability of biologically active IGF-1 in the control of aging and longevity [129, 130]. …”

mTOR regulates the expression of DNA damage response enzymes in long‐lived Snell dwarf, GHRKO, and PAPPA‐KO mice

“…Mice in which CNOT6 has been deleted are viable but, with exception of some bone abnormalities, do not have obvious changes in phenotype. However, CNOT3 heterozygous mice (Morita et al ., 2011) display some phenotypes reminiscent of Snell (Bartke & Brown‐Borg, 2004; Boylston et al ., 2006), Ames dwarf (Boylston et al ., 2006), GHRKO (Brown‐Borg & Bartke, 2012), and PAPPA‐KO mice (Hill et al ., 2015), including higher insulin sensitivity, improved glucose tolerance, and higher oxygen consumption. Here, we present evidence suggesting that Snell, GHRKO, and PAPPA‐KO mice express high levels of NDRG1 and MGMT proteins that are under the control of mTORC1 activity, and that this regulation involves post‐transcriptional mechanisms that may depend on alteration of the CCR4‐NOT complex.…”