Identification of targets of leptin action in rat hypothalamus.

Schwartz, Michael W.; Seeley, Randy J.; Campfield, L. Arthur; Burn, Paul; Baskin, Denis G.

doi:10.1172/jci118891

Cited by 1,396 publications

(903 citation statements)

References 34 publications

(30 reference statements)

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“…In the present study, we found that leptin directly increased the mRNA levels of both CRF and Ucn2/3 in hypothalamic N39 cells, indicating that leptin acts directly on CRF and Ucn2/3 neurons via the Ob-Rb in the hypothalamus. Both in vivo and in vitro studies have shown that leptin increases expression of CRF in the hypothalamus [12,28,43,54]. In fact, simultaneous injection of leptin and a non-specific CRF receptor antagonist confirmed that a ligand for CRF receptor contributes to leptin's anorectic effect [21,59].…”

Section: Discussionmentioning

confidence: 95%

Regulation of corticotropin-releasing factor and urocortin 2/3 mRNA by leptin in hypothalamic N39 cells

et al. 2013

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Corticotropin-releasing factor (CRF) activates the pituitary-adrenal axis during stress, and shows anorectic effects via CRF type 1 receptors in the hypothalamus.Both urocortin (Ucn) 2 and Ucn3 also act as anorectic neuropeptides via CRF type 2 receptors. Leptin, a product of the obesity gene secreted mainly from adipose tissue, reduces food intake and increases energy expenditure. A possible interaction between leptin and CRF/Ucns has been suggested, as leptin can regulate expression and activation of CRF and Ucns in the hypothalamus. This study aimed to explore the possible function of leptin in the hypothalamus, and its effects in regulating CRF and Ucns. The study identified mRNA expression of the leptin receptor (Ob-R) and its subtypes, CRF, and Ucn2/3 in mouse hypothalamic N39 cells. Leptin stimulated signal transducer and activators of transcription type 3 (STAT3) phosphorylation, directly increased the mRNA levels of both CRF and Ucn2/3 in hypothalamic cells, and increased Ob-Rb mRNA levels. A Janus kinase inhibitor inhibited the leptin-mediated increase in STAT3 phosphorylation, and then the increases in CRF and Ucn2/3 mRNA levels. Leptin may contribute to a stress response or anorectic effect via the regulation 2 of CRF and Ucn2/3 in the hypothalamus.

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Section: Discussionmentioning

confidence: 95%

Regulation of corticotropin-releasing factor and urocortin 2/3 mRNA by leptin in hypothalamic N39 cells

et al. 2013

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“…It had been shown that direct delivery of leptin to the lateral or third ventricle suppresses food intake up to 24 h after treatment (156,192). The finding was consistent with the hypothalamic model, but did not rule out the possibility of extrahypothalamic contribution.…”

Section: Interoceptorsmentioning

confidence: 87%

The Neuroanatomical Axis for Control of Energy Balance

Grill

Kaplan

2002

Frontiers in Neuroendocrinology

351

219

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The hypothalamic feeding-center model, articulated in the 1950s, held that the hypothalamus contains the interoceptors sensitive to blood-borne correlates of available or stored fuels as well as the integrative substrates that process metabolic and visceral afferent signals and issue commands to brainstem mechanisms for the production of ingestive behavior. A number of findings reviewed here, however, indicate that sensory and integrative functions are distributed across a central control axis that includes critical substrates in the basal forebrain as well as in the caudal brainstem. First, the interoceptors relevant to energy balance are distributed more widely than had been previously thought, with a prominent brainstem complement of leptin and insulin receptors, glucose-sensing mechanisms, and neuropeptide mediators. The physiological relevance of this multiple representation is suggested by the demonstration that similar behavioral effects can be obtained independently by stimulation of respective forebrain and brainstem subpopulations of the same receptor types (e.g., leptin, CRH, and melanocortin). The classical hypothalamic model is also challenged by the integrative achievements of the chronically maintained, supracollicular decerebrate rat. Decerebrate and neurologically intact rats show similar discriminative responses to taste stimuli and are similarly sensitive to intake-inhibitory feedback from the gut. Thus, the caudal brainstem, in neural isolation from forebrain influence, is sufficient to mediate ingestive responses to a range of visceral afferent signals. The decerebrate rat, however, does not show a hyperphagic response to food deprivation, suggesting that interactions between forebrain and brainstem are necessary for the behavioral response to systemic/ metabolic correlates of deprivation in the neurologically intact rat. At the same time, however, there is evidence suggesting that hypothalamic-neuroendocrine responses to fasting depend on pathways ascending from brainstem. Results reviewed are consistent with a distributionist (as opposed to hierarchical) model for the control of energy balance that emphasizes: (i) control mechanisms endemic to hypothalamus and brainstem that drive their unique effector systems on the basis of local interoceptive, and in the brainstem case, visceral, afferent inputs and (ii) a set of uni-and bidirectional interactions that coordinate adaptive neuroendocrine, autonomic, and behavioral responses to changes in metabolic status. KEY WORDS: feeding behavior; leptin; glucose sensing; decerebrate; neuropeptide; hypothalamic model; caudal brainstem; energy balance.

