Developmental changes in hypothalamic leptin receptor: relationship with the postnatal leptin surge and energy balance neuropeptides in the postnatal rat

Cottrell, Elizabeth; Cripps, Roselle L.; Duncan, J.L.; Barrett, Perry; Mercer, Julian G.; Herwig, Annika; Ozanne, Susan E.

doi:10.1152/ajpregu.90690.2008

Cited by 84 publications

(87 citation statements)

References 48 publications

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“…In the adult, the ventricular lining of the hypothalamus (the location of hypothalamic neural stem cells) shows little, if any, response to leptin in vivo (ref. 30 and data not shown). Likewise, we were unable to reliably and robustly detect an effect of leptin on hypothalamic neurospheres in vitro (data not shown).…”

Section: Figurementioning

confidence: 76%

Remodeling of the arcuate nucleus energy-balance circuit is inhibited in obese mice

McNay¹,

Briançon²,

Kokoeva³

et al. 2012

J. Clin. Invest.

274

299

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In the CNS, the hypothalamic arcuate nucleus (ARN) energy-balance circuit plays a key role in regulating body weight. Recent studies have shown that neurogenesis occurs in the adult hypothalamus, revealing that the ARN energy-balance circuit is more plastic than originally believed. Changes in diet result in altered gene expression and neuronal activity in the ARN, some of which may reflect hypothalamic plasticity. To explore this possibility, we examined the turnover of hypothalamic neurons in mice with obesity secondary to either high-fat diet (HFD) consumption or leptin deficiency. We found substantial turnover of neurons in the ARN that resulted in ongoing cellular remodeling. Feeding mice HFD suppressed neurogenesis, as demonstrated by the observation that these mice both generated fewer new neurons and retained more old neurons. This suppression of neuronal turnover was associated with increased apoptosis of newborn neurons. Leptin-deficient mice also generated fewer new neurons, an observation that was explained in part by a loss of hypothalamic neural stem cells. These data demonstrate that there is substantial postnatal turnover of the arcuate neuronal circuitry in the mouse and reveal the unexpected capacity of diet and leptin deficiency to inhibit this neuronal remodeling. This insight has important implications for our understanding of nutritional regulation of energy balance and brain function. IntroductionThe hypothalamus is a critical regulator of energy balance. Lesions of the ventromedial nucleus (1) or arcuate nucleus (ARN) (2) result in obesity, while lesions of the lateral hypothalamic area (3) result in weight loss. Energy-related signals such as leptin (4, 5) are integrated by responsive neurons in the ARN and ventromedial hypothalamus. In particular, leptin stimulates the anorexigenic proopiomelanocortin (POMC) neurons and inhibits orexigenic neuropeptide Y (NPY) neurons. In situations of negative energy balance, reduced leptin levels inhibit the activity of POMC neurons and activate NPY neurons. While this feedback circuit is essential for normal energy homeostasis (see review refs. 6, 7), most obesity is associated with dysregulation of the circuit and leptin resistance (8).Two commonly studied mouse models of obesity, the high-fat diet-induced (HFD-induced) obesity (DIO) model (9) and the more severe obesity arising from the lack of leptin (4, 5), share features such as increased fat mass, hyperglycemia, hyperinsulinemia, and activation of the adrenal axis but are distinct in that DIO mice have elevated peripheral leptin levels and are resistant to both endogenous and exogenous leptin (8). DIO mice also become resistant to centrally administered leptin (10). This phenomenon is reversible, with leptin responsiveness returning several months after cessation of HFD consumption (11).The molecular and cellular mechanisms underlying hypothalamic dysfunction in the context of obesity over long-time frames are still not fully understood. Possible mechanisms include impaired leptin transport acr...

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Section: Figurementioning

confidence: 76%

Remodeling of the arcuate nucleus energy-balance circuit is inhibited in obese mice

McNay¹,

Briançon²,

Kokoeva³

et al. 2012

J. Clin. Invest.

274

299

View full text Add to dashboard Cite

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“…Neurons in the ARC express POMC around E 12 [69] and NPY around E 14 [70] . The expression of both orexigenic and anorexigenic neuropeptides continues to increase during the postnatal period, reaching their maximum values around postnatal day (PND) 15 [71] . Although neurogenesis occurs prenatally, the establishment of connections between neurons in the different nuclei takes place postnatally, with innervation between neurons of the ARC and DMH being established at PND 6 and between neurons of the ARC and PVN and LH occurring at PND 10 and PND 12, respectively [72] .…”

