Prolactin receptors in Rip-cre cells, but not in AgRP neurons, are involved in energy homeostasis

Abstract

Among its many functions, prolactin has been implicated in energy homeostasis, particularly during pregnancy and lactation. The arcuate nucleus is a key site in the regulation of energy balance. The aim of this study was to examine whether arcuate nucleus neuronal populations involved in energy homeostasis are prolactin responsive and if they can mediate the effects of prolactin on energy homeostasis. To determine if Agrp neurons or Rip-Cre neurons are prolactin responsive, transgenic mice expressing the reporter td-tomato in Agrp neurons (td-tomato/AgRP-Cre) or Rip-Cre neurons (td-tomato/Rip-Cre) were treated with prolactin and perfused 45 minutes later. Brains were processed for double-labeled immunohistochemistry for pSTAT5, a marker of prolactin-induced intracellular signaling, and td-tomato. In addition, Agrp-Cre mice and Rip-Cre mice were crossed with mice in which the prolactin receptor gene (Prlr) was flanked with LoxP sites (Prlr^lox/lox mice). The Prlr^lox/lox construct was designed such that Cre-mediated recombination resulted in deletion of the Prlr and expression of GFP in its place. In td-tomato/Rip-Cre mice, prolactin-induced pSTAT5 was co-localized with td-tomato, indicating that there is a subpopulation of Rip-Cre neurons in the arcuate nucleus that respond to prolactin. Furthermore, mice with a specific deletion of Prlr in Rip-Cre neurons had lower body weights, increased oxygen consumption, increased running wheel activity, and numerous cells in the arcuate nucleus had positive GFP staining indicating deletion of Prlr from Rip-Cre neurons. In contrast, no co-localization of td-tomato and pSTAT5 was observed in td-tomato/Agrp-Cre mice following prolactin treatment. Moreover, Prlr^lox/lox/Agrp-Cre mice had no positive GFP staining in the arcuate nucleus and did not differ in body weight compared to litter mate controls. Overall these results indicate that Rip-Cre neurons in the arcuate nucleus are responsive to prolactin and may play a role in the orexigenic effects of prolactin, while prolactin does not directly affect Agrp neurons.

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