Hindbrain leptin receptor stimulation enhances the anorexic response to cholecystokinin

Williams, D.B.; Baskin, Denis G.; Schwartz, Michael W.

doi:10.1152/ajpregu.00182.2009

Cited by 45 publications

(42 citation statements)

References 29 publications

(43 reference statements)

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“…This effect could be partly mediated by the stimulation of ARH melanocortin neurons, which project to the NTS, since mice lacking OB-Rb in both AgRP and POMC neurons show increased meal sizes and blunted response to the early anorectic effects of leptin (55). In addition, leptin directly injected into the dorsal vagal complex enhances CCK-induced anorectic effects (89), and knocking down leptin receptor expression in the dorsal vagal complex of rats eliminates CCK-induced feeding suppression (90). Collectively, these data suggest that leptin acts on a distributed network of neurons in the brainstem and hypothalamus to regulate feeding, and reciprocal connections between these two brain regions assure proper coordination of food intake over longer periods of time.…”

Section: Figurementioning

confidence: 99%

Sixteen years and counting: an update on leptin in energy balance

Gautron¹,

Elmquist²

2011

J. Clin. Invest.

311

251

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Cloned in 1994, the ob gene encodes the protein hormone leptin, which is produced and secreted by white adipose tissue. Since its discovery, leptin has been found to have profound effects on behavior, metabolic rate, endocrine axes, and glucose fluxes. Leptin deficiency in mice and humans causes morbid obesity, diabetes, and various neuroendocrine anomalies, and replacement leads to decreased food intake, normalized glucose homeostasis, and increased energy expenditure. Here, we provide an update on the most current understanding of leptin-sensitive neural pathways in terms of both anatomical organization and physiological roles. IntroductionThe nervous system regulates energy balance at the organismal level by constantly adjusting energy intake, expenditure, and storage. The influence of the nervous system over metabolic functions was first suggested at the beginning of the 20th century when excessive adiposity was associated with pituitary tumors and injury to the hypothalamus (1). However, it was not until the 1940s that selective surgical lesions of certain hypothalamic areas were found to result in extreme obesity or leanness in rats (2, 3). Over the last few decades, numerous discoveries substantially extended our understanding of the neural control of metabolism. However, it is safe to say that none were more important than the cloning of the ob gene by Friedman and colleagues in 1994 (4). The ob gene encodes the protein leptin, which is a hormone produced and secreted by the white adipose tissue, and consequently, its circulating levels are closely related to body fat mass (5, 6). Leptin deficiency in mice homozygous for a mutant ob gene (ob/ob mice) causes morbid obesity, diabetes, and various neuroendocrine anomalies, and leptin replacement leads to decreased food intake, normalized glucose homeostasis, and increased energy expenditure (7-10). Several splice variants of the leptin receptor have been identified, and the "short forms" are widely expressed in multiple tissues (11). The "long form" of the leptin receptor encodes a protein with a longer cytoplasmic domain (OB-Rb) that is highly expressed in particular sites within the CNS (refs. 10, 12, and Table 1). The short forms of the leptin receptor are also present within the CNS (11), but OB-Rb is sufficient for leptin actions on metabolism (13,14). OB-Rb is a type 1 cytokine receptor, which stimulates the JAK/STAT3 pathway (15) and PI3K (16,17). Leptin induces transcriptional changes of several genes via the JAK/STAT3 pathway, and rapid changes in cellular activity and membrane potential may underlie the acute actions of leptin (18). While actions of this hormone in peripheral tissues have been identified, studies in genetically modified mice have demonstrated that leptin action only in the CNS is sufficient to regulate body weight, feeding, energy expenditure, and glucose metabolism (13,(19)(20)(21).Since leptin is clearly not the only metabolic signal acting on the brain, the range of its effects on behavior, metabolism, and endocrinology is trul...

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Section: Figurementioning

confidence: 99%

Sixteen years and counting: an update on leptin in energy balance

Gautron¹,

Elmquist²

2011

J. Clin. Invest.

311

251

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“…Sections were deparaffinized in Leica Bond dewax solution (Leica Microsystems, Buffalo Grove, IL) and rehydrated through 95% EtOH. Immunohistochemical staining of pSTAT3 was performed using a modification of previously published methods (23,46), using a Leica Bond-MAX automated immunostainer (Leica Microsystems). An antigen retrieval (heat-induced epitope retrieval) technique was used in which slides were incubated in citrate buffer (pH 6.0, Bond Epitope Retrieval Solution 1; Leica Microsystems) at 100°C for 10 min.…”

