Biology subjects

Gereben, B.

Publications and source records attributed to Gereben, B..

4 recordsLinked to original sources

bioRxiv2026

Brain-wide mapping of proglucagon expression in mice identifies fasting-responsive GLP-1 neurons in the posterior hypothalamic nucleus

ObjectiveGlucagon-like peptide-1 (GLP-1), a peptide neurotransmitter in the brain, is synthesized from proglucagon, encoded by the glucagon gene (Gcg). Besides medullary GLP-1 neurons, Gcg-expressing neuron populations were identified in the olfactory bulb and basolateral amygdala. However, several lines of evidence suggest that additional Gcg neuron populations might exist. MethodsWe conducted a brain-wide mapping of Gcg-expressing cells by fluorescent in situ hybridization in C57BL/6J and FVB/Ant mice. Proglucagon and GLP-1 expression were studied with immunofluorescence. We characterized a Gcg-Cre;tdTomato mouse line and studied the expression of proglucagon-processing enzymes in Gcg-expressing neuron populations. We used adeno-associated virus-mediated tracing in Gcg-Cre mice to map the projections of hypothalamic Gcg neurons. ResultsGcg-expressing neuron populations were identified in the olfactory bulb, claustrum, piriform cortex, basolateral amygdala, posterior hippocampus, posterior hypothalamic nucleus (PH), periaqueductal gray/dorsal raphe, and dorsal nucleus of the lateral lemniscus. These neurons express lower Gcg mRNA levels than medullary GLP-1 neurons. Proglucagon and GLP-1-immunoreactivity (C-terminus) were detected in almost all Gcg-expressing neuron populations, along with the mRNAs for prohormone convertases 1/3 and 2, enzymes generating GLP-1 or glucagon, respectively. Fasting markedly increased Gcg mRNA, proglucagon and GLP-1 synthesis in the PH. PH Gcg neurons project densely to the ventral and intermediate lateral septum, preoptic region, ventrolateral preoptic nucleus, lateral hypothalamus and zona incerta, establishing close contacts with both GLP-1 receptor-positive and -negative neurons. ConclusionsProglucagon is expressed in 9 distinct neuron populations. Feeding status regulates GLP-1 synthesis in PH neurons that likely control feeding- or energy balance-related functions.

neuroscience↗

bioRxiv2023

Estrogen-dependent development and transcriptome regulation of the lateral septal kisspeptin system

While hypothalamic kisspeptin (KP) neurons play well-established roles in the estrogen-dependent regulation of reproduction, little is known about extrahypothalamic KP-producing (KPLS) neurons of the lateral septum. Our studies on Kiss1-Cre/ZsGreen transgenic mice revealed that KP expression in the LS is linked to puberty and estrogen receptor signaling and neurons reach higher numbers in females. Viral tracing uncovered that KPLS axons abundantly innervate gonadotropin-releasing hormone neurons, the hypothalamic supramammillary nucleus and various limbic structures. RNA-Seq analysis of laser-microdissected KPLS neurons revealed a unique transcriptome profile containing markers of GABAergic and peptidergic (Penk, Cartpt, Vgf) cotransmission and 571 estrogen-dependent transcripts. Immunohistochemical evidence for homologous neurons in the post mortem human brain indicate that the KPLS neurons may contribute to evolutionarily conserved regulatory mechanisms. The KPLS system now emerges as a novel player in the estrogen-dependent control of gonadotropin-releasing hormone neurons and currently unknown hypothalamic and limbic functions requiring clarification.

neuroscience↗

bioRxiv2022

A PATHWAY FOR T3 SIGNALING IN THE BRAIN TO IMPROVE THE VARIABLE EFFECTIVENESS OF THERAPY WITH L-T4

The effectiveness of therapy for hypothyroidism with levothyroxine (L-T4) depends on patients ability to activate T4 to T3 --altered in carriers of a common deiodinase polymorphism (Thr92Ala-DIO2). Some patients that exhibit impaired mood and cognition improve with liothyronine (L-T3), but the underlying mechanisms remain unknown. Here we show that the T3-indicator mouse carrying the Thr92Ala-DIO2 polymorphism exhibits a hippocampal-specific reduction in T3 activation and signaling that limits the effectiveness of L-T4 therapy. To understand the L-T3 effect, we used a compartmentalized microfluid device and identified a novel neuronal pathway of T3 transport and action that involves axonal T3 uptake into clathrin-dependent, endosomal/non-degradative lysosomes (NDLs). NDLs-containing T3 are retrogradely transported via microtubules, delivering relatively large amounts of T3 to the cell nucleus, doubling the expression of the T3-responsive reporter gene. The NDLs also contain the monocarboxylate transporter 8 (Mct8) and the type 3 deiodinase (Dio3), which transports and inactivates T3, respectively. Notwithstanding, T3 gets away from degradation because D3 active center is in the cytosol. These findings provide (i) a basis for the variable effectiveness of L-T4 therapy, (ii) a pathway for L-T3 to reach neurons, and (iii) resolve the paradox of T3 signaling in the brain amid high D3 activity.

neuroscience↗

bioRxiv2020

The transcriptional repressor Zfp125 modifies hepatic energy metabolism in response to fasting and insulin resistance

Zfp125 is a transcriptional repressor that inhibits hepatic VLDL secretion. Here we show that mice with liver-specific Zfp125 knockdown exhibited lower respiratory quotient, reduced glycemia and pyruvate-stimulated liver glucose output, and higher levels of {beta}-hydroxyl-butyrate. Microarray and ChIP-seq studies identified Zfp125 peaks in the promoter of 135 metabolically relevant genes, including genes involved in fatty acid oxidation and ketogenesis, e.g. Ppara, Cpt1a, Bdh1 and Hmgcs2. Repression by Zfp125 involved recruitment of the corepressors Kap1 and the histone methyl transferase Setdb1, increasing the levels of H3K9me3, a heterochromatin marker of gene silencing. The resulting increase in acetyl-CoA levels accelerated gluconeogenesis through allosteric activation of pyruvate carboxylase. Zfp125 knockdown in isolated mouse hepatocytes amplified the induction of ketogenesis by glucagon or insulin resistance, whereas the expression of key gluconeogenic genes Pck1 and G6pc was amplified by Zfp125. These findings place Zfp125 at the center of fuel dysregulation of type 2 diabetes.

physiology↗