Conditional knockout of leptin receptor in neural stem cells leads to obesity in mice and affects neuronal differentiation in the hypothalamus early after birth

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 Lepr flox/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; Lepr flox/flox mice compared with the controls. By contrast, in Nes-Cre; Lepr flox/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.

Trends in Gliosis in Obesity, and the Role of Antioxidants as a Therapeutic Alternative

“…The mechanism of action that affects glial cells shows that diet plays an important role, so that HFD increases the expression of leptin receptors in astrocytes [ 58 , 59 ], inducing localized astrogliosis between anorexigenic neurons and blood vessels in the arcuate nucleus of the basal medial hypothalamus, altering metabolism and food intake. This hypothalamic inflammation is involved in the process of leptin and insulin resistance, leading to obesity and, quite possibly, diabetes [ 60 ]. There are other structures of the brain that can be affected by these neuroinflammation processes, such as the frontal cortex, the parietal cortex, the basal ganglia, the thalamus, the hippocampus, and the cerebellum, which are mainly related to high-level cognitive functions.…”

Recent Advances in the Knowledge of the Mechanisms of Leptin Physiology and Actions in Neurological and Metabolic Pathologies

“…Although leptin receptors were initially identified in hypothalamic neurons, they are widely distributed in different cell types of the cerebral cortex and hippocampus, areas involved in cognition and memory processes. Expression of ObRb in neural precursor cells is necessary for preserving an adequate body weight in addition to the differentiation of these precursors into neural or glial cells after birth [ 107 ]. Leptin is an activator of transcription through triggering CREB protein, that is required for leptin-stimulated synapse formation and also augments the expression of miRNA-132, a well-known CREB target, which is necessary for leptin-induced synaptogenesis [ 108 ].…”

Constitutive and conditional gene knockout mice for the study of intervertebral disc degeneration: Current status, decision considerations, and future possibilities

“…The notochord secretes a kind of protein called Sonic hedgehog (Shh), which induces the differentiation of motor neurons, ventral interneurons and floor plate cells. 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 In IVDs, the Shh promoter driven Cre recombinase was only expressed in NP cells. 108 , 109 , 110 Thus, the Shh Cre mice has high specificity and becomes an available tool for studying IVDs.…”

“…Shh Cre mice have also been used in the studies of nervous system disease. Ren et al 104 used Shh Cre mice to establish mouse models of which Lepr was deleted in neural stem cells and found abnormal differentiation of hypothalamic neurons in the early postnatal period. This change also makes it possible for neuropeptide Y neurons to become abnormal.…”