Dexamethasone Rescues an Acute High-Fat Diet-Induced Decrease in Human Growth Hormone Gene Expression in Male Partially Humanized CD-1 Mice.

Abstract

Obesity in puberty, already a time of insulin resistance, increases the risk of developing type 2 diabetes. Human (h) growth hormone (GH) levels also peak during puberty, where it contributes to growth and energy homeostasis through positive effects on maintaining pancreatic β cell mass. Thus, it is important to understand the effects of overeating and obesity on hGH production in puberty. Three days of overeating in young male adults or high-fat diet (HFD) in pubescent male transgenic (171hGH/CS) CD-1 mice containing the hGH gene (hGH-N) results in excess insulin and a decrease in hGH production. This reduction in these mice occurred during the light phase of the daily cycle, and was associated with decreased availability of the clock-related transcription factor Brain and Muscle ARNT-Like 1 (Bmal1). However, the HFD-induced decrease in hGH-N expression was blocked by forced daily swim activity, which is expected to increase glucocorticoid (GC) levels. The aim of the study was to assess whether GCs, specifically daily injections with a pharmacological dose of dexamethasone (DEX) in the light or dark phase of the daily cycle, can limit the negative effect of HFD for 3 days on hGH-N expression in male 171hGH/CS mice. DEX treatment increased or rescued hGH-N RNA levels, and was associated with elevated Bmal1 transcripts when assessed 12 h after final treatment, and at a time when serum corticosterone levels were suppressed >90%. In addition, a diet-dependent effect on hGH-N RNA levels was observed at 36 h after final treatment, but only in the light stage, presumably due to residual effects of DEX treatment and/or recovery of endogenous corticosterone levels. This is the first evidence for a direct effect of GCs on hGH-N expression in vivo and the ability to potentially limit the negative effect of overeating/obesity on hGH production in puberty.