Ghrelin and hypothalamic development: too little and too much of a good thing

Abstract

Neural centers in the hypothalamus regulate food intake and body weight in response to hormones and other neural stimuli, and dysfunctional communication between the brain and gut underlies metabolic disorders, including obesity. In this issue of the JCI, Steculorum and colleagues present evidence that the gastric peptide ghrelin mediates neural fiber growth in the arcuate nucleus of the hypothalamus during the neonatal period. Neonatal mice subjected to either increased or decreased ghrelin action during this developmental period had an increased risk of obesity in adulthood. Together, the results of this study support a model whereby neural organization at key stages of development sets the foundation for metabolic health later in life.

Figure 1. Alterations in ghrelin levels during the neonatal period promote metabolic dysfunction in adulthood.

When ghrelin is antagonized or removed, there is an increase in neuronal projections from the ARH to the PVN, with a predominance of projections from orexigenic AgRP/NPY neurons. Exposure to exogenous ghrelin in the neonatal period results in a reduction of neuronal connections between the ARH and PVN; however, were there is still a predominance of AgRP/NPY projections. Ghrelin may exert its trophic effect on hypothalamic neurons via leptin and/or through direct interaction with neurons within the ARH. The net effect of altered ghrelin signaling during development is a positive energy balance and glucose intolerance in adulthood.