Metabolic homeostasis in mice with disrupted Clock gene expression in peripheral tissues.
The role of peripheral vs. central circadian rhythms and Clock in the maintenance of metabolic homeostasis and with aging was examined by using Clock(Delta19)+MEL mice. These have preserved suprachiasmatic nucleus and pineal gland rhythmicity but arrhythmic Clock gene expression in the liver and skeletal muscle. Clock(Delta19)+MEL mice showed fasting hypoglycemia in young-adult males, fasting hyperglycemia in older females, and substantially impaired glucose tolerance overall. Clock(Delta19)+MEL mice had substantially reduced plasma insulin and plasma insulin/glucose nocturnally in males and during a glucose tolerance test in females, suggesting impaired insulin secretion. Clock(Delta19)+MEL mice had reduced hepatic expression and loss of rhythmicity of gck, pfkfb3, and pepck mRNA, which is likely to impair glycolysis and gluconeogenesis. Clock(Delta19)+MEL mice also had reduced glut4 mRNA in skeletal muscle, and this may contribute to poor glucose tolerance. Whole body insulin tolerance was enhanced in Clock(Delta19)+MEL mice, however, suggesting enhanced insulin sensitivity. These responses occurred although the Clock(Delta19) mutation did not cause obesity and reduced plasma free fatty acids while increasing plasma adiponectin. These studies on clock-gene disruption in peripheral tissues and metabolic homeostasis provide compelling evidence of a relationship between circadian rhythms and the glucose/insulin and adipoinsular axes. It is, however, premature to declare that clock-gene disruption causes the full metabolic syndrome.
Research Centre for Reproductive Health, Discipline of Obstetrics and Gynaecology, School of Paediatrics and Reproductive Health, Univ. of Adelaide, Medical School, Frome Road, Adelaide, South Australia, 5005. david.kennaway@adelaide.edu.au
David J
DJ
Kennaway
Julie A
JA
Owens
Athena
A
Voultsios
Michael J
MJ
Boden
Tamara J
TJ
Varcoe
D000818:Animals; D001786:Blood Glucose; D056926:CLOCK Proteins; D004734:Energy Metabolism / Q000235:genetics* / Q000502:physiology; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D005786:Gene Expression Regulation; D005951:Glucose Tolerance Test; D006706:Homeostasis / Q000235:genetics* / Q000502:physiology; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012727:Sex Characteristics; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics*
D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D012333:RNA, Messenger; D015534:Trans-Activators; D056926:CLOCK Proteins; C538944:Clock protein, mouse