A critical period for the trophic actions of leptin on AgRP neurons in the arcuate nucleus of the hypothalamus

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The arcuate nucleus of the hypothalamus (ARH) represents a critical interface between peripheral hormonal cues and neural circuits that control body weight (Hetherington & Ranson, 1940; Hewson, Tung, Connell, Tookman, & Dickson, 2002; Mirshamsi et al., 2004; Myers, MUnzberg, Leinninger, & Leshan, 2009; Saper, Chou, & Elmquist, 2002; Schwartz, Woods, Porte, Seeley, & Baskin, 2000; Sternson, Atasoy, Betley, Henry, & Xu, 2016). Within the ARH, neurons that co‐express neuropeptide Y (NPY) and agouti‐related peptide (AgRP) are activated or inhibited by signals that convey information about energy balance (Atasoy, Betley, Su, & Sternson, 2012; Betley, Cao, Ritola, & Sternson, 2013; Garfield et al., 2016; Gropp et al., 2005; Hahn, Breininger, Baskin, & Schwartz, 1998; Zarjevski, Cusin, Vettor, Rohner‐Jeanrenaud, & Jeanrenaud, 1993). The adipocyte‐derived hormone, leptin, is required for central nervous system regulation of energy homeostasis and directly impacts the activity of AgRP neurons to rapidly alter feeding behavior and energy metabolism through connections to a distributed network of nuclei controlling downstream neuroendocrine and autonomic output (Atasoy et al., 2012; Betley et al., 2013; Bouyer & Simerly, 2013; Campfield, Smith, Guisez, Devos, & Burn, 1995; Carter, Soden, Zweifel, & Palmiter, 2013; Garfield et al., 2016; Grill et al., 2002; Halaas et al., 1995; Huo, Maeng, Bjørbæk, & Grill, 2007; Scott, Williams, Rossi, Lee, & Elmquist, 2011; Zhang et al., 1994).
The projections of ARH neurons are established primarily during the first two postnatal weeks, concomitant with a naturally occurring surge in leptin secretion (Ahima, Prabakaran, & Flier, 1998; Bouret, 2004). During this time, leptin signals through the b‐form of its receptor (LepRb) at the level of the ARH to stimulate growth of axonal projections from AgRP neurons (Bouret, 2004; Bouret, Draper, & Simerly, 2004; Bouyer & Simerly, 2013). Thus, in the leptin deficient (Lepob/ob) mouse, AgRP projections to several key nuclei controlling energy balance are severely diminished, including projections to the paraventricular (PVH) and dorsomedial (DMH) nuclei of the hypothalamus (Bouret, 2004; Bouret et al., 2004; Bouyer & Simerly, 2013). This diminished innervation is largely rescued by treatment with exogenous leptin during the postnatal period (P4–P14) when the surge in leptin secretion normally occurs (Atasoy et al., 2012; Betley et al., 2013; Bouret et al., 2004; Bouyer & Simerly, 2013; Garfield et al., 2016; Gropp et al., 2005; Hahn et al., 1998; Zarjevski et al., 1993). Moreover, impairments in food intake, adiposity, and certain aspects of autonomic function are improved when Lepob/ob mice are treated with leptin only during this restricted postnatal period. However, leptin treatment in mature Lepob/ob animals is ineffective at restoring normal patterns of ARH innervation (Atasoy et al., 2012; Betley et al., 2013; Bouret et al., 2004; Bouyer & Simerly, 2013; Campfield et al., 1995; Carter et al., 2013; Garfield et al., 2016; Grill et al., 2002; Halaas et al., 1995; Huo et al., 2007; Scott et al., 2011; Zhang et al., 1994), suggesting that the trophic actions of leptin are restricted to a discrete developmental critical period.
Postnatal leptin also appears to influence targeting of ARH neurons to specific parts of the PVH. AgRP neurons project to two broad subgroups of neurons within the PVH: neuroendocrine neurons that send projections to the median eminence and posterior pituitary to mediate hormonal responses, and preautonomic neurons that project to the brainstem, spinal cord, limbic system, and other hypothalamic sites to coordinate autonomic and goal‐directed behaviors (Ahima et al., 1998; Biag et al., 2011; Bouret, 2004; Bouyer & Simerly, 2013; Cowley et al., 1999; Saper et al., 2002; Swanson, 2000).
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