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Global loss of bmal1 expression alters adipose tissue hormones, gene expression and glucose metabolism.

Kennaway DJ, Varcoe TJ, Voultsios A, Boden MJ - PLoS ONE (2013)

Bottom Line: The close relationship between circadian rhythm disruption and poor metabolic status is becoming increasingly evident, but role of adipokines is poorly understood.Furthermore, the expression of epigonadal fat Adipoq, Retn, Nampt, AdipoR1 and AdipoR2 and liver Pfkfb3 mRNA were down-regulated.These results show for the first time that global loss of Bmal1, and the consequent arrhythmicity, results in compensatory changes in adipokines involved in the cellular control of glucose metabolism.

View Article: PubMed Central - PubMed

Affiliation: Robinson Institute, University of Adelaide, Adelaide, South Australia, Australia.

ABSTRACT
The close relationship between circadian rhythm disruption and poor metabolic status is becoming increasingly evident, but role of adipokines is poorly understood. Here we investigated adipocyte function and the metabolic status of mice with a global loss of the core clock gene Bmal1 fed either a normal or a high fat diet (22% by weight). Bmal1 mice aged 2 months were killed across 24 hours and plasma adiponectin and leptin, and adipose tissue expression of Adipoq, Lep, Retn and Nampt mRNA measured. Glucose, insulin and pyruvate tolerance tests were conducted and the expression of liver glycolytic and gluconeogenic enzyme mRNA determined. Bmal1 mice displayed a pattern of increased plasma adiponectin and plasma leptin concentrations on both control and high fat diets. Bmal1 male and female mice displayed increased adiposity (1.8 fold and 2.3 fold respectively) on the normal diet, but the high fat diet did not exaggerate these differences. Despite normal glucose and insulin tolerance, Bmal1 mice had increased production of glucose from pyruvate, implying increased liver gluconeogenesis. The Bmal1 mice had arrhythmic clock gene expression in epigonadal fat and liver, and loss of rhythmic transcription of a range of metabolic genes. Furthermore, the expression of epigonadal fat Adipoq, Retn, Nampt, AdipoR1 and AdipoR2 and liver Pfkfb3 mRNA were down-regulated. These results show for the first time that global loss of Bmal1, and the consequent arrhythmicity, results in compensatory changes in adipokines involved in the cellular control of glucose metabolism.

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The relative gene expression across 24 h of clock and liver enzyme genes in the liver of male wild-type and Bmal1  mice fed a normal rodent diet.(a) Bmal1, (b) Per2, (c) Pfkfb3, (d) Pck, (e) Fbp1, (f) G6pc, (g) Gck and (h) Adipor2. The data are the relative expression for each gene compared to Actin mRNA (mean ± s.e.m., n = 4 for each genotype), wild-type mice (open circles) and Bmal1  mice (closed circles). The highest expression of each gene for wild-type mice was set at one. The apparent absence of an SEM bar indicates that it is obscured by the symbol. The shaded areas represent the period of darkness.
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pone-0065255-g006: The relative gene expression across 24 h of clock and liver enzyme genes in the liver of male wild-type and Bmal1 mice fed a normal rodent diet.(a) Bmal1, (b) Per2, (c) Pfkfb3, (d) Pck, (e) Fbp1, (f) G6pc, (g) Gck and (h) Adipor2. The data are the relative expression for each gene compared to Actin mRNA (mean ± s.e.m., n = 4 for each genotype), wild-type mice (open circles) and Bmal1 mice (closed circles). The highest expression of each gene for wild-type mice was set at one. The apparent absence of an SEM bar indicates that it is obscured by the symbol. The shaded areas represent the period of darkness.

Mentions: In the liver overall Per2, Pck1 (phosphoenolpyruvate carboxykinase 1), Fbp1 (fructose-1,6-bisphosphatase 1), G6pc (glucose-6-phosphatase ), Gck (glucokinase) and Adipor2 mRNA expression did not vary with genotype, whereas Pfkfb3 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3) mRNA was decreased by 25% in male Bmal1 mice compared to wild type mice (Fig. 6; P<0.05). Bmal1, Per2, Pfkfb3, Pck1, Fbp1 and Gck mRNA was expressed rhythmically in the wild type mice (P<0.05), whereas G6pc and Adipor2 mRNA expression was arrhythmic. Expression of all genes analysed in male Bmal1 mice was arrhythmic.


