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Interleukin 6 deficiency modulates the hypothalamic expression of energy balance regulating peptides during pregnancy in mice.

Pazos P, Lima L, Casanueva FF, Diéguez C, García MC - PLoS ONE (2013)

Bottom Line: Pregnancy is associated with hyperphagia, increased adiposity and multiple neuroendocrine adaptations.Maternal adipose tissue secretes rising amounts of interleukin 6 (IL6), which acts peripherally modulating metabolic function and centrally increasing energy expenditure and reducing body fat.Trh expression was also stimulated at gestational day 13 and lack of Il6 blunted this effect.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology/Research Center of Molecular Medicine and Chronic Diseases (CIMUS), University of Santiago de Compostela, Santiago de Compostela, Spain ; Instituto de Investigación Sanitaria de Santiago de Compostela, Santiago de Compostela, Spain ; CIBER Fisiopatología Obesidad y Nutrición (CB06/03), Instituto de Salud Carlos III (ISCIII), Ministerio de Economía y Competitividad (MINECO), Santiago de Compostela, Spain.

ABSTRACT
Pregnancy is associated with hyperphagia, increased adiposity and multiple neuroendocrine adaptations. Maternal adipose tissue secretes rising amounts of interleukin 6 (IL6), which acts peripherally modulating metabolic function and centrally increasing energy expenditure and reducing body fat. To explore the role of IL6 in the central mechanisms governing dam's energy homeostasis, early, mid and late pregnant (gestational days 7, 13 and 18) wild-type (WT) and Il6 knockout mice (Il6-KO) were compared with virgin controls at diestrus. Food intake, body weight and composition as well as indirect calorimetry measurements were performed in vivo. Anabolic and orexigenic peptides: neuropeptide Y (Npy) and agouti-related peptide (Agrp); and catabolic and anorectic neuropeptides: proopiomelanocortin (Pomc), corticotrophin and thyrotropin-releasing hormone (Crh and Trh) mRNA levels were determined by in situ hybridization. Real time-PCR and western-blot were used for additional tissue gene expression and protein studies. Non-pregnant Il6-KO mice were leaner than WT mice due to a decrease in fat but not in lean body mass. Pregnant Il6-KO mice had higher fat accretion despite similar body weight gain than WT controls. A decreased fat utilization in absence of Il6 might explain this effect, as shown by increased respiratory exchange ratio (RER) in virgin Il6-KO mice. Il6 mRNA levels were markedly enhanced in adipose tissue but reduced in hypothalamus of mid and late pregnant WT mice. Trh expression was also stimulated at gestational day 13 and lack of Il6 blunted this effect. Conversely, in late pregnant mice lessened hypothalamic Il6 receptor alpha (Il6ra), Pomc and Crh mRNA were observed. Il6 deficiency during this stage up-regulated Npy and Agrp expression, while restoring Pomc mRNA levels to virgin values. Together these results demonstrate that IL6/IL6Ra system modulates Npy/Agrp, Pomc and Trh expression during mouse pregnancy, supporting a role of IL6 in the central regulation of body fat in this physiological state.

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Increased PVN Trh mRNA content in mid-pregnant WT but not in Il6-KO mice.12 weeks old WT and Il6-KO mice were time-pregnant and PVN gene expression was assessed by radioactive in situ hybridization in coronal brain sections from early (n = 8–10), mid (n = 7–12) and late (n = 12–15) pregnant mice. Age and genotype matched virgin females were used as controls (n = 7–15). A–C. Crh (A) and Trh (B) mRNA levels were normalized in percentage to WT virgin control values and expressed as mean ± SEM (right panel). Representative in situ hybridization autoradiographic images are shown in the left panel. One-way ANOVA, *P<0.05, **P<0.01 and ****P <0.0001.
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pone-0072339-g008: Increased PVN Trh mRNA content in mid-pregnant WT but not in Il6-KO mice.12 weeks old WT and Il6-KO mice were time-pregnant and PVN gene expression was assessed by radioactive in situ hybridization in coronal brain sections from early (n = 8–10), mid (n = 7–12) and late (n = 12–15) pregnant mice. Age and genotype matched virgin females were used as controls (n = 7–15). A–C. Crh (A) and Trh (B) mRNA levels were normalized in percentage to WT virgin control values and expressed as mean ± SEM (right panel). Representative in situ hybridization autoradiographic images are shown in the left panel. One-way ANOVA, *P<0.05, **P<0.01 and ****P <0.0001.

Mentions: The aforementioned gestational changes in the hypothalamic peptidergic systems involved in the regulation of food intake and energy expenditure are not restricted to the ARC. In fact, the principal neuroendocrine outputs from the PVN, the parvicellular secretory neurons producing Trh and Crh are also affected [48]. Thus, the pattern of mRNA expression in the PVN of Crh and Trh was assessed during pregnancy, as were the influence of Il6 deficiency on this setting. Our results showed that mRNA levels of Crh were decreased throughout gestation (−34% as a mean, P<0.05 for virgin versus pregnant WT mice at gestational days 7, 13 and 18, one-way ANOVA) (Figure 8A). This inhibition was similar in all pregnancy stages, as were the Crh mRNA content in the PVN from WT and Il6-KO in the virgin and pregnant groups, respectively.


