Reproductive neuronal circuitry in adaptive changes of energy balance

The crosstalk between metabolism and reproduction is essential for species survival. When dysfunctional, this interaction may decrease reproductive efficiency, but in physiological conditions of high energy demands, e.g., pregnancy and lactation, it is highly beneficial. Females display adaptive responses that assure offspring survival and health, including increased food intake and suppression of the reproductive function. Some of these physiological responses are modulated by leptin actions in neuronal pathways that are still unclear. The hypothalamic ventral premammillary nucleus (PMv) is a key integrative node of metabolic cues and reproductive status, comprised of either leptin-depolarized or -hyperpolarized neurons. Here, we show that the subset of leptin-hyperpolarized neurons coexpresses dopamine transporter (DAT) and prolactin receptor. DAT expression is higher in prepubertal conditions, when reproductive function is suppressed. These neurons innervate AgRP presynaptic terminals and may potentiate their inhibitory actions on reproduction. We further applied a mathematical model to reconcile our new findings with the current literature and to verify if those neurons are putative components of the metabolic control of reproduction. In our model, leptin-depolarized PMv neurons project to and directly stimulate kisspeptin and gonadotropin releasing hormone (GnRH) neurons. Leptin-hyperpolarized PMv DAT neurons are directly stimulated by prolactin and project to inhibitory control sites. During conditions of high prolactin levels, i.e., late pregnancy and lactation, this pathway may overcome the former, facilitating AgRP actions in the suppression of the reproductive function. Our model also predicts that overstimulation of this pathway may underlie earlier puberty and reproductive deficits observed in conditions of metabolic dysfunction. Significance StatementWomen with excess or low energy stores (e.g., obesity or anorexia) have reproductive deficits, including altered puberty onset, disruption of reproductive cycles and decreased fertility. If able to conceive, they show higher risks of miscarriages and preterm birth. The hypothalamic circuitry controlling the interplay between metabolism and reproduction is undefined. Neurons in the ventral premammillary nucleus express leptin receptor and project to reproductive control sites. Those neurons are essentially glutamatergic, but functionally and phenotypically heterogeneous. They either depolarize or hyperpolarize in response to leptin. We show that leptin-hyperpolarized neurons coexpress dopamine transporter and prolactin receptor, and project to AgRP inhibitory output. Computational modeling was applied to build a neuronal network integrating metabolism and reproduction in typical and dysfunctional physiology.