Hypothalamic control of puberty: from neuronal circuits to mechanisms for its metabolic regulation.

The hypothalamus is a singular brain region with essential roles in the control of a wide diversity of vegetative functions, from growth and energy balance to reproduction. These processes are governed by interconnected neuroendocrine pathways that enable proper adjustment of fundamental biological programs to internal and external cues along the lifespan. Puberty is a key maturational phenomenon that permits full sexual and somatic maturation, and attainment of reproductive capacity, together with important psychological changes. Puberty is to a large extent, a brain-driven phenomenon, with the hypothalamus playing a major role as the essential hub for the integration of central and peripheral signals, responsible for driving puberty onset and its modulation by endogenous and environmental factors. Our understanding of the hypothalamic circuits governing puberty has expanded enormously in the last decades, as exemplified by the discovery and later characterization of the roles of neurons producing kisspeptins, aka Kiss1 neurons, as major gatekeepers of puberty onset, mainly through their role as indispensable upstream activators of GnRH neurons. In recent years, the intimate molecular programs and co-players of Kiss1 neurons that participate in pubertal control have been partially exposed. In addition, given the paramount importance of metabolic signals in the modulation of puberty, the nature and mechanisms of action of different factors, converging at the hypothalamus, that participate in pubertal modulation by the metabolic and nutritional status have been disclosed. While characterization of these regulatory circuits is still uncomplete, this review aims to provide a synoptic and updated view of our current knowledge of the essential elements responsible for the hypothalamic control of puberty, also as a means to understand the putative basis for acquired pubertal disorders, including those linked to metabolic perturbations, such as early-onset obesity or undernutrition.