Abstract
<title>Abstract</title> <p>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 Dlx5-6-dependent 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</p>