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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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Reduced hypothalamic Il6 and Il6ra but increased WAT Il6 mRNA expression in pregnant WT mice.12 weeks old WT (C57BL6) mice were time-pregnant and samples for RNA extractions were obtained from WAT and hypothalamus at early, mid and late pregnancy: gestational days 7 (n = 5), 13 (n = 8) and 18 (n = 6), respectively. Age matched virgin females were used as controls (n = 5–9). A–C. Gestational expression pattern of Il6 mRNA in adipose tissue (A) and hypothalamus (B), and hypothalamic Il6ra mRNA levels (C) were determined by RT-qPCR. Expression of genes were measured in duplicates, normalized to 18s and expressed in percentage to WT virgin control values. The bars represent the mean ± SEM. Two-tailed t-test, *P<0.05 and **P<0.01 versus corresponding WT virgin controls.
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pone-0072339-g005: Reduced hypothalamic Il6 and Il6ra but increased WAT Il6 mRNA expression in pregnant WT mice.12 weeks old WT (C57BL6) mice were time-pregnant and samples for RNA extractions were obtained from WAT and hypothalamus at early, mid and late pregnancy: gestational days 7 (n = 5), 13 (n = 8) and 18 (n = 6), respectively. Age matched virgin females were used as controls (n = 5–9). A–C. Gestational expression pattern of Il6 mRNA in adipose tissue (A) and hypothalamus (B), and hypothalamic Il6ra mRNA levels (C) were determined by RT-qPCR. Expression of genes were measured in duplicates, normalized to 18s and expressed in percentage to WT virgin control values. The bars represent the mean ± SEM. Two-tailed t-test, *P<0.05 and **P<0.01 versus corresponding WT virgin controls.

Mentions: Adipose tissue Il6 mRNA expression increased as pregnancy progressed. Il6 mRNA levels were similar in adipose tissue of virgin and 7 days pregnant WT mice, but increased three fold on gestational days 13 and 18 (Figure 5A, percentage of WT virgin values at gestational days 13 and 18: 303.71±71.20 and 255.32±42,39, P<0.01, t-test). Conversely, hypothalamic Il6 mRNA levels were a 60 and 50% lower in mid- and late pregnant mice than in corresponding virgin controls (Figure 5B, P<0.01). Hypothalamic Il6ra mRNA showed a slightly different profile during pregnancy from that of Il6, with decreased expression levels in pregnant mice at gestational days 7 and 18 in comparison to non-pregnant values (P<0.05, Figure 5C).


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)

Reduced hypothalamic Il6 and Il6ra but increased WAT Il6 mRNA expression in pregnant WT mice.12 weeks old WT (C57BL6) mice were time-pregnant and samples for RNA extractions were obtained from WAT and hypothalamus at early, mid and late pregnancy: gestational days 7 (n = 5), 13 (n = 8) and 18 (n = 6), respectively. Age matched virgin females were used as controls (n = 5–9). A–C. Gestational expression pattern of Il6 mRNA in adipose tissue (A) and hypothalamus (B), and hypothalamic Il6ra mRNA levels (C) were determined by RT-qPCR. Expression of genes were measured in duplicates, normalized to 18s and expressed in percentage to WT virgin control values. The bars represent the mean ± SEM. Two-tailed t-test, *P<0.05 and **P<0.01 versus corresponding WT virgin controls.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3756067&req=5

pone-0072339-g005: Reduced hypothalamic Il6 and Il6ra but increased WAT Il6 mRNA expression in pregnant WT mice.12 weeks old WT (C57BL6) mice were time-pregnant and samples for RNA extractions were obtained from WAT and hypothalamus at early, mid and late pregnancy: gestational days 7 (n = 5), 13 (n = 8) and 18 (n = 6), respectively. Age matched virgin females were used as controls (n = 5–9). A–C. Gestational expression pattern of Il6 mRNA in adipose tissue (A) and hypothalamus (B), and hypothalamic Il6ra mRNA levels (C) were determined by RT-qPCR. Expression of genes were measured in duplicates, normalized to 18s and expressed in percentage to WT virgin control values. The bars represent the mean ± SEM. Two-tailed t-test, *P<0.05 and **P<0.01 versus corresponding WT virgin controls.
Mentions: Adipose tissue Il6 mRNA expression increased as pregnancy progressed. Il6 mRNA levels were similar in adipose tissue of virgin and 7 days pregnant WT mice, but increased three fold on gestational days 13 and 18 (Figure 5A, percentage of WT virgin values at gestational days 13 and 18: 303.71±71.20 and 255.32±42,39, P<0.01, t-test). Conversely, hypothalamic Il6 mRNA levels were a 60 and 50% lower in mid- and late pregnant mice than in corresponding virgin controls (Figure 5B, P<0.01). Hypothalamic Il6ra mRNA showed a slightly different profile during pregnancy from that of Il6, with decreased expression levels in pregnant mice at gestational days 7 and 18 in comparison to non-pregnant values (P<0.05, Figure 5C).

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