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

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

Cristal M Hill et al. Age (Dordr). 2015 Jun.

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.

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Figures

Fig. 1

Fig. 1

Visceral fat is increased in PAPP-A KO mice fed an HFHS diet. PAPP-A KO and normal littermates consumed either an LFLS or HFHS diet for 12 weeks. Weekly body weights were recorded during the feeding phase. a Absolute weight gain. b Normalized body weight gain. c Normalized percentage gains in subcutaneous adipose tissue (AD), retroperitoneal AD, and brown AD. All values are presented as mean. The error bars represent the SEM. *P < 0.05

Fig. 2

Fig. 2

Long-lived PAPP-A KO mice are resistant to metabolic dysfunction induced by an HFHS diet. PAPP-A KO and normal littermates consumed either an LFLS or HFHS diet for 12 weeks; GTT were performed during week 6 and week 10 of the study. a, b Glucose tolerance test (GTT) at 6 and 10 weeks. Sixteen-hour-fasted mice underwent GTT by i.p. injection with 1 g glucose per kg of BW. c, d Insulin tolerance test (ITT) at 6 and 10 weeks. Mice were injected i.p. with 0.1 IU porcine insulin per kilogram of BW. ITT data expressed as percentage of initial blood glucose concentration. e Average blood glucose levels. f Fasted insulin levels. g Circulating IGF-1 levels. All values are presented as mean. The error bars represent the SEM. *P < 0.05, **P < 0.001

Fig. 3

Fig. 3

Anti-inflammatory cytokine levels are increased in PAPP-A KO mice fed an HFHS diet. Mice were fasted for 16 h, and collected plasma was used for assays. a Mouse interleukin 2 (mIL-2). b mIL-6. c mTNF-a. d Anti-inflammatory m-IL-4. e Adiponectin. All values are presented as mean. The error bars represent the SEM. *P < 0.05, **P < 0.001, ***P < 0.0001

Fig. 4

Fig. 4

Normal mice fed an HFHS diet have an increased level of PAPP-A protease. a Relative gene expression of hepatic IL-6 in normal mice fed either an LFLS (n = 6) or HFHS (n = 6) diet. b Relative gene expression of hepatic PAPP-A in normal mice fed either an LFLS (n = 6) or HFHS (n = 6) diet. c Circulating PAPP-A protein levels in mice fed either an LFLD (n = 6) or HFHS (n = 6). All values are presented as mean. The error bars represent the SEM. *P < 0.05, **P < 0.001

Fig. 5

Fig. 5

PAPP-A KO mice fed an HFHS diet have increased VO2 and decreased RQ. PAPP-A KO mice (n = 4) and normal littermates (n = 3) fed STD were placed in the metabolic chambers to measure VO2 and RQ. Following initial metabolic measurements, PAPP-A KO mice (n = 4) and normal littermates (n = 3) fed STD for 12 months and sequentially switched to HFHS for 10 weeks. Body weights were recorded during the feeding phase, mice were placed in indirect calorimetry chambers, and at the terminal phase plasma was collected for leptin assay. a Absolute weight gain. b Average food intake. c Circulating leptin levels. d VO2 in PAPP-A KO mice and normal mice fed STD. e VO2 in PAPP-A KO mice and normal mice fed HFHS. f RQ in PAPP-A KO mice and normal mice fed STD. g RQ in PAPP-A KO mice and normal mice fed HFHS

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