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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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Average daily intake in Il6-KO mice throughout pregnancy.Food intake was measured daily in individually housed 12 weeks old virgin (n = 21) and pregnant WT and Il6-KO mice (n = 15–16). A–B. Average daily intake (A) was calculated for early (gestational days 0–7), mid (gestational days 7–13) and late pregnancy (gestational days 13–18). Food intake values normalized in percentage to animal body weight (B). Two-way ANOVA for repeated measurements, *P<0.05, **P<0.01, ***P <0.001 and ****P<0.0001, ns =  not significant.
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pone-0072339-g002: Average daily intake in Il6-KO mice throughout pregnancy.Food intake was measured daily in individually housed 12 weeks old virgin (n = 21) and pregnant WT and Il6-KO mice (n = 15–16). A–B. Average daily intake (A) was calculated for early (gestational days 0–7), mid (gestational days 7–13) and late pregnancy (gestational days 13–18). Food intake values normalized in percentage to animal body weight (B). Two-way ANOVA for repeated measurements, *P<0.05, **P<0.01, ***P <0.001 and ****P<0.0001, ns =  not significant.

Mentions: Next, we evaluated whether the profile of fat accretion in Il6-KO pregnant mice was related to changes in average daily food intake during early (gestational days 0–7), mid (gestational days 7–13) and late gestation (gestational days 13–18) (Figure 2). Non-pregnant 12 weeks old Il6-KO mice ate less amount of food than their corresponding WT controls when values are expressed on an absolute (−7,3% as a mean, Figure 2A), but not on a weight corrected basis (Figure 2B) (absolute: genotype F (1, 40)  = 17.86, P < 0.001, time F (2, 80)  = 5.823, P < 0,01 and genotype X time F (2, 80)  = 1.180, not significant, two-way repeated measures ANOVA), (relative: time F (2, 80)  = 5.581, P<0.01, genotype F (1, 40)  = 0.0246 and genotype X time F (2, 80)  = 0.322, not significant). Food consumption increased progressively during pregnancy (group F (3, 69)  = 55.61, time F (2, 138)  = 81.32 and group X time F (6, 138)  = 15.13, P < 0.0001 for all), and was higher than non-pregnant levels by its first week (P<0.05, Figure 2A). At this time point absolute food intake values were similar in both genotypes, being lower in Il6-KO than in WT mice throughout the rest of the gestational period (genotype F (1, 29)  = 15.33, P < 0.001, time F (2, 58)  = 125.7, P < 0.001 and genotype X time F (2, 58)  = 4.324, P<0.05) (gestational days 13 and 18: P<0.01 and P<0.001, respectively). However, when food intake values in pregnant mice were corrected by body mass no effect of Il6 deficiency was seen in this parameter (Figure 2B) (genotype F (1, 29)  = 0.151, P = 0.443, time F (2, 58)  = 25.521, P < 0.0001 and genotype X time F (2, 58)  = 3.367, P<0.05).


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)

Average daily intake in Il6-KO mice throughout pregnancy.Food intake was measured daily in individually housed 12 weeks old virgin (n = 21) and pregnant WT and Il6-KO mice (n = 15–16). A–B. Average daily intake (A) was calculated for early (gestational days 0–7), mid (gestational days 7–13) and late pregnancy (gestational days 13–18). Food intake values normalized in percentage to animal body weight (B). Two-way ANOVA for repeated measurements, *P<0.05, **P<0.01, ***P <0.001 and ****P<0.0001, ns =  not significant.
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Related In: Results  -  Collection

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pone-0072339-g002: Average daily intake in Il6-KO mice throughout pregnancy.Food intake was measured daily in individually housed 12 weeks old virgin (n = 21) and pregnant WT and Il6-KO mice (n = 15–16). A–B. Average daily intake (A) was calculated for early (gestational days 0–7), mid (gestational days 7–13) and late pregnancy (gestational days 13–18). Food intake values normalized in percentage to animal body weight (B). Two-way ANOVA for repeated measurements, *P<0.05, **P<0.01, ***P <0.001 and ****P<0.0001, ns =  not significant.
Mentions: Next, we evaluated whether the profile of fat accretion in Il6-KO pregnant mice was related to changes in average daily food intake during early (gestational days 0–7), mid (gestational days 7–13) and late gestation (gestational days 13–18) (Figure 2). Non-pregnant 12 weeks old Il6-KO mice ate less amount of food than their corresponding WT controls when values are expressed on an absolute (−7,3% as a mean, Figure 2A), but not on a weight corrected basis (Figure 2B) (absolute: genotype F (1, 40)  = 17.86, P < 0.001, time F (2, 80)  = 5.823, P < 0,01 and genotype X time F (2, 80)  = 1.180, not significant, two-way repeated measures ANOVA), (relative: time F (2, 80)  = 5.581, P<0.01, genotype F (1, 40)  = 0.0246 and genotype X time F (2, 80)  = 0.322, not significant). Food consumption increased progressively during pregnancy (group F (3, 69)  = 55.61, time F (2, 138)  = 81.32 and group X time F (6, 138)  = 15.13, P < 0.0001 for all), and was higher than non-pregnant levels by its first week (P<0.05, Figure 2A). At this time point absolute food intake values were similar in both genotypes, being lower in Il6-KO than in WT mice throughout the rest of the gestational period (genotype F (1, 29)  = 15.33, P < 0.001, time F (2, 58)  = 125.7, P < 0.001 and genotype X time F (2, 58)  = 4.324, P<0.05) (gestational days 13 and 18: P<0.01 and P<0.001, respectively). However, when food intake values in pregnant mice were corrected by body mass no effect of Il6 deficiency was seen in this parameter (Figure 2B) (genotype F (1, 29)  = 0.151, P = 0.443, time F (2, 58)  = 25.521, P < 0.0001 and genotype X time F (2, 58)  = 3.367, P<0.05).

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