Starvation-induced regulation of carbohydrate transport at the blood-brain barrier is TGF-β-signaling dependent

Abstract

During hunger or malnutrition animals prioritize alimentation of the brain over other organs to ensure its function and thus their survival. This so-called brain sparing is described from Drosophila to humans. However, little is known about the molecular mechanisms adapting carbohydrate transport. Here, we used Drosophila genetics to unravel the mechanisms operating at the blood-brain barrier (BBB) under nutrient restriction. During starvation, expression of the carbohydrate transporter Tret1-1 is increased to provide more efficient carbohydrate uptake. Two mechanisms are responsible for this increase. Similarly to the regulation of mammalian GLUT4, Rab-dependent intracellular shuttling is needed for Tret1-1 integration into the plasma membrane, even though Tret1-1 regulation is independent of insulin signaling. In addition, starvation induces transcriptional upregulation controlled by TGF-β signaling. Considering TGF-β-dependent regulation of the glucose transporter GLUT1 in murine chondrocytes, our study reveals an evolutionarily conserved regulatory paradigm adapting the expression of sugar transporters at the BBB.

Plasticity of Carbohydrate Transport at the Blood-Brain Barrier

“…That BBB transport defects can regulate systemic metabolism is a very interesting finding that will foster exciting follow up studies to unravel the regulatory mechanisms. It has been shown previously that Tret1-1 is upregulated upon starvation-induced hypoglycemia (Hertenstein et al, 2020). Together with the data reported here, this suggests that any alteration that leads to insufficient carbohydrate uptake results in compensatory upregulation of transport proteins, most likely to ensure sufficient energy provision to the nervous system.…”

“…Together with the data reported here, this suggests that any alteration that leads to insufficient carbohydrate uptake results in compensatory upregulation of transport proteins, most likely to ensure sufficient energy provision to the nervous system. In the case of starvation, Tret1-1 is upregulated via TGF-β signaling (Hertenstein et al, 2020). Since this signaling seems to be induced by hypoglycemia, it is very unlikely that TGFβ signaling is also regulating compensatory upregulation in the case of transporter loss (Hertenstein et al, 2020).…”

“…In the case of starvation, Tret1-1 is upregulated via TGF-β signaling (Hertenstein et al, 2020). Since this signaling seems to be induced by hypoglycemia, it is very unlikely that TGFβ signaling is also regulating compensatory upregulation in the case of transporter loss (Hertenstein et al, 2020). Mammalian GLUT1 and SGLT1 and 2 have also been shown to be dynamically upregulated upon hypoglycemia or other insults like oxygen and glucose deprivation as a result of ischemia (Boado and Pardridge, 1993;Kumagai et al, 1995;Nishizaki et al, 1995;Nishizaki and Matsuoka, 1998;Simpson et al, 1999, reviewed in Elfeber et al, 2004Enerson and Drewes, 2006;Vemula et al, 2009;Yu et al, 2013;Patching, 2016;Rehni and Dave, 2018).…”

“…The only other carbohydrate transporter known to be expressed in the Drosophila BBB, besides Pippin and MFS3, is Tret1-1 (Volkenhoff et al, 2015). As Pippin and MFS3, Tret1-1 facilitates uptake of glucose and trehalose when heterologously expressed in Xenopus oocytes (Kanamori et al, 2010;Hertenstein et al, 2020). To assess if Tret1-1 could compensate for the loss of either Pippin or MFS3 in the null mutants, we stained null mutant L3 brains for Tret1-1 expression in the perineurial glial cells.…”

“…Furthermore, the trehalose transporter 1-1 (Tret1-1) is expressed specifically in the perineurial glial cells of the Drosophila BBB (Volkenhoff et al, 2015). Tret1-1 is homologous to mammalian GLUT6 and GLUT8 and has been shown to transport trehalose and glucose (Kanamori et al, 2010;Hertenstein et al, 2020). How carbohydrates are taken up into the subperineurial glial cells of the BBB and the other neural cells in the Drosophila nervous system is currently unknown.…”