Section: Hypothalamic Developmentmentioning

confidence: 99%

Leptin in Early Life: A Key Factor for the Development of the Adult Metabolic Profile

Granado¹,

Fuente-Martín²,

García‐Cáceres³

et al. 2012

Obes Facts

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Leptin levels during the perinatal period are important for the development of metabolic systems involved in energy homeostasis. In rodents, there is a postnatal leptin surge, with circulating leptin levels increasing around postnatal day (PND) 5 and peaking between PND 9 and PND 10. At this time circulating leptin acts as an important trophic factor for the development of hypothalamic circuits that control energy homeostasis and food seeking and reward behaviors. Blunting the postnatal leptin surge results in long-term leptin insensitivity and increased susceptibility to diet-induced obesity during adulthood. Pharmacologically increased leptin levels in the postnatal period also have long-term effects on metabolism. Nevertheless, this effect is controversial as postnatal hyperleptinemia is reported to both increase and decrease the predisposition to obesity in adulthood. The different effects reported in the literature could be explained by the different moments at which this hormone was administered, suggesting that modifications of the neonatal leptin surge at specific time points could selectively affect the development of central and peripheral systems that are undergoing modifications at this moment resulting in different metabolic and behavioral outcomes. In addition, maternal nutrition and the hormonal environment during pregnancy and lactation may also modulate the offspring's response to postnatal modifications in leptin levels. This review highlights the importance of leptin levels during the perinatal period in the development of metabolic systems that control energy homeostasis and how modifications of these levels may induce long-lasting and potentially irreversible effects on metabolism.

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“…Tanycytes sense biologically active hormones and metabolites from the ventricle and portal blood vessels, and they connect the ventricle and neighbouring pars tuberalis via networks of cisterna (Guerra et al 2010, Frayling et al 2011, Bolborea & Dale 2013, Balland et al 2014. They express receptors and/or transport proteins for a wide variety of known and unknown biologically active compounds (Graham et al 2003, Rodriguez et al 2005, Barrett et al 2007, Coppola et al 2007, Cottrell et al 2009, Nilaweera et al 2011, Shearer et al 2012, Dardente et al 2014. Notably, tanycytes express type 2 deiodinase (Dio2) at very high levels.…”

Section: Introductionmentioning

confidence: 99%

Dual signal transduction pathways activated by TSH receptors in rat primary tanycyte cultures

Bolborea¹,

Helfer²,

Ebling³

et al. 2015

Journal of Molecular Endocrinology

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Tanycytes play multiple roles in hypothalamic functions, including sensing peripheral nutrients and metabolic hormones, regulating neurosecretion and mediating seasonal cycles of reproduction and metabolic physiology. This last function reflects the expression of TSH receptors in tanycytes, which detect photoperiod-regulated changes in TSH secretion from the neighbouring pars tuberalis. The present overall aim was to determine the signal transduction pathway by which TSH signals in tanycytes. Expression of the TSH receptor in tanycytes of 10-day-old Sprague Dawley rats was observed by in situ hybridisation. Primary ependymal cell cultures prepared from 10-day-old rats were found by immunohistochemistry to express vimentin but not GFAP and by PCR to express mRNA for Dio2, Gpr50, Darpp-32 and Tsh receptors that are characteristic of tanycytes. Treatment of primary tanycyte/ependymal cultures with TSH (100 IU/l) increased cAMP as assessed by ELISA and induced a cAMP-independent increase in the phosphorylation of ERK1/2 as assessed by western blot analysis. Furthermore, TSH (100 IU/l) stimulated a 2.17-fold increase in Dio2 mRNA expression. We conclude that TSH signal transduction in cultured tanycytes signals via Ga s to increase cAMP and via an alternative G protein to increase phosphorylation of ERK1/2.

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Developmental changes in hypothalamic leptin receptor: relationship with the postnatal leptin surge and energy balance neuropeptides in the postnatal rat

Cited by 84 publications

References 48 publications

Remodeling of the arcuate nucleus energy-balance circuit is inhibited in obese mice

Remodeling of the arcuate nucleus energy-balance circuit is inhibited in obese mice

Leptin in Early Life: A Key Factor for the Development of the Adult Metabolic Profile

Dual signal transduction pathways activated by TSH receptors in rat primary tanycyte cultures

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