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Abstract
Leptin, secreted by peripheral adipocytes, binds the leptin receptor (Lepr) in the hypothalamus, thereby contributing to the regulation of satiety and body weight. Lepr is expressed in the embryonic brain as early as embryonic day 12.5. However, the function of Lepr in neural precursor cells in the brain has not been resolved. To address this issue, we crossed the Leprflox/flox mice with each of Shh-Cre mice (Shh, sonic hedgehog) and Nestin (Nes)-Cre mice. We found that deletion of Lepr specifically in nestin-expressing cells led to extreme obesity, but the conditional null of Lepr in Shh-expressing cells had no obvious phenotype. Moreover, the level of leptin-activated pSTAT3 decreased in the anterior and central subregions of the arcuate hypothalamus of Shh-Cre; Leprflox/flox mice compared with the controls. By contrast, in Nes-Cre; Leprflox/flox mice, the level of leptin-activated pSTAT3 decreased in all subregions including the anterior, central, and posterior arcuate hypothalamus as well as the dorsomedial, ventromedial, and median eminence of the hypothalamus, revealing that the extensive lack of Lepr in the differentiated neurons of the hypothalamus in the conditional null mice. Notably, conditional deletion of Lepr in nestin-expressing cells enhanced the differentiation of neural precursor cells into neurons and oligodendroglia but inhibited differentiation into astrocytes early in postnatal development of hypothalamus. Our results suggest that Lepr expression in neural precursor cells is essential for maintaining normal body weight as well as the differentiation of neural precursor cells to the neural/glial fate in the hypothalamus shortly after birth.
Highlights
Leptin, an adipose-derived hormone, is a critical regulator of diverse metabolic processes including satiety, energy expenditure, and glucose homeostasis [1, 2]
Nes-Cre;Leprf/f mice become obese by postnatal day 35 (P35) but no obvious obesity phenotype is observed for Sonic hedgehog (Shh)-Cre;Leprf/f mice Shh is required for the normal function of orexinergic and anorexinergic cells in the hypothalamus as well as for maintaining the proper size of the lateral hypothalamus [8, 15]
Body weight of the ShhcKO mice showed no difference with the control group (Fig. 1a), suggesting that leptin receptor (Lepr) is not required for normal neurogenesis in cells that express Shh
Summary
An adipose-derived hormone, is a critical regulator of diverse metabolic processes including satiety, energy expenditure, and glucose homeostasis [1, 2]. Leptin binds and activates the long isoform of leptin receptor (Lepr), Like Leptin, Sonic hedgehog (Shh) ligand and its signaling pathway regulate aspects of growth and metabolism that are relevant to hypothalamic patterning [8,9,10,11]. After embryonic day 9.5, Shh-expressing hypothalamic progenitors give rise to neurons and astrocytes of the entire tuberal region and in particular the ventromedial nucleus [12]. Lepr is expressed in the ventricular zone of the telencephalon and mesencephalon at embryonic day 12.5 [13] as well as in the ARH during early postnatal development in rodents [14]. The function of Lepr in neural precursor cells (NPCs), especially the Shh-expressing NPCs in the brain, has not been determined
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