Collective and Individual Functions of Leptin Receptor Modulated Neurons Controlling Metabolism and Ingestion
Departments of Medicine and Neuroscience, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 12461, USA. Endocrinology
(Impact Factor: 4.5).
05/2008; 149(4):1773-85. DOI: 10.1210/en.2007-1132
Two known types of leptin-responsive neurons reside within the arcuate nucleus: the agouti gene-related peptide (AgRP)/neuropeptide Y (NPY) neuron and the proopiomelanocortin (POMC) neuron. By deleting the leptin receptor gene (Lepr) specifically in AgRP/NPY and/or POMC neurons of mice, we examined the several and combined contributions of these neurons to leptin action. Body weight and adiposity were increased by Lepr deletion from AgRP and POMC neurons individually, and simultaneous deletion in both neurons (A+P LEPR-KO mice) further increased these measures. Young (periweaning) A+P LEPR-KO mice exhibit hyperphagia and decreased energy expenditure, with increased weight gain, oxidative sparing of triglycerides, and increased fat accumulation. Interestingly, however, many of these abnormalities were attenuated in adult animals, and high doses of leptin partially suppress food intake in the A+P LEPR-KO mice. Although mildly hyperinsulinemic, the A+P LEPR-KO mice displayed normal glucose tolerance and fertility. Thus, AgRP/NPY and POMC neurons each play mandatory roles in aspects of leptin-regulated energy homeostasis, high leptin levels in adult mice mitigate the importance of leptin-responsiveness in these neurons for components of energy balance, suggesting the presence of other leptin-regulated pathways that partially compensate for the lack of leptin action on the POMC and AgRP/NPY neurons.
Available from: Deborah Suchecki
- "Thus, PSD most likely led to increased expression of hypothalamic leptin receptors as a compensatory response to reduced leptin plasma levels and increased production of orexigenic neuropeptides (Galvão et al., 2009; Martins et al., 2010), in an attempt to maintain energy homeostasis. Knock out of leptin (Balthasar et al., 2004; Van de Wall et al., 2008), but not insulin (Konner et al., 2007), receptors in ARC neurons produces hyperphagia and increased body weight. The lack of change in insulin receptors throughout PSD may be related to the fact that blood glucose in sleepdeprived animals was, somehow, kept stable. "
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ABSTRACT: Studies have shown a gradual reduction of sleep time in the general population, accompanied by increased food intake, representing a risk for developing obesity, type II diabetes and cardiovascular disease. Rats subjected to paradoxical sleep deprivation (PSD) exhibit feeding and metabolic alterations, both of which are regulated by the communication between peripheral signals and the hypothalamus. This study aimed to investigate the daily change of 96 h of PSD-induced food intake, body weight, blood glucose, plasma insulin and leptin concentrations and the expression of their receptors in the hypothalamus of Wistar rats. Food intake was assessed during the light and dark phases and was progressively increased in sleep-deprived animals, during the light phase. PSD produced body weight loss, particularly on the first day, and decreased plasma insulin and leptin levels, without change in blood glucose levels. Reduced leptin levels were compensated by increased expression of leptin receptors in the hypothalamus, whereas no compensations occurred in insulin receptors. The present results on body weight loss and increased food intake replicate previous studies from our group. The fact that reduced insulin levels did not lead to compensatory changes in hypothalamic insulin receptors, suggests that this hormone may be, at least in part, responsible for PSD-induced dysregulation in energy metabolism.
Available from: David A Bechtold
- "Substantial progress has been made in the identification of central cellular pathways involved in mediating the effects of leptin on energy intake. These include neurons of the arcuate hypothalamic nucleus, which contain either proopiomelanocortin (POMC) or neuropeptide Y (NPY)/agouti-related peptide (Balthasar et al., 2004; Mercer et al., 1996; van de Wall et al., 2007), as well as neurons in the ventromedial hypothalamic nucleus that contain SF-1/ PACAP (Dhillon et al., 2006; Hawke et al., 2009). However, selective deletion of Lepr in first-order sensing neurons in the arcuate and ventromedial nuclei produces relatively mild obese phenotypes , suggesting additional populations of leptin-sensing neurons and, in particular, populations that mediate the important effects of leptin on adaptive thermogenesis and energy expenditure . "
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ABSTRACT: Leptin is a critical regulator of metabolism, which acts on brain receptors (Lepr) to reduce energy intake and increase energy expenditure. Some of the cellular pathways mediating leptin's anorectic actions are identified, but those mediating the thermogenic effects have proven more difficult to decipher. We define a population of neurons in the dorsomedial hypothalamic nucleus (DMH) containing the RFamide PrRP, which is activated by leptin. Disruption of Lepr selectively in these cells blocks thermogenic responses to leptin and causes obesity. A separate population of leptin-insensitive PrRP neurons in the brainstem is required, instead, for the satiating actions of the gut-derived hormone cholecystokinin (CCK). Global deletion of PrRP (in a loxSTOPlox-PrRP mouse) results in obesity and attenuated responses to leptin and CCK. Cre-recombinase-mediated reactivation of PrRP in brainstem rescues the anorectic actions of CCK, but reactivation in the hypothalamus is required to re-establish the thermogenic effect of leptin.
Available from: Sang Hyun Moh
- "These studies employed different experimental models such as insulin receptor knock out and db/db mice, and Zucker fa/fa rats which lack leptin receptors in both CNS and periphery (Chua et al., 1996; Bruning et al., 2000; Koch et al., 2008). In addition neuron-specific leptin receptor knockout mice provided obvious evidence on the role of leptin action in the CNS (Balthasar et al., 2004; van de Wall et al., 2008). "
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ABSTRACT: The central actions of leptin and insulin are essential for the regulation of energy and glucose homeostasis. In addition to the crucial effects on the hypothalamus, emerging evidence suggests that the leptin and insulin signaling can act on other brain regions to mediate the reward value of nutrients. Recent studies have indicated the midbrain dopaminergic neurons as a potential site for leptin' and insulin's actions on mediating the feeding behaviors and therefore affecting the energy balance. Although molecular details about the integrative roles of leptin and insulin in this subset of neurons remain to be investigated, substantial body of evidence by far imply that the signaling pathways regulated by leptin and insulin may play an essential role in the regulation of energy balance through the control of food-associated reward. This review therefore describes the convergence of energy regulation and reward system, particularly focusing on leptin and insulin signaling in the midbrain dopaminergic neurons.
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