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.

Obesity and regulation of human placental lactogen production in pregnancy

“…Disruption of the Pit-1 complex and chromosomal loop, including through a high fat vs regular chow diet in partially humanised 171 hGH/CS transgenic mice, has a negative effect on hGH-N/GH1 expression. 67,70,71 To date, no placenta-specific factor, equivalent to pituitary-specific Pit-1 and capable of binding hPL LCR and gene promoter sequences, has been identified. However, the zinc finger DNA-binding transcription factor paternally-expressed gene 3 (PEG3/PW1), the imprinted gene product of the paternal allele, has emerged as a potential candidate.…”

Sleep deprivation and diet affect human GH gene expression in transgenic mice in vivo

“…Significant reductions in Per2 transcript levels were also seen in HFD mice after acute SD in the dark/active phase (43.8%, p=0.0106) and light/inactive phase (54.4%, p=0.0420) of the daily cycle (Figure 3). GH synthesis and secretion also follow a circadian and diurnal rhythm, and levels are known to be affected by diet (6,13). A significant decrease in relative RNA levels of hGH-N but not mGh transcript levels was observed during the dark/active phase (ZT 14 + 20; 74.6%, p=0.0284, n=9,10) in 171hGH/CS TG mice fed a HFD versus RCD.…”

Trans-omics approaches used to characterise fish nutritional biorhythms in leopard coral grouper (Plectropomus leopardus)

“…CLOCK-interacting pacemaker ( cipc ) was also found to exhibit 24-h rhythms. Since circadian rhythm is known to involve growth hormone expression 20 , we examined the expression pattern of growth hormone-related genes. The growth hormone receptor ( ghr ) a and b showed circadian patterns.…”