Section: Leptin Sensitivity In Age-matched Lean Dio and Weight-redumentioning

confidence: 99%

Effects of leptin replacement alone and with exendin-4 on food intake and weight regain in weight-reduced diet-induced obese rats

Reidelberger

Haver

Chelikani

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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. Effects of leptin replacement alone and with exendin-4 on food intake and weight regain in weight-reduced diet-induced obese rats. Am J Physiol Endocrinol Metab 302: E1576 -E1585, 2012. First published April 17, 2012; doi:10.1152/ajpendo.00058.2012.-Weight loss in obese humans produces a relative leptin deficiency, which is postulated to activate potent orexigenic and energy conservation mechanisms to restrict weight loss and promote weight regain. Here we determined whether leptin replacement alone or with GLP-1 receptor agonist exendin-4 attenuates weight regain or promotes greater weight loss in weight-reduced diet-induced obese (DIO) rats. Forty percent restriction in daily intake of a high-fat diet in DIO rats for 4 wk reduced body weight by 12%, body fat by 29%, and plasma leptin by 67% and normalized leptin sensitivity. When food restriction ended, body weight, body fat, and plasma leptin increased rapidly. Daily administration of leptin [3-h intraperitoneal (ip) infusions (4 nmol·kg Ϫ1 ·h Ϫ1 )] at onset and end of dark period for 3 wk did not attenuate hyperphagia and weight regain, nor did it affect mean daily meal sizes or meal numbers. Exendin-4 (50 pmol·kg Ϫ1 ·h Ϫ1 ) infusions during the same intervals prevented postrestriction hyperphagia and weight regain by normalizing meal size. Coadministration of leptin and exendin-4 did not reduce body weight more than exendin-4 alone. Instead, leptin began to attenuate the inhibitory effects of exendin-4 on food intake, meal size, and weight regain by the end of the second week of administration. Plasma leptin in rats receiving leptin was sevenfold greater than in rats receiving vehicle and 17-fold greater than in rats receiving exendin-4. Together, these results do not support the hypothesis that leptin replacement alone or with exendin-4 attenuates weight regain or promotes greater weight loss in weight-reduced DIO rats. food restriction; hyperphagia; leptin sensitivity; glucagon-like peptide-1 receptor agonist OBESITY IS A CHRONIC, stigmatized, and costly disease that is rarely curable and is increasing in prevalence in most of the world (4). Current therapies for producing weight loss in obese individuals, i.e., dieting, exercise, and medications, are woefully ineffective in producing long-term weight loss. This is likely due to redundancy and plasticity in the complex physiological system that controls food intake and regulates energy reserves. Many experts believe that multidrug therapy aimed at different components of this regulatory system will be required to produce a significant reduction in adiposity (4,13,21,22).An important early step in the development of antiobesity drugs is determining whether chronic administration of anorexigenic substances, alone or in combination, can produce a prolonged decrease in daily food intake and adiposity in experimental animals. Methods of administration usually include daily injections or insertion of an osmotic minipump beneath the skin or into the peritoneal cavity to deliver substances continuously for 1 wk...

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“…Celles-ci ont ensuite été étendues à l'intégration des signaux intestinaux avec les affé-rences mélanocortinergiques descendant de l'hypothalamus, et les signaux hormonaux de disponibilité énergé-tique. Ainsi, l'administration dans le cmNTS de leptine ou de melanotan 2 (un agoniste des récepteurs 3 et 4 aux mélanocortines) à des doses sans effet sur la prise alimentaire, augmente la réponse anorexique qu'induit une administration intrapéritonéale de cholécystokinine (CCK) [16,17]. Plus récemment, nous avons montré, dans des expériences similaires, que la détection de la leucine par les neurones du cmNTS est également intégrée aux signaux neuronaux et hormonaux quement par ces neurones et qui permettraient de les identifier.…”

Section: Nouvelleunclassified

Le rôle du noyau du tractus solitaire dans la détection et l’intégration de multiples signaux métaboliques

Blouet

2013

Med Sci (Paris)

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Hindbrain leptin receptor stimulation enhances the anorexic response to cholecystokinin

Cited by 45 publications

References 29 publications

Sixteen years and counting: an update on leptin in energy balance

Sixteen years and counting: an update on leptin in energy balance

Effects of leptin replacement alone and with exendin-4 on food intake and weight regain in weight-reduced diet-induced obese rats

Le rôle du noyau du tractus solitaire dans la détection et l’intégration de multiples signaux métaboliques

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