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Fibroblast growth factor 21 is not required for the reductions in circulating insulin-like growth factor-1 or global cell proliferation rates in response to moderate calorie restriction in adult mice.

Thompson AC, Bruss MD, Nag N, Kharitonenkov A, Adams AC, Hellerstein MK - PLoS ONE (2014)

Bottom Line: Accordingly, elucidating the mechanism(s) by which IGF-1 is reduced in response to CR holds therapeutic potential in the fight against age-related diseases.We found that in response to moderate CR, circulating GH and hepatic janus kinase 2 (JAK2) phosphorylation levels are unchanged but that hepatic signal transducer and activator of transcription 5 (STAT5) phosphorylation levels are reduced, identifying STAT5 phosphorylation as a potential key site of CR action within the somatotropic axis.However, compared to AL-fed WT mice, AL-fed FGF21-knockout mice exhibited higher basal rates of cell proliferation, suggesting anti-mitotic effects of FGF21.

View Article: PubMed Central - PubMed

Affiliation: Department of Nutritional Science and Toxicology, University of California, Berkeley, California, United States of America.

ABSTRACT
Calorie restriction (CR) delays aging and extends lifespan in numerous organisms, including mice. Down-regulation of the somatotropic axis, including a reduction in insulin-like growth factor-1 (IGF-1), likely plays an important role in CR-induced lifespan extension, possibly by reducing cell proliferation rates, thereby delaying replicative senescence and inhibiting tumor promotion. Accordingly, elucidating the mechanism(s) by which IGF-1 is reduced in response to CR holds therapeutic potential in the fight against age-related diseases. Up-regulation of fibroblast growth factor 21 (FGF21) is one possible mechanism given that FGF21 expression is induced in response to nutritional deprivation and has been implicated as a negative regulator of IGF-1 expression. Here we investigated alterations in hepatic growth hormone (GH)-mediated IGF-1 production and signaling as well as the role of FGF21 in the regulation of IGF-1 levels and cell proliferation rates in response to moderate CR in adult mice. We found that in response to moderate CR, circulating GH and hepatic janus kinase 2 (JAK2) phosphorylation levels are unchanged but that hepatic signal transducer and activator of transcription 5 (STAT5) phosphorylation levels are reduced, identifying STAT5 phosphorylation as a potential key site of CR action within the somatotropic axis. Circadian measurements revealed that the relative level of FGF21 expression is both higher and lower in CR vs. ad libitum (AL)-fed mice, depending on the time of measurement. Employing FGF21-knockout mice, we determined that FGF21 is not required for the reduction in IGF-1 levels or cell proliferation rates in response to moderate CR. However, compared to AL-fed WT mice, AL-fed FGF21-knockout mice exhibited higher basal rates of cell proliferation, suggesting anti-mitotic effects of FGF21. This work provides insights into both GH-mediated IGF-1 production in the context of CR and the complex network that regulates FGF21 and IGF-1 expression and cell proliferation rates in response to nutritional status.

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Body weight and food intake in WT and FGF21-KO mice fed AL or CR.A) Body weight trajectories and B) percent body weight change relative to initial body weight over the 6-week study. C) Daily food intake trajectories and D) cumulative average daily food intake over the 6-week study (n = 9–10 per genotype per diet). For A and C, a one-way ANOVA with a Tukey post hoc test was used at each time point for all between-group analyses. Groups not sharing a common letter at a given time point are significantly different (p<0.05). For B and D, a two-way ANOVA with a Bonferroni post hoc test was used for all between-group analyses (* p<0.05, *** p<0.001).
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pone-0111418-g003: Body weight and food intake in WT and FGF21-KO mice fed AL or CR.A) Body weight trajectories and B) percent body weight change relative to initial body weight over the 6-week study. C) Daily food intake trajectories and D) cumulative average daily food intake over the 6-week study (n = 9–10 per genotype per diet). For A and C, a one-way ANOVA with a Tukey post hoc test was used at each time point for all between-group analyses. Groups not sharing a common letter at a given time point are significantly different (p<0.05). For B and D, a two-way ANOVA with a Bonferroni post hoc test was used for all between-group analyses (* p<0.05, *** p<0.001).

Mentions: Consistent with previous findings, FGF21-KO mice weighed significantly more than WT mice on an AL diet [35], [37], [39], [40]. Similarly, FGF21-KO mice weighed significantly more than WT mice on a CR diet (Figure 3A). There was no significant difference in the percentage of weight gain over the course of the study between the two AL groups (Figure 3B). FGF21-KO mice, however, lost a significantly greater percentage of their body weight on a CR diet than WT mice (Figure 3B). On a week-by-week basis, the food intake of FGF21-KO mice tended to be higher compared to WT mice on either an AL or CR diet (Figure 3C). The overall average daily food intake of FGF21-KO mice was significantly higher compared to WT mice on either an AL or CR diet (Figure 3D).


