title: Evidence for a Circadian Effect on the Reduction of Human Growth Hormone Gene Expression in Response to Excess Caloric Intake.
abstract: Rhythmicity of biological functions is fundamental for optimal adaptations to environmental cues. Growth hormone (GH) is a major metabolic homeostatic factor that is secreted with a circadian pattern, but whether it is synthesized rhythmically is unknown. We used transgenic mice containing the human (h) GH gene (hGH1) locus to investigate the rhythmicity of hGH synthesis and secretion and to show that RNA and secreted protein levels oscillate over a 24-h cycle. Analysis of hGH1 promoter sequences revealed an enhancer motif (E-box) element that binds the circadian transcriptional machinery (Bmal1 and Clock). Furthermore, Bmal1/Clock were able to transactivate the hGH1 promoter, and mutation of this E-box element adversely affected basal activity after gene transfer. The ability of Bmal1 to bind the hGH1 promoter region containing the E-box element was confirmed in the hGH1 transgenic mouse pituitary in situ Occupancy was reduced in mice fed a high fat diet during the light (inactive) stage of the daily cycle in mice and corresponded to a decrease in hGH1 RNA levels. The decreases in occupancy and RNA levels were not seen, however, during the dark (active) stage. A chromatin loop required for efficient postnatal hGH1 expression was negatively affected by the high fat diet in the light but not dark stage similar to the pattern observed with Bmal1 association with the promoter region. This is the first evidence that hGH synthesis follows a diurnal rhythm and of dynamic associations of the circadian machinery with a component of a chromosomal structure of the hGH1 locus that is essential for efficient expression.
authors.affiliation: From the Departments of Internal Medicine and.
authors.forename: Hana
authors.initials: H
authors.lastname: Vakili
authors.affiliation: Physiology & Pathophysiology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba R3E 0J9, Canada.
authors.forename: Yan
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Physiology & Pathophysiology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba R3E 0J9, Canada peter.cattini@umanitoba.ca.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Cattini
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism; D002940:Circadian Rhythm; D002149:Energy Intake; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D019382:Human Growth Hormone / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010902:Pituitary Gland / Q000378:metabolism*; D011401:Promoter Regions, Genetic
chemical_list: D056930:ARNTL Transcription Factors; C538960:BMAL1 protein, human; C538961:Bmal1 protein, mouse; D019382:Human Growth Hormone; D056926:CLOCK Proteins; C538943:CLOCK protein, human; C538944:Clock protein, mouse
keywords: Chromosomal conformation; circadian rhythm; excess caloric intake; gene transcription; growth hormone; pituitary gland; transgenic mice