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 null 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 null mice displayed a pattern of increased plasma adiponectin and plasma leptin concentrations on both control and high fat diets. Bmal1 null 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 null mice had increased production of glucose from pyruvate, implying increased liver gluconeogenesis. The Bmal1 null 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.
Highlights
The links between circadian rhythms of gene expression, hormone secretion and metabolism have emerged over recent years
Across 24 hours, plasma insulin was lower and adiponectin and leptin were both higher in 2 month old male Bmal1 null mice compared to wild-type mice while plasma glucose and free fatty acids were unchanged
In this study we show for the first time that global disruption of gene rhythmicity in both male and female Bmal1 null mice alters plasma levels of adiponectin and leptin and adipokine gene expression (Adipoq, Nampt and Retn mRNA)
Summary
The links between circadian rhythms of gene expression, hormone secretion and metabolism have emerged over recent years. The ClockD19 mutants produce a protein that can bind to BMAL1, but not induce gene expression, resulting in a loss of rhythmic gene expression in peripheral tissues, but not the SCN [12]. This mutation has been shown to be associated with obesity [10], hyperinsulinaemia [10], decreased glucose tolerance [7,11], increased insulin sensitivity [7,11], hyper-lipidaemia, and decreased plasma free fatty acids [7]. Bmal null mice are infertile [18,19] and as they age, develop a range of physiological deficits including arthropathy [20] and altered cardiovascular function [21]
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