Dlx5-6-dependent GABAergic programs shape hypothalamic control of energy balance and insulin sensitivity
Abstract
GABA-neurons are essential components of hypothalamic circuits that coordinate feeding, energy expenditure, glucose metabolism, and adaptive responses to peripheral metabolic signals. The homeodomain transcription factors Dlx5 and Dlx6 are well-established regulators of GABA-neurons development, but their contribution to the organization of metabolic control circuits remains incompletely understood. Here, we investigated the metabolic consequences of conditional Dlx5-6 deletion in VGAT-expressing GABA-neurons. Mice lacking Dlx5-6 in this lineage displayed reduced body weight and lean mass, decreased locomotor activity, and lower whole-body energy expenditure, together with altered substrate utilization. Despite this reduced metabolic expenditure, mutant mice showed improved insulin sensitivity, characterized by reduced glucose-stimulated insulin secretion and enhanced glucose lowering during insulin tolerance testing. In addition, Dlx5-6 deletion impaired the behavioral response to circulating metabolic hormones: ghrelin failed to stimulate food intake, and leptin failed to suppress refeeding after fasting. These physiological alterations were associated with developmental remodeling of hypothalamic AgRP/NPY circuitry, including an increased number of AgRP-expressing neurons at P21 and increased NPY-positive projections to selected hypothalamic and thalamic targets. In adult mice, ghrelin-induced neuronal activation was redistributed toward the median eminence, suggesting altered integration of peripheral hunger signals. Together, these findings identify Dlx5-6dependent GABAergic programs as important determinants of hypothalamic circuit organization and systemic metabolic regulation. Rather than simply controlling food intake, Dlx5-6-dependent GABAergic mechanisms appear to shape the balance between energy conservation, nutrient partitioning, hormonal responsiveness, and glucose homeostasis
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BibTeX
@misc{hassouna2026dlx56dependent,
title = {{Dlx5-6-dependent GABAergic programs shape hypothalamic control of energy balance and insulin sensitivity}},
author = {Rim Hassouna and Anthony Ansoult and Julien Castel and Nour Mesto and Sonya Yung and Raphael Denis and Giuseppe Gangarossa and Giovanni Levi and Nicolas Narboux-Nême and Claire Martin and Serge Luquet},
howpublished = {HAL},
year = {2026},
month = jul,
doi = {10.21203/rs.3.rs-10315915/v1},
url = {https://hal.science/hal-05856873v1},
note = {CC BY 4.0},
}
RIS
TY - UNPB
TI - Dlx5-6-dependent GABAergic programs shape hypothalamic control of energy balance and insulin sensitivity
AU - Rim Hassouna
AU - Anthony Ansoult
AU - Julien Castel
AU - Nour Mesto
AU - Sonya Yung
AU - Raphael Denis
AU - Giuseppe Gangarossa
AU - Giovanni Levi
AU - Nicolas Narboux-Nême
AU - Claire Martin
AU - Serge Luquet
PY - 2026
DA - 2026/07/17
PB - HAL
DO - 10.21203/rs.3.rs-10315915/v1
UR - https://hal.science/hal-05856873v1
AB - GABA-neurons are essential components of hypothalamic circuits that coordinate feeding, energy expenditure, glucose metabolism, and adaptive responses to peripheral metabolic signals. The homeodomain transcription factors Dlx5 and Dlx6 are well-established regulators of GABA-neurons development, but their contribution to the organization of metabolic control circuits remains incompletely understood. Here, we investigated the metabolic consequences of conditional Dlx5-6 deletion in VGAT-expressing GABA-neurons. Mice lacking Dlx5-6 in this lineage displayed reduced body weight and lean mass, decreased locomotor activity, and lower whole-body energy expenditure, together with altered substrate utilization. Despite this reduced metabolic expenditure, mutant mice showed improved insulin sensitivity, characterized by reduced glucose-stimulated insulin secretion and enhanced glucose lowering during insulin tolerance testing. In addition, Dlx5-6 deletion impaired the behavioral response to circulating metabolic hormones: ghrelin failed to stimulate food intake, and leptin failed to suppress refeeding after fasting. These physiological alterations were associated with developmental remodeling of hypothalamic AgRP/NPY circuitry, including an increased number of AgRP-expressing neurons at P21 and increased NPY-positive projections to selected hypothalamic and thalamic targets. In adult mice, ghrelin-induced neuronal activation was redistributed toward the median eminence, suggesting altered integration of peripheral hunger signals. Together, these findings identify Dlx5-6dependent GABAergic programs as important determinants of hypothalamic circuit organization and systemic metabolic regulation. Rather than simply controlling food intake, Dlx5-6-dependent GABAergic mechanisms appear to shape the balance between energy conservation, nutrient partitioning, hormonal responsiveness, and glucose homeostasis
ER -