title: Global loss of bmal1 expression alters adipose tissue hormones, gene expression and glucose metabolism.
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.
authors.affiliation: Robinson Institute, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: David John
authors.initials: DJ
authors.lastname: Kennaway
authors.forename: Tamara Jayne
authors.initials: TJ
authors.lastname: Varcoe
authors.forename: Athena
authors.initials: A
authors.lastname: Voultsios
authors.forename: Michael James
authors.initials: MJ
authors.lastname: Boden
mesh_terms: D056930:ARNTL Transcription Factors / Q000172:deficiency*; D054392:Adipokines / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D059305:Diet, High-Fat / Q000009:adverse effects; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006019:Glycolysis / Q000187:drug effects; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D019289:Pyruvic Acid / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D056930:ARNTL Transcription Factors; D054392:Adipokines; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D012333:RNA, Messenger; D019289:Pyruvic Acid; D005947:Glucose