Interleukin 6 deficiency modulates the hypothalamic expression of energy balance regulating peptides during pregnancy in mice.

Pazos P, Lima L, Casanueva FF, Diéguez C, García MC - PLoS ONE (2013)

Increased PVN Trh mRNA content in mid-pregnant WT but not in Il6-KO mice.12 weeks old WT and Il6-KO mice were time-pregnant and PVN gene expression was assessed by radioactive in situ hybridization in coronal brain sections from early (n = 8–10), mid (n = 7–12) and late (n = 12–15) pregnant mice. Age and genotype matched virgin females were used as controls (n = 7–15). A–C. Crh (A) and Trh (B) mRNA levels were normalized in percentage to WT virgin control values and expressed as mean ± SEM (right panel). Representative in situ hybridization autoradiographic images are shown in the left panel. One-way ANOVA, *P<0.05, **P<0.01 and ****P <0.0001.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3756067&req=5

pone-0072339-g008: Increased PVN Trh mRNA content in mid-pregnant WT but not in Il6-KO mice.12 weeks old WT and Il6-KO mice were time-pregnant and PVN gene expression was assessed by radioactive in situ hybridization in coronal brain sections from early (n = 8–10), mid (n = 7–12) and late (n = 12–15) pregnant mice. Age and genotype matched virgin females were used as controls (n = 7–15). A–C. Crh (A) and Trh (B) mRNA levels were normalized in percentage to WT virgin control values and expressed as mean ± SEM (right panel). Representative in situ hybridization autoradiographic images are shown in the left panel. One-way ANOVA, *P<0.05, **P<0.01 and ****P <0.0001.
Mentions: The aforementioned gestational changes in the hypothalamic peptidergic systems involved in the regulation of food intake and energy expenditure are not restricted to the ARC. In fact, the principal neuroendocrine outputs from the PVN, the parvicellular secretory neurons producing Trh and Crh are also affected [48]. Thus, the pattern of mRNA expression in the PVN of Crh and Trh was assessed during pregnancy, as were the influence of Il6 deficiency on this setting. Our results showed that mRNA levels of Crh were decreased throughout gestation (−34% as a mean, P<0.05 for virgin versus pregnant WT mice at gestational days 7, 13 and 18, one-way ANOVA) (Figure 8A). This inhibition was similar in all pregnancy stages, as were the Crh mRNA content in the PVN from WT and Il6-KO in the virgin and pregnant groups, respectively.

Bottom Line: Pregnancy is associated with hyperphagia, increased adiposity and multiple neuroendocrine adaptations.Maternal adipose tissue secretes rising amounts of interleukin 6 (IL6), which acts peripherally modulating metabolic function and centrally increasing energy expenditure and reducing body fat.Trh expression was also stimulated at gestational day 13 and lack of Il6 blunted this effect.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology/Research Center of Molecular Medicine and Chronic Diseases (CIMUS), University of Santiago de Compostela, Santiago de Compostela, Spain ; Instituto de Investigación Sanitaria de Santiago de Compostela, Santiago de Compostela, Spain ; CIBER Fisiopatología Obesidad y Nutrición (CB06/03), Instituto de Salud Carlos III (ISCIII), Ministerio de Economía y Competitividad (MINECO), Santiago de Compostela, Spain.

ABSTRACT
Pregnancy is associated with hyperphagia, increased adiposity and multiple neuroendocrine adaptations. Maternal adipose tissue secretes rising amounts of interleukin 6 (IL6), which acts peripherally modulating metabolic function and centrally increasing energy expenditure and reducing body fat. To explore the role of IL6 in the central mechanisms governing dam's energy homeostasis, early, mid and late pregnant (gestational days 7, 13 and 18) wild-type (WT) and Il6 knockout mice (Il6-KO) were compared with virgin controls at diestrus. Food intake, body weight and composition as well as indirect calorimetry measurements were performed in vivo. Anabolic and orexigenic peptides: neuropeptide Y (Npy) and agouti-related peptide (Agrp); and catabolic and anorectic neuropeptides: proopiomelanocortin (Pomc), corticotrophin and thyrotropin-releasing hormone (Crh and Trh) mRNA levels were determined by in situ hybridization. Real time-PCR and western-blot were used for additional tissue gene expression and protein studies. Non-pregnant Il6-KO mice were leaner than WT mice due to a decrease in fat but not in lean body mass. Pregnant Il6-KO mice had higher fat accretion despite similar body weight gain than WT controls. A decreased fat utilization in absence of Il6 might explain this effect, as shown by increased respiratory exchange ratio (RER) in virgin Il6-KO mice. Il6 mRNA levels were markedly enhanced in adipose tissue but reduced in hypothalamus of mid and late pregnant WT mice. Trh expression was also stimulated at gestational day 13 and lack of Il6 blunted this effect. Conversely, in late pregnant mice lessened hypothalamic Il6 receptor alpha (Il6ra), Pomc and Crh mRNA were observed. Il6 deficiency during this stage up-regulated Npy and Agrp expression, while restoring Pomc mRNA levels to virgin values. Together these results demonstrate that IL6/IL6Ra system modulates Npy/Agrp, Pomc and Trh expression during mouse pregnancy, supporting a role of IL6 in the central regulation of body fat in this physiological state.

Show MeSH
Related in: MedlinePlus