Ghrelin's orexigenic action in the lateral hypothalamic area involves indirect recruitment of orexin neurons and arcuate nucleus activation

Objective: Ghrelin is a potent orexigenic hormone, and the lateral hypothalamic area (LHA) has been suggested as a putative target mediating ghrelin's effects on food intake. Here, we aimed to investigate the presence of neurons expressing ghrelin receptor (a.k.a. growth hormone secretagogue receptor, GHSR) in the mouse LHA (LHA^GHSR neurons), its physiological implications and the neuronal circuit recruited by local ghrelin action. Methods: We investigated the distribution of LHA^GHSR neurons using different histologic strategies, including the use of a reporter mice expressing enhanced green fluorescent protein under the control of the GHSR promoter. Also, we investigated the physiological implications of local injections of ghrelin within the LHA, and the extent to which the orexigenic effect of intra-LHA-injected ghrelin involves the arcuate nucleus (ARH) and orexin neurons of the LHA (LHA^orexin neurons) Results: We found that: 1) LHA^GHSR neurons are homogeneously distributed throughout the entire LHA; 2) intra-LHA injections of ghrelin transiently increase food intake and locomotor activity; 3) ghrelin's orexigenic effect in the LHA involves the indirect recruitment of LHA^orexin neurons and the activation of ARH neurons; and 4) LHA^GHSR neurons are not targeted by plasma ghrelin. Conclusions: We provide a compelling neuroanatomical and functional characterization of LHA^GHSR neurons in male mice that indicates that LHA^GHSR cells are part of a hypothalamic neuronal circuit that potently induces food intake.