Fibroblast growth factor 21 is not required for the reductions in circulating insulin-like growth factor-1 or global cell proliferation rates in response to moderate calorie restriction in adult mice.

Thompson AC, Bruss MD, Nag N, Kharitonenkov A, Adams AC, Hellerstein MK - PLoS ONE (2014)

Body weight and food intake in WT and FGF21-KO mice fed AL or CR.A) Body weight trajectories and B) percent body weight change relative to initial body weight over the 6-week study. C) Daily food intake trajectories and D) cumulative average daily food intake over the 6-week study (n = 9–10 per genotype per diet). For A and C, a one-way ANOVA with a Tukey post hoc test was used at each time point for all between-group analyses. Groups not sharing a common letter at a given time point are significantly different (p<0.05). For B and D, a two-way ANOVA with a Bonferroni post hoc test was used for all between-group analyses (* p<0.05, *** p<0.001).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4219748&req=5

pone-0111418-g003: Body weight and food intake in WT and FGF21-KO mice fed AL or CR.A) Body weight trajectories and B) percent body weight change relative to initial body weight over the 6-week study. C) Daily food intake trajectories and D) cumulative average daily food intake over the 6-week study (n = 9–10 per genotype per diet). For A and C, a one-way ANOVA with a Tukey post hoc test was used at each time point for all between-group analyses. Groups not sharing a common letter at a given time point are significantly different (p<0.05). For B and D, a two-way ANOVA with a Bonferroni post hoc test was used for all between-group analyses (* p<0.05, *** p<0.001).
Mentions: Consistent with previous findings, FGF21-KO mice weighed significantly more than WT mice on an AL diet [35], [37], [39], [40]. Similarly, FGF21-KO mice weighed significantly more than WT mice on a CR diet (Figure 3A). There was no significant difference in the percentage of weight gain over the course of the study between the two AL groups (Figure 3B). FGF21-KO mice, however, lost a significantly greater percentage of their body weight on a CR diet than WT mice (Figure 3B). On a week-by-week basis, the food intake of FGF21-KO mice tended to be higher compared to WT mice on either an AL or CR diet (Figure 3C). The overall average daily food intake of FGF21-KO mice was significantly higher compared to WT mice on either an AL or CR diet (Figure 3D).

Bottom Line: Accordingly, elucidating the mechanism(s) by which IGF-1 is reduced in response to CR holds therapeutic potential in the fight against age-related diseases.We found that in response to moderate CR, circulating GH and hepatic janus kinase 2 (JAK2) phosphorylation levels are unchanged but that hepatic signal transducer and activator of transcription 5 (STAT5) phosphorylation levels are reduced, identifying STAT5 phosphorylation as a potential key site of CR action within the somatotropic axis.However, compared to AL-fed WT mice, AL-fed FGF21-knockout mice exhibited higher basal rates of cell proliferation, suggesting anti-mitotic effects of FGF21.

View Article: PubMed Central - PubMed

Affiliation: Department of Nutritional Science and Toxicology, University of California, Berkeley, California, United States of America.

ABSTRACT
Calorie restriction (CR) delays aging and extends lifespan in numerous organisms, including mice. Down-regulation of the somatotropic axis, including a reduction in insulin-like growth factor-1 (IGF-1), likely plays an important role in CR-induced lifespan extension, possibly by reducing cell proliferation rates, thereby delaying replicative senescence and inhibiting tumor promotion. Accordingly, elucidating the mechanism(s) by which IGF-1 is reduced in response to CR holds therapeutic potential in the fight against age-related diseases. Up-regulation of fibroblast growth factor 21 (FGF21) is one possible mechanism given that FGF21 expression is induced in response to nutritional deprivation and has been implicated as a negative regulator of IGF-1 expression. Here we investigated alterations in hepatic growth hormone (GH)-mediated IGF-1 production and signaling as well as the role of FGF21 in the regulation of IGF-1 levels and cell proliferation rates in response to moderate CR in adult mice. We found that in response to moderate CR, circulating GH and hepatic janus kinase 2 (JAK2) phosphorylation levels are unchanged but that hepatic signal transducer and activator of transcription 5 (STAT5) phosphorylation levels are reduced, identifying STAT5 phosphorylation as a potential key site of CR action within the somatotropic axis. Circadian measurements revealed that the relative level of FGF21 expression is both higher and lower in CR vs. ad libitum (AL)-fed mice, depending on the time of measurement. Employing FGF21-knockout mice, we determined that FGF21 is not required for the reduction in IGF-1 levels or cell proliferation rates in response to moderate CR. However, compared to AL-fed WT mice, AL-fed FGF21-knockout mice exhibited higher basal rates of cell proliferation, suggesting anti-mitotic effects of FGF21. This work provides insights into both GH-mediated IGF-1 production in the context of CR and the complex network that regulates FGF21 and IGF-1 expression and cell proliferation rates in response to nutritional status.

Show MeSH
Related in: MedlinePlus