Glut2‐dependent glucose‐sensing controls thermoregulation by enhancing the leptin sensitivity of NPY and POMC neurons

Abstract

The physiological contribution of glucose in thermoregulation is not completely established nor whether this control may involve a regulation of the melanocortin pathway. Here, we assessed thermoregulation and leptin sensitivity of hypothalamic arcuate neurons in mice with inactivation of glucose transporter type 2 (Glut2)-dependent glucose sensing. Mice with inactivation of Glut2-dependent glucose sensors are cold intolerant and show increased susceptibility to food deprivation-induced torpor and abnormal hypothermic response to intracerebroventricular administration of 2-deoxy-d-glucose compared to control mice. This is associated with a defect in regulated expression of brown adipose tissue uncoupling protein I and iodothyronine deiodinase II and with a decreased leptin sensitivity of neuropeptide Y (NPY) and proopiomelanocortin (POMC) neurons, as observed during the unfed-to-refed transition or following i.p. leptin injection. Sites of central Glut-2 expression were identified by a genetic tagging approach and revealed that glucose-sensitive neurons were present in the lateral hypothalamus, the dorsal vagal complex, and the basal medulla but not in the arcuate nucleus. NPY and POMC neurons were, however, connected to nerve terminals from Glut2-expressing neurons. Thus, our data suggest that glucose controls thermoregulation and the leptin sensitivity of NPY and POMC neurons through activation of Glut2-dependent glucose-sensing neurons located outside of the arcuate nucleus.

GLUT2, glucose sensing and glucose homeostasis

“…Our studies on NTS Glut2-expressing neurons have shown that these are indeed activated by hypoglycaemia to control parasympathetic activity and glucagon secretion [75]. On the other hand, Glut2-expressing neurons of the basolateral medulla are activated by glucose injections as revealed by c-fos immunostaining [63]. Whether they are GE neurons that negatively control glucagon secretion will, however, require direct analysis using electrophysiological and optogenetic techniques.…”

“…This was shown by the much lower hypothermic response induced by i.c.v. 2-DG injections in RIPGlut1;Glut2 −/− as compared with control mice [63]. This was secondary to reduced activation of brown fat uncoupling protein 1 and deiodinase-2 expression by the sympathetic nervous system and was associated with fastinginduced torpor in the Glut2-null mice.…”

“…In rats, a careful immunohistochemical mapping of GLUT2 expression at the light and electron microscopy levels revealed its presence in most brain structures, and expression was found in neurons, astrocytes, endothelial cells and tanycytes, which are specialised astrocytes lining the lower part of the third ventricle [60][61][62]. In mice, using a genetic reporter system in which a fluorescent protein is expressed under the control of the Glut2 promoter (Glut2-Cre transgenic mice crossed with Rosa26tdTomato mice), the distribution of GLUT2 expressing cells in the brain was found to be very similar to that of the rat [63].…”

Glial hypothalamic inhibition of GLUT2 expression alters satiety, impacting eating behavior

“…However, those that exist have been corroborated by the use of mice expressing a fluorescent reporter gene (eYFP) under the control of the GLUT2 promoter, GLUT2‐eYFP mice (Mounien et al, 2010). GLUT2 was found in neurons and astrocytes dispersed in many structures, including the hypothalamus, the brain stem, the thalamic area (Arluison, Quignon, Thorens, Leloup, & Penicaud, 2004; Labouebe, Boutrel, Tarussio, & Thorens, 2016) and in tanycytes (Garcia et al, 2003).…”

“…Furthermore, GLUT2‐positive α2‐ and β1‐tanycytes are located in the lateral walls of the 3V and make contact with orexigenic AN neurons, which produce neuropeptide Y (NPY) and agouti‐related protein (AGRP), and anorexigenic AN neurons, which produce proopiomelanocortin (POMC) and the cocaine‐amphetamine‐regulated transcript (CART), through their extensive processes (Broberger, Johansen, Johansson, Schalling, & Hokfelt, 1998; Elias et al, 1998; Kristensen et al, 1998). Interestingly, GLUT2‐eYFP mice showed the absence of labeling in POMC or NPY neurons (Mounien et al, 2010); however, these mice showed labeled nerve terminals, presumably from GLUT2‐expressing cells, which have their soma outside the AN, suggesting an indirect control of AN neurons by glucose (Mounien et al, 2010; Thorens, 2005). Recently, GLUT2 was also detected in neurons of the nucleus tractus solitarius (NTS), specifically in a hypoglycemia‐activated neuronal population, which stimulates vagal activity and glucagon secretion, indicating a role for GLUT2 in the hypoglycemic condition (Lamy et al, 2014).…”