Developmental programming of hypothalamic melanocortin circuits

Abstract

The melanocortin system plays a critical role in the central regulation of food intake and energy balance. This system consists of neurons producing pro-opiomelanocortin (POMC), melanocortin receptors (MC4Rs), and the endogenous antagonist agouti-related peptide (AgRP). Pomc and Mc4r deficiency in rodents and humans causes early onset of obesity, whereas a loss of Agrp function is associated with leanness. Accumulating evidence shows that many chronic diseases, including obesity, might originate during early life. The melanocortin system develops during a relatively long period beginning during embryonic life with the birth of POMC and AgRP neurons and continuing postnatally with the assembly of their neuronal circuitry. The development of the melanocortin system requires the tight temporal regulation of molecular factors, such as transcription factors and axon guidance molecules, and cellular mechanisms, such as autophagy. It also involves a complex interplay of endocrine and nutritional factors. The disruption of one or more of these developmental factors can lead to abnormal maturation and function of the melanocortin system and has profound metabolic consequences later in life.

Fig. 1. Important periods of hypothalamic development.

The development of a functional hypothalamus occurs in two major phases: the determination of cell numbers, which includes neurogenesis, neuronal migration, and cell fate, and the formation of functional circuits, which includes axon growth and the formation of functional synapses. In rodents, neurogenesis, neuronal migration, and cell fate occur during mid-to-late gestation, while axon growth and synapse formation occur primarily postnatally.

Fig. 2. Factors regulating melanocortin system development.

Hypothalamic development involves cell-intrinsic cellular and molecular factors as well as endocrine signals and genetic and environmental factors.