Intestinal gluconeogenesis controls the neonatal development of hypothalamic feeding circuits

Abstract

Objective: Intestinal gluconeogenesis (IGN) regulates adult energy homeostasis in part by controlling the same hypothalamic targets as leptin. In neonates, leptin exhibits a neonatal surge controlling axonal outgrowth between the different hypothalamic nuclei involved in feeding circuits and autonomic innervation of peripheral tissues involved in energy and glucose homeostasis. Interestingly, IGN is induced during this specific time-window. We hypothesized that the neonatal pic of IGN also regulates the development of hypothalamic feeding circuits and sympathetic innervation of adipose tissues.

Methods: We genetically induced neonatal IGN by overexpressing G6pc1 the catalytic subunit of glucose-6-phosphatase (the mandatory enzyme of IGN) at birth or at twelve days after birth. The neonatal development of hypothalamic feeding circuits was studied by measuring Agouti-related protein (AgRP) and Pro-opiomelanocortin (POMC) fiber density in hypothalamic nuclei of 20-day-old pups. The effect of the neonatal induction of intestinal G6pc1 on sympathetic innervation of the adipose tissues was studied via tyrosine hydroxylase (TH) quantification. The metabolic consequences of the neonatal induction of intestinal G6pc1 were studied in adult mice challenged with a high-fat/high-sucrose (HFHS) diet for 2 months.

Results: Induction of intestinal G6pc1 at birth caused a neonatal reorganization of AgRP and POMC fiber density in the paraventricular nucleus of the hypothalamus, increased brown adipose tissue tyrosine hydroxylase levels, and protected against high-fat feeding-induced metabolic disorders. In contrast, inducing intestinal G6pc1 12 days after birth did not impact AgRP/POMC fiber densities, adipose tissue innervation or adult metabolism.

Conclusion: These findings reveal that IGN at birth but not later during postnatal life controls the development of hypothalamic feeding circuits and sympathetic innervation of adipose tissues, promoting a better management of metabolism in adulthood.

Keywords: Agouti-related peptide (AgRP); Developmental programming; Hypothalamic development; Intestinal gluconeogenesis; Neonatal period; Obesity; Pro-opiomelanocortin (POMC).