Glial Endozepines Reverse High-Fat Diet-Induced Obesity by Enhancing Hypothalamic Response to Peripheral Leptin

Glial endozepines and energy balance: Old peptides with new tricks

“…The highest expression is observed in astrocytes from the hypothalamus and the cerebellum, where DBI/ACBP is among the 20 most‐transcribed genes. Interestingly, astrocytes and tanycytes expressing DBI/ACBP were visualized both in the mediobasal and mediodorsal hypothalamus and in the caudal brainstem (Compère et al, 2010; Guillebaud et al, 2017; Guillebaud et al, 2020; Lanfray et al, 2013).…”

“…In rodents, adrenalectomy, an experimental condition known to normalize diet‐induced obesity (Trocki, Baer, & Castonguay, 1995), upregulates DBI/ACBP mRNA expression within the hypothalamus (Nishida et al, 2006). Of note, DBI/ACBP mRNA levels within the ARC, the median eminence (EM), the ependymal layer of the third ventricle, the edge of the lateral ventricle and the NTS are reduced by acute fasting (24 hr) and restored by refeeding (Compère et al, 2010; Guillebaud et al, 2020; Lanfray et al, 2013). In 24‐hr‐food‐deprived mice, intraperitoneal (i.p.)…”

“…glucose injection (3.5 mg/rat) restores DBI/ACBP mRNA expression downregulated by overnight fasting, and an increase in glucose concentration in the culture medium stimulates ODN release from hypothalamic explants (Lanfray et al, 2013). However, reduced DBI/ACBP mRNA expression was observed in the hypothalamus and NTS of diet‐induced mice (Guillebaud et al, 2020). At the hypothalamic level, tanycytes that control the access of nutrients and metabolic hormones to the parenchyma (reviewed in Prevot et al (2018)) appear as a local source of endozepines.…”

“…I.c.v. injection of ODN and OP dose‐dependently reduced food intake in fasted and ad libitum fed rodents (Bouyakdan et al, 2015; de Mateos‐Verchere et al, 2001; do Rego et al, 2007; Guillebaud et al, 2017; Guillebaud et al, 2020; Lanfray et al, 2013), an effect that persists under systemic or i.c.v. pretreatment with the GABA A R‐BZ‐binding site null/silent allosteric modulator flumazenil or with the TSPO antagonist PK11195 and is mimicked by the selective ODN‐GPCR agonist cyclo 1‐8 OP.…”

“…Indeed, central administration of OP or cyclo 1‐8 OP does not induce anorexia when MC4Rs are pharmacologically blocked (Lanfray et al, 2013) or knocked out (Bouyakdan et al, 2015). Furthermore, patch‐clamp analyses revealed that bath application of OP (Guillebaud et al, 2020), ODN or cyclo 1‐8 OP (Bouyakdan et al, 2019) on hypothalamic slices activates POMC neurons, independent of the GABA A R‐BZ‐binding site, an effect blocked by the selective ODN‐GPCR antagonist cyclo 1‐8 [D‐Leu 5 ]OP (Bouyakdan et al, 2019). Unilateral intraparenchymal injection of OP confirms that the ARC is a target site for the endozepine‐induced anorexigenic effect (Lanfray et al, 2013).…”