Glucose Enhances Basal or Melanocortin-Induced cAMP-Response Element Activity in Hypothalamic Cells

Abstract

Melanocyte-stimulating hormone (MSH)-induced activation of the cAMP-response element (CRE) via the CRE-binding protein in hypothalamic cells promotes expression of TRH and thereby restricts food intake and increases energy expenditure. Glucose also induces central anorexigenic effects by acting on hypothalamic neurons, but the underlying mechanisms are not completely understood. It has been proposed that glucose activates the CRE-binding protein-regulated transcriptional coactivator 2 (CRTC-2) in hypothalamic neurons by inhibition of AMP-activated protein kinases (AMPKs), but whether glucose directly affects hypothalamic CRE activity has not yet been shown. Hence, we dissected effects of glucose on basal and MSH-induced CRE activation in terms of kinetics, affinity, and desensitization in murine, hypothalamic mHypoA-2/10-CRE cells that stably express a CRE-dependent reporter gene construct. Physiologically relevant increases in extracellular glucose enhanced basal or MSH-induced CRE-dependent gene transcription, whereas prolonged elevated glucose concentrations reduced the sensitivity of mHypoA-2/10-CRE cells towards glucose. Glucose also induced CRCT-2 translocation into the nucleus and the AMPK activator metformin decreased basal and glucose-induced CRE activity, suggesting a role for AMPK/CRTC-2 in glucose-induced CRE activation. Accordingly, small interfering RNA-induced down-regulation of CRTC-2 expression decreased glucose-induced CRE-dependent reporter activation. Of note, glucose also induced expression of TRH, suggesting that glucose might affect the hypothalamic-pituitary-thyroid axis via the regulation of hypothalamic CRE activity. These findings significantly advance our knowledge about the impact of glucose on hypothalamic signaling and suggest that TRH release might account for the central anorexigenic effects of glucose and could represent a new molecular link between hyperglycaemia and thyroid dysfunction.

Deregulation of CRTCs in Aging and Age-Related Disease Risk

“…White Adipose Tissue Insulin Resistance [52] Lung Unknown [12] Liver Regulation of lipogenesis [21] Gluconeogenesis [13,29,31] Muscle Mitochondrial biogenesis [12] Immune System Macrophage M1 to M2 interconversion (promotes insulin sensitivity) [45] T helper (Th)17 cells differentiation [46] Brain Hypothalamic glucose sensing [62,63] Pancreas (Beta cells) Insulin secretion [25,54,55] CRTC3…”

Deregulation of CRTCs in Aging and Age-Related Disease Risk

“…By immunolocalization, mammalian CRTC2 is detected both in nuclei and cytosol of brain tissues. CRTC2 nuclear expression is present in hippocampus, trigeminal and hypoglossal [62], and its cytoplasmic expression has been detected specifically in lateral hypothalamic area of dissected tissues [62], but also in hypothalamic cell cultures [62,63]. Therefore CRTC2 likely has cell-type specific functions in brain that depend upon its subcellular localization.…”

“…Hypothalamic CRTC2 phosphorylation reflects nutrient state, being dephosphorylated in fed mice, phosphorylated after fasting and dephosphorylated after glucose [62]. Coupled with this, CRTC2 translocates into hypothalamic cell nuclei during exposure to high glucose [63]. CREB expression is also increased after glucose treatment [63].…”

“…Coupled with this, CRTC2 translocates into hypothalamic cell nuclei during exposure to high glucose [63]. CREB expression is also increased after glucose treatment [63]. In addition, expression of CREB target genes, such as insulin receptor substrate 2 (Irs2) and thyrotropin releasing hormone (TRH), require activation of CRTC2, via inhibition of AMPK in hypothalamic cells [62,63].…”

“…CREB expression is also increased after glucose treatment [63]. In addition, expression of CREB target genes, such as insulin receptor substrate 2 (Irs2) and thyrotropin releasing hormone (TRH), require activation of CRTC2, via inhibition of AMPK in hypothalamic cells [62,63]. These data demonstrate that the AMPK/CRTC2/CREB axis is conserved in the mammalian central nervous system.…”