title: Effect of peripheral circadian dysfunction on metabolic disease in response to a diabetogenic diet.
abstract: BMAL1 is a core component of the transcription/translation machinery that regulates central and peripheral circadian rhythms that coordinate behavior and metabolism, respectively. Our objective was to determine the impact of BMAL1 in adipose alone or in combination with liver on metabolic phenotypes. Control, adipose-Bmal1 knockout (ABKO), and liver- and adipose-Bmal1 knockout (LABKO) female mice were placed in TSE System metabolic chambers for metabolic phenotyping. A second cohort of male mice was fed a control or diabetogenic diet, and body weight and composition, glucose tolerance, insulin sensitivity, and serum and hepatic lipids were measured. Both female ABKO and LABKO mice exhibited increased food consumption compared with control mice. ABKO mice also exhibited increased overall activity predominantly during the light phase compared with both control and LABKO mice and were protected from increased weight gain. When the male cohort was challenged with a diabetogenic diet, LABKO mice had increased body weight due to increased fat mass compared with control and ABKO mice. However, these mice did not present further impairments in glycemic control, adipose inflammation, or liver injury. LABKO mice had increased hepatic cholesterol and elevated expression of cholesterol synthesis and uptake genes. Our data indicate that deletion of this allele in adipose or in combination with liver alters feeding behavior and locomotor activity. However, obesity is exacerbated only with the combination of liver and adipose deletion.
authors.affiliation: Department of Pharmaceutical Sciences.
authors.forename: Sonja S
authors.initials: SS
authors.lastname: Pijut
authors.affiliation: Department of Pharmaceutical Sciences.
authors.forename: Danielle E
authors.initials: DE
authors.lastname: Corbett
authors.affiliation: Department of Pharmaceutical Sciences.
authors.forename: Yuhuan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Nutritional Sciences.
authors.forename: Jianing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Biostatistics.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Charnigo
authors.affiliation: Department of Pharmaceutical Sciences, Barnstable Brown Kentucky Diabetes and Obesity Center, and Graduate Center for Nutritional Sciences, University of Kentucky, Lexington, Kentucky Gregory.Graf@uky.edu.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Graf
mesh_terms: D056930:ARNTL Transcription Factors / Q000378:metabolism*; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D021081:Chronobiology Disorders / Q000209:etiology* / Q000378:metabolism*; D002940:Circadian Rhythm; D003921:Diabetes Mellitus, Experimental / Q000209:etiology / Q000378:metabolism; D004032:Diet / Q000009:adverse effects; D005260:Female; D008099:Liver / Q000378:metabolism*; D008297:Male; D008659:Metabolic Diseases / Q000209:etiology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic
chemical_list: D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse
keywords: brain and muscle arnt-like protein-1; cholesterol; circadian; insulin resistance; obesity