Obesity alters gene expression for GH/IGF-I axis in mouse mammary fat pads: differential role of cortistatin and somatostatin - PubMed (original) (raw)

Obesity alters gene expression for GH/IGF-I axis in mouse mammary fat pads: differential role of cortistatin and somatostatin

Alicia Villa-Osaba et al. PLoS One. 2015.

Abstract

Locally produced growth hormone (GH) and IGF-I are key factors in the regulation of mammary gland (MG) development and may be important in breast cancer development/progression. Somatostatin (SST) and cortistatin (CORT) regulate GH/IGF-I axis at various levels, but their role in regulating GH/IGF-I in MGs remains unknown. Since obesity alters the expression of these systems in different tissues and is associated to MG (patho) physiology, we sought to investigate the role of SST/CORT in regulating GH/IGF-I system in the MGs of lean and obese mice. Therefore, we analyzed GH/IGF-I as well as SST/CORT and ghrelin systems expression in the mammary fat pads (MFPs) of SST- or CORT-knockout (KO) mice and their respective littermate-controls fed a low-fat (LF) or a high-fat (HF) diet for 16 wks. Our results demonstrate that the majority of the components of GH/IGF-I, SST/CORT and ghrelin systems are locally expressed in mouse MFP. Expression of elements of the GH/IGF-I axis was significantly increased in MFPs of HF-fed control mice while lack of endogenous SST partially suppressed, and lack of CORT completely blunted, the up-regulation observed in obese WT-controls. Since SST/CORT are known to exert an inhibitory role on the GH/IGFI axis, the increase in SST/CORT-receptor sst2 expression in MFPs of HF-fed CORT- and SST-KOs together with an elevation on circulating SST in CORT-KOs could explain the differences observed. These results offer new information on the factors (GH/IGF-I axis) involved in the endocrine/metabolic dysregulation of MFPs in obesity, and suggest that CORT is not a mere SST sibling in regulating MG physiology.

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Conflict of interest statement

Competing Interests: The authors of this manuscript have the following competing interests: RML currently serves as Associate Editor for this journal. There are no competing financial interests. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1

Fig 1. Impact of LF- and HF- diet on body weight in WT, CORT-KO and SST-KO female mice.

Values represent percentage of body weight increase compared to 100% of LF diet fed mice. Global differences by 2-way ANOVA are shown at the top of each graphic (G: genotype effect; D: diet effect I: effect of interaction between genotype and diet; *, p<0.05; **, p<0.01; ***, p<0.001). Asterisks above the bars (*, p<0.05; ***, p<0.001) indicate significant differences between groups by Bonferroni post-hoc.

Fig 2

Fig 2. Plasma leptin levels in WT, CORT-KO and SST-KO mice fed under LF and HF diets.

Values represent mean ± SEM of ng/ml of plasma leptin. Global differences by 2-way ANOVA are shown at the top of each graphic (G: genotype effect; D: diet effect I: effect of interaction between genotype and diet; *, p<0.05; **, p<0.01; ***, p<0.001). Asterisks above the bars (*, p<0.05) indicate significant differences between groups by Bonferroni post-hoc.

Fig 3

Fig 3. Characterization of GH/IGF-I axis and the regulatory SST/CORT/ghrelin/receptors system in mammary fat pads of female mice (expressed as absolute copy number/50 ng total cDNA).

Values represent means ± SEM of the mRNA copy number of each transcript (n = 5–6 mice).

Fig 4

Fig 4. Impact of diet-induced obesity on the expression of GH-IGF-I axis in the mammary fat pads of CORT-KO, SST-KO and their respective control mice.

mRNA levels of GH-R, IGF-I, IGF-II, IGF-IR and PRL-R were measured by qPCR. Values represent means ± SEM of the mRNA copy number of each transcript adjusted by the normalization factor (n = 5–6). Global differences by 2-way ANOVA are shown at the top of each graphic (G: genotype effect; D: diet effect I: effect of interaction between genotype and diet; *, p<0.05; **, p<0.01; ***, p<0.001). Asterisks above the bars (*, p<0.05; **, p<0.01; ***, p<0.001) indicate significant differences between groups by Bonferroni post-hoc.

Fig 5

Fig 5. Impact of diet-induced obesity on the expression of SST/CORT/receptor subtypes in the mammary fat pads of CORT-KO, SST-KO and their respective control mice.

mRNA levels of sst1, sst2, sst3, sst4 were measured by qPCR. Values represent means ± SEM of the mRNA copy number of each transcript adjusted by the normalization factor (n = 5–6). Global differences by 2-way ANOVA are shown at the top of each graphic (G: genotype effect; D: diet effect I: effect of interaction between genotype and diet; *, p<0.05; **, p<0.01; ***, p<0.001). Asterisks above the bars (*, p<0.05; **, p<0.01) indicate significant differences between groups by Bonferroni post-hoc.

Fig 6

Fig 6. Impact of diet-induced obesity on the expression of ghrelin system in the mammary fat pads of CORT-KO, SST-KO and their respective control mice.

mRNA levels of ghrelin, In2-ghrelin, GOAT were measured by qPCR. Values represent means ± SEM of the mRNA copy number of each transcript adjusted by the normalization factor (n = 5–6). Global differences by 2-way ANOVA are shown at the top of each graphic (G: genotype effect; D: diet effect I: effect of interaction between genotype and diet; *, p<0.05).

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This work has been funded by the following grants: BFU2010-19300, PI-0369-2012, BIO-0139, PI13/00651, CIBERobn (to RML and JPC), and “Sara Borrell” program CD11/00276 (to MDG). Ciber is an initiative of Instituto de Salud Carlos III, Ministerio de Sanidad, Servicios Sociales e Igualdad, Spain. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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