Global loss of bmal1 expression alters adipose tissue hormones, gene expression and glucose metabolism.

Kennaway DJ, Varcoe TJ, Voultsios A, Boden MJ - PLoS ONE (2013)

The relative gene expression across 24 h of clock and liver enzyme genes in the liver of male wild-type and Bmal1  mice fed a normal rodent diet.(a) Bmal1, (b) Per2, (c) Pfkfb3, (d) Pck, (e) Fbp1, (f) G6pc, (g) Gck and (h) Adipor2. The data are the relative expression for each gene compared to Actin mRNA (mean ± s.e.m., n = 4 for each genotype), wild-type mice (open circles) and Bmal1  mice (closed circles). The highest expression of each gene for wild-type mice was set at one. The apparent absence of an SEM bar indicates that it is obscured by the symbol. The shaded areas represent the period of darkness.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3672145&req=5

pone-0065255-g006: The relative gene expression across 24 h of clock and liver enzyme genes in the liver of male wild-type and Bmal1 mice fed a normal rodent diet.(a) Bmal1, (b) Per2, (c) Pfkfb3, (d) Pck, (e) Fbp1, (f) G6pc, (g) Gck and (h) Adipor2. The data are the relative expression for each gene compared to Actin mRNA (mean ± s.e.m., n = 4 for each genotype), wild-type mice (open circles) and Bmal1 mice (closed circles). The highest expression of each gene for wild-type mice was set at one. The apparent absence of an SEM bar indicates that it is obscured by the symbol. The shaded areas represent the period of darkness.
Mentions: In the liver overall Per2, Pck1 (phosphoenolpyruvate carboxykinase 1), Fbp1 (fructose-1,6-bisphosphatase 1), G6pc (glucose-6-phosphatase ), Gck (glucokinase) and Adipor2 mRNA expression did not vary with genotype, whereas Pfkfb3 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3) mRNA was decreased by 25% in male Bmal1 mice compared to wild type mice (Fig. 6; P<0.05). Bmal1, Per2, Pfkfb3, Pck1, Fbp1 and Gck mRNA was expressed rhythmically in the wild type mice (P<0.05), whereas G6pc and Adipor2 mRNA expression was arrhythmic. Expression of all genes analysed in male Bmal1 mice was arrhythmic.

Bottom Line: The close relationship between circadian rhythm disruption and poor metabolic status is becoming increasingly evident, but role of adipokines is poorly understood.Furthermore, the expression of epigonadal fat Adipoq, Retn, Nampt, AdipoR1 and AdipoR2 and liver Pfkfb3 mRNA were down-regulated.These results show for the first time that global loss of Bmal1, and the consequent arrhythmicity, results in compensatory changes in adipokines involved in the cellular control of glucose metabolism.

View Article: PubMed Central - PubMed

Affiliation: Robinson Institute, University of Adelaide, Adelaide, South Australia, Australia.

ABSTRACT
The close relationship between circadian rhythm disruption and poor metabolic status is becoming increasingly evident, but role of adipokines is poorly understood. Here we investigated adipocyte function and the metabolic status of mice with a global loss of the core clock gene Bmal1 fed either a normal or a high fat diet (22% by weight). Bmal1 mice aged 2 months were killed across 24 hours and plasma adiponectin and leptin, and adipose tissue expression of Adipoq, Lep, Retn and Nampt mRNA measured. Glucose, insulin and pyruvate tolerance tests were conducted and the expression of liver glycolytic and gluconeogenic enzyme mRNA determined. Bmal1 mice displayed a pattern of increased plasma adiponectin and plasma leptin concentrations on both control and high fat diets. Bmal1 male and female mice displayed increased adiposity (1.8 fold and 2.3 fold respectively) on the normal diet, but the high fat diet did not exaggerate these differences. Despite normal glucose and insulin tolerance, Bmal1 mice had increased production of glucose from pyruvate, implying increased liver gluconeogenesis. The Bmal1 mice had arrhythmic clock gene expression in epigonadal fat and liver, and loss of rhythmic transcription of a range of metabolic genes. Furthermore, the expression of epigonadal fat Adipoq, Retn, Nampt, AdipoR1 and AdipoR2 and liver Pfkfb3 mRNA were down-regulated. These results show for the first time that global loss of Bmal1, and the consequent arrhythmicity, results in compensatory changes in adipokines involved in the cellular control of glucose metabolism.

Show MeSH
Related in: MedlinePlus