A novel role of the corticotrophin‐releasing hormone regulating peptide, teneurin C‐terminal associated peptide 1, on glucose uptake into the brain

Abstract

Teneurin C-terminal associated peptide (TCAP) is an ancient paracrine signalling agent that evolved via lateral gene transfer from prokaryotes into an early metazoan ancestor. Although it bears structural similarity to corticotrophin-releasing hormone (CRH), it inhibits the in vivo actions of CRH. The TCAPs are highly expressed in neurones, where they induce rapid cytoskeletal rearrangement and are neuroprotective. Because these processes are highly energy-dependent, this suggests that TCAP has the potential to regulate glucose uptake because glucose is the primary energy substrate in brain, and neurones require a steady supply to meet the high metabolic demands of neuronal communication. Therefore, the objective of the present study was to assess the effect of TCAP-mediated glucose uptake in the brain and in neuronal cell models. TCAP-mediated F-deoxyglucose (FDG) uptake into brain tissue was assessed in male wild-type Wistar rats by functional positron emission tomography. TCAP-1 increased FDG uptake by over 40% into cortical regions of the brain, demonstrating that TCAP-1 can significantly enhance glucose supply. Importantly, a single nanomolar injection of TCAP-1 increased brain glucose after 3 days and decreased blood glucose after 1 week. This is corroborated by a decreased serum concentration of insulin and an increased serum concentration of glucagon. In immortalised hypothalamic neurones, TCAP-1 increased ATP production and enhanced glucose uptake by increasing glucose transporter recruitment to the plasma membrane likely via AKT and mitogen-activated protein kinase/ERK phosphorylation events. Taken together, these data demonstrate that TCAP-1 increases glucose metabolism in neurones, and may represent a peptide signalling agent that regulated glucose uptake before insulin and related peptides.

Information Processing in Affective Disorders: Did an Ancient Peptide Regulating Intercellular Metabolism Become Co‐Opted for Noxious Stress Sensing?

“…[ 105 ] In corroboration of these cellular actions, synthetic TCAP‐1 regulates anxious, depressive, and addictive behaviors in rats. [ 93,107–111 ] Moreover, modulation of mitochondrial activity by TCAP‐1 has been implicated in both in vitro [ 112 ] and in vivo [ 105 ] studies. Importantly, this peptide antagonizes the action of CRF in vivo and in vitro.…”

“…[ 102 ] Related to this, TCAP modulates cytoskeletal regulation in vitro and in vivo [ 103,104,106 ] and stimulates glucose transport independent of insulin in the CNS. [ 105 ] In corroboration of these cellular actions, synthetic TCAP‐1 regulates anxious, depressive, and addictive behaviors in rats. [ 93,107–111 ] Moreover, modulation of mitochondrial activity by TCAP‐1 has been implicated in both in vitro [ 112 ] and in vivo [ 105 ] studies.…”

“…[ 97–100 ] However, like the teneurins, the TCAP region shows affinity with the latrophilins. [ 100–102 ] Similarly, the action of the TCAP peptide, like other GPCR ligands, shows multiple signal transduction pathways including cAMP, [ 92,93,103 ] MEK‐ERK, [ 104 ] and IP 3 ‐DAG‐PKC‐Ca 2+ [ 105 ] as well as modulating adhesion. [ 102 ] Related to this, TCAP modulates cytoskeletal regulation in vitro and in vivo [ 103,104,106 ] and stimulates glucose transport independent of insulin in the CNS.…”

Teneurins and Teneurin C-Terminal Associated Peptide (TCAP) in Metabolism: What’s Known in Fish?

“…More recently, TCAP-1 was shown to exhibit metabolic effects in rats (Hogg et al, 2018), as TCAP-1 decreased blood glucose 40% in both Wistar rats and in the type II diabetic insulin-insensitive pathological model, Goto-Kakizaki rats (Hogg et al, 2018). Furthermore, TCAP-1 decreased insulin and increased serum glucagon levels, suggesting an effect on glucose metabolism systemically (Hogg et al, 2018).…”

“…More recently, TCAP-1 was shown to exhibit metabolic effects in rats (Hogg et al, 2018), as TCAP-1 decreased blood glucose 40% in both Wistar rats and in the type II diabetic insulin-insensitive pathological model, Goto-Kakizaki rats (Hogg et al, 2018). Furthermore, TCAP-1 decreased insulin and increased serum glucagon levels, suggesting an effect on glucose metabolism systemically (Hogg et al, 2018). Similarly, TCAP-1 increases glucose uptake, similar to, but independent of, insulin in mouse mHypoE-38 hypothalamic cells, in vitro , with an accompanied decrease in cytosolic calcium levels and increased plasma membrane expression of GLUT3, the primary glucose transporter for neurons (Hogg et al, 2018).…”