Abstract
Glucose provides vital energy for cells and contributes to gene expression. The hypothalamus is key for metabolic homeostasis, but effects of glucose on hypothalamic gene expression have not yet been investigated in detail. Thus, herein, we monitored the glucose-dependent transcriptome in murine hypothalamic mHypoA-2/10 cells by total RNA-seq analysis. A total of 831 genes were up- and 1390 genes were downregulated by at least 50%. Key genes involved in the cholesterol biosynthesis pathway were upregulated, and total cellular cholesterol levels were significantly increased by glucose. Analysis of single genes involved in fundamental cellular signaling processes also suggested a significant impact of glucose. Thus, we chose ≈100 genes involved in signaling and validated the effects of glucose on mRNA levels by qRT-PCR. We identified Gnai1–3, Adyc6, Irs1, Igfr1, Hras, and Elk3 as new glucose-dependent genes. In line with this, cAMP measurements revealed enhanced noradrenalin-induced cAMP levels, and reporter gene assays elevated activity of the insulin-like growth factor at higher glucose levels. Key data of our studies were confirmed in a second hypothalamic cell line. Thus, our findings link extra cellular glucose levels with hypothalamic lipid synthesis and pivotal intracellular signaling processes, which might be of particular interest in situations of continuously increased glucose levels.
Highlights
Glucose is a universal source of energy and a key player in diabetes and obesity. plasma glucose levels are kept rather constant at 5.50 mM after fasting, they can reach up to mM after food intake, vary during the day and increasing after fasting even to mM in diabetic patients [1,2,3,4]
Pyruvate (1 mM) was constantly present to ensure equal mitochondrial ATP levels. This protocol led to enhanced activity of a CREB/CRTC2-dependent reporter gene but did not affect activity of signal transducers and activators of transcription or of nuclear factors-activated in T cells [37]
We found that mRNA levels of succinate dehydrogenase (Sdha) and TATA-box-binding protein (Tbp) were glucoseindependent (Figure S1A)
Summary
Glucose is a universal source of energy and a key player in diabetes and obesity. plasma glucose levels are kept rather constant at 5.50 mM after fasting, they can reach up to mM after food intake, vary during the day and increasing after fasting even to mM in diabetic patients [1,2,3,4]. The brain is exposed to dynamic changes of extracellular glucose concentrations after food uptake and confronted with increased glucose levels in diabetic patients [1,7,8,9,10,11,12]. Drugs such as heroin induce rapid and significant spikes in brain glucose levels [13], further highlighting the dynamics of brain glucose levels. Effects of altered extracellular glucose levels on signaling induced by both hormones in hypothalamic cells have not been systematically investigated far
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