Growth hormone receptor in lateral hypothalamic neurons is required for increased food-seeking behavior during food restriction in male mice.

Growth hormone (GH) action in the brain regulates neuroendocrine axes, energy and glucose homeostasis, and several neurological functions. The lateral hypothalamic area (LHA) contains numerous neurons that respond to a systemic GH injection by expressing the phosphorylated STAT5, a GH receptor (GHR) signaling marker. However, the potential role of GHR signaling in the LHA is unknown. In this study, we demonstrated that approximately 70% of orexin- and leptin receptor (LepR)-expressing neurons in the LHA are responsive to GH. Male mice carrying inactivation of the Ghr gene in the LHA were generated via bilateral injections of an adeno-associated virus. In ad libitum-fed mice, GHR ablation in LHA neurons did not significantly change energy and glucose homeostasis. Subsequently, mice were subjected to 5 days of 40% food restriction. Food restriction decreased body weight, energy expenditure, and carbohydrate oxidation. These effects were similarly observed in control and LHA^ΔGHR mice. While food-deprived control mice progressively increased ambulatory/exploratory activity and food-seeking behavior, LHA^ΔGHR mice did not show hyperactivity induced by food restriction. GHR ablation in the LHA reduced the percentage of orexin neurons expressing c-Fos during food restriction. Additionally, an acute GH injection increased the expression of c-Fos in LHA^ORX neurons. Inactivation of Ghr in LepR-expressing cells did not prevent hyperactivity in food-deprived mice, whereas whole-brain Ghr knockout mice showed reduced ambulatory activity during food restriction. Our findings indicate that GHR signaling in the LHA regulates the activity of orexin neurons and is necessary to increase food-seeking behavior in food-deprived male mice.Significance Statement Growth hormone (GH)-deficient patients frequently present problems in appetite, memory, mood, well-being, metabolism, and sleep. The mechanisms behind these alterations are unknown, but neurons in the lateral hypothalamic area (LHA) are involved in the regulation of all these functions. Here, we showed in male mice that orexin neurons in the LHA express GH receptors, and GH increases the activity of these cells. Unlike control animals, mice carrying inactivation of GH receptors in LHA neurons are unable to increase their ambulatory/exploratory activity when subjected to food restriction, which increases food-seeking behavior. Thus, our study revealed a new neuronal population affected by GH action that can regulate several neurological aspects, including feeding, arousal, reward, and motivated behaviors.