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“…Interestingly, leptin appears to be both upstream and downstream of hypothalamic CRF 2 action, perhaps providing a physiological context for the current findings. Leptin has receptors on CRFergic hypothalamic neurons (Hakansson et al, 1998), provokes secretion of CRF receptor agonists from hypothalamic explants (Costa et al, 1997;Raber et al, 1997), and stimulates PVN CRF (Schwartz et al, 1996) and VMH CRF 2 mRNA synthesis (Hashimoto et al, 2004). Conversely, Zucker obese (fa/fa) rats, which lack a fully functional leptin receptor, have reduced VMH CRF 2 mRNA expression (Richard et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Delayed Satiety-Like Actions and Altered Feeding Microstructure by a Selective Type 2 Corticotropin-Releasing Factor Agonist in Rats: Intra-Hypothalamic Urocortin 3 Administration Reduces Food Intake by Prolonging the Post-Meal Interval

Fekete

Inoue

Zhao

et al. 2006

Neuropsychopharmacol

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Brain corticotropin-releasing factor/urocortin (CRF/Ucn) systems are hypothesized to control feeding, with central administration of 'type 2' urocortins producing delayed anorexia. The present study sought to identify the receptor subtype, brain site, and behavioral mode of action through which Ucn 3 reduces nocturnal food intake in rats. Non-food-deprived male Wistar rats (n ¼ 176) were administered Ucn 3 into the lateral (LV) or fourth ventricle, or into the ventromedial or paraventricular nuclei of the hypothalamus (VMN, PVN) or the medial amygdala (MeA), regions in which Ucn 3 is expressed in proximity to CRF 2 receptors. LV Ucn 3 suppressed ingestion during the third-fourth post-injection hours. LV Ucn 3 anorexia was reversed by cotreatment with astressin 2 -B, a selective CRF 2 antagonist and not observed following equimole subcutaneous or fourth ventricle administration. Bilateral intra-VMN and intra-PVN infusion, more potently than LV infusion, reduced the quantity (57-73%) and duration of ingestion (32-68%) during the third-fourth post-infusion hours. LV, intra-PVN and intra-VMN infusion of Ucn 3 slowed the eating rate and reduced intake by prolonging the post-meal interval. Intra-VMN Ucn 3 reduced feeding bout size, and intra-PVN Ucn 3 reduced the regularity of eating from pellet to pellet. Ucn 3 effects were behaviorally specific, because minimal effective anorectic Ucn 3 doses did not alter drinking rate or promote a conditioned taste aversion, and site-specific, because intra-MeA Ucn 3 produced a nibbling pattern of more, but smaller meals without altering total intake. The results implicate the VMN and PVN of the hypothalamus as sites for Ucn 3-CRF 2 control of food intake.

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Identification of targets of leptin action in rat hypothalamus.

Cited by 1,396 publications

References 34 publications

Regulation of corticotropin-releasing factor and urocortin 2/3 mRNA by leptin in hypothalamic N39 cells

Regulation of corticotropin-releasing factor and urocortin 2/3 mRNA by leptin in hypothalamic N39 cells

The Neuroanatomical Axis for Control of Energy Balance

Delayed Satiety-Like Actions and Altered Feeding Microstructure by a Selective Type 2 Corticotropin-Releasing Factor Agonist in Rats: Intra-Hypothalamic Urocortin 3 Administration Reduces Food Intake by Prolonging the Post-Meal Interval

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