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  1. Evaluation Summary:

    The current study examined in detail the role of oxytocin neurons in the hypothalamus in regulating food intake. The current study extends our understanding of the role of this peptide in regulating complex behaviors.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

  2. Reviewer #1 (Public Review):

    The study investigated the role of oxytocin (OT) in the paraventricular hypothalamic nucleus (PVH) and oxytocin receptor (OTR) in the hypothalamus in the regulation of food intake using conditional knockout of oxytocin in adults by adreno-associated virus (AAV) approaches. Although pharmacological studies have demonstrated that oxytocin/oxytocin receptors regulate food intake behavior, constitutive knockout (KO) models are not aligned with pharmacological studies. To overcome this discrepancy between pharmacological and developmental genetic approaches, the authors used AAV to knockout oxytocin/oxytocin receptors in adults of mice, circumventing developmental compensations. They found that adult KO of OT in the PVH, but not supraoptic nucleus (SO), led to obesity due to hyperphagia. They also investigated whether OTR in the anterior or posterior side of the hypothalamus contributes to OT-mediated food intake behavior, and found that the posterior hypothalamic areas are key for that. Overall, the experiments are thoughtfully designed, and the manuscript is well written. However, there are questions that authors need to address, in particular their OT KO model.

  3. Reviewer #2 (Public Review):

    The authors examine the role of oxytocin signaling for regulating appetite and body weight in mice. They use loss of function perturbations in adult mice to avoid the potential for developmental compensation that is often observed with energy homeostasis systems. The experiments show a strong effect for oxytocin loss of function to lead to increased food intake and body weight. This is localized to the PVH oxytocin neurons and not the supraoptic nucleus population. Loss of oxytocin receptor in the posterior hypothalamus has a similar effect. This work provides important support for the notion that oxytocin is a key energy homeostasis neuropeptide with a role in suppressing over eating behavior.

  4. Reviewer #3 (Public Review):

    The manuscript by Inada et al. examines the role of hypothalamic oxytocin (OT) signaling in feeding behavior. They demonstrate that conditional knockout (KO) of OT in the adult paraventricular hypothalamic nucleus (PVH) increases body weight through increases in food intake, and that conditional knockout of the OT receptor in the posterior hypothalamus has a similar effect. The authors therefore conclude that OT signaling in the posterior hypothalamus, presumably through oxytocin produced in the PVH, contributes to energy balance control.

    There has been conflicting literature on the role of OT in feeding behavior. Although pharmacological and genetic approaches have suggested an anorexic effect of OT, knockout of OT or OT receptor has minimal effect on feeding. To address this apparent discrepancy, the authors use conditional knockout models to manipulate OT signaling. This allows not only temporal control of OT and OT receptor, but also allows investigation of signaling in different brain regions (versus, for example, whole body or organ). That the conditional knockout mice display hyperphagia and obesity begins to settle this conflict in the literature.


    1. There is not much conceptual advance in the study. The data largely confirm what pharmacological and RNAi knockdown studies have previously demonstrated.

    2. The finding that IP injection of OT partially rescues the phenotype of the KO mouse lacks rigor and proper controls. It is important to show that the dose of OT used does not influence body weight in wildtype mice in order to make the conclusion that it "rescues" the phenotype of the KP mouse.

    3. There is little anatomical precision in the manipulation of OT receptors in the "posterior hypothalamus." Understanding which of these brain regions (e.g. ARH, VMH, LHA, DMH, others?) is involved in mediating these effects would be very informative.