Ageing increases SOCS-3 expression in rat hypothalamus: effects of food restriction

Peralta, Sara; Carrascosa, Jóse M.; Gallardo, Nilda; Ros, Manuel; Arribas, Carmen

doi:10.1016/s0006-291x(02)00906-3

Cited by 82 publications

(57 citation statements)

References 15 publications

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“…In the current experiment, the fact that the arcuate nucleus presents normal leptin-induced STAT3 phosphorylation during pregnancy suggests that transport into the brain is not significantly compromised. The underlying cause of the decrease in leptin-induced STAT3 phosphorylation in the VMN and PVN is unknown but could include decreases in the Ob-Rz, as has been demonstrated in the VMN in pregnant rats (Ladyman & Grattan 2005) or increases in inhibitory molecules of the JAK/STAT pathway such as SOCS or PTP1B, which have been seen in diet-induced (Bjorbaek et al 1998, Munzberg et al 2004, White et al 2009 or age-induced leptin-resistant animals (Peralta et al 2002, Morrison et al 2007.…”

Section: Discussionmentioning

confidence: 99%

Suppression of leptin-induced hypothalamic JAK/STAT signalling and feeding response during pregnancy in the mouse

Ladyman¹,

Fieldwick²,

Grattan³

2012

Reproduction

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Hyperphagia during pregnancy, despite rising concentrations of the satiety hormone leptin, suggests that a state of leptin resistance develops. This study investigated the satiety response and hypothalamic responses to leptin during pregnancy in the mouse. Pregnant (day 13) and nonpregnant mice received an i.p. injection of either leptin or vehicle and then 24-h food intake was measured. Further groups of pregnant and nonpregnant mice were perfused 2 h after leptin or vehicle injections and brains were processed for pSTAT3 and pSTAT5 immunohistochemistry. Leptin treatment significantly decreased food intake in nonpregnant mice. In pregnant mice, however, leptin treatment did not suppress food intake, indicating a state of leptin resistance. In the arcuate nucleus, leptin treatment increased the number of cells positive for pSTAT3, a marker of leptin activity, to a similar degree in both nonpregnant and pregnant mice. In the ventromedial nucleus (VMN), the leptin-induced increase in pSTAT3-positive cell number was significantly reduced in pregnant mice compared to that in nonpregnant mice. In nonpregnant mice, leptin treatment had no effect on the number of pSTAT5-positive cells, suggesting that in this animal model, leptin does not act through STAT5. In pregnant mice, basal levels of pSTAT5 were higher than in nonpregnant mice, and leptin treatment led to a decrease in the number of pSTAT5-positive cells in the hypothalamus. Overall, these results demonstrate that during pregnancy in the mouse, a state of leptin resistance develops, and this is associated with a reduced sensitivity of the VMN to leptin.Reproduction (2012) 144 83-90

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Section: Discussionmentioning

confidence: 99%

Suppression of leptin-induced hypothalamic JAK/STAT signalling and feeding response during pregnancy in the mouse

Ladyman¹,

Fieldwick²,

Grattan³

2012

Reproduction

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“…Enhanced leptin sensitivity and attenuation of diet-induced obesity are also observed in mice with heterozygous SOCS3 deficiency (Howard et al 2004). Finally, leptin-resistant lethal yellow (A y /a) mice (Bjørbaek et al 1998), diet-induced obese C57BL/6J mice (Münzberg et al 2004) and age-induced obese F344!BN (Scarpace et al 2002) and Wistar (Peralta et al 2002) rats have all been shown to have excessive hypothalamic expression of SOCS3, indicating its importance in aetiologically different forms of obesity.…”

Section: Discussionmentioning

confidence: 99%

Regulation of body mass and adiposity in the field vole, Microtus agrestis: a model of leptin resistance

Król¹,

Speakman²

2007

Journal of Endocrinology

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Adult mammals are typically highly resistant to perturbations in their energy balance. In obese humans, however, this control appears to be lost. Apart from a few exceptional cases, this loss of control occurs despite appropriate levels of circulating leptin -suggesting that elevated adiposity may be a consequence of failure to respond to the leptin signal: leptin resistance. When cold-acclimated male field voles (Microtus agrestis) are transferred from short (SD, 8 h light) to long (LD, 16 h light) photoperiods, they increase dramatically in body mass and fatness for about 4 weeks. After this period, their mass stabilizes at a new plateau about 25% higher than animals maintained in SD. The increase in adiposity is not caused by significant increases in food intake, but reflects an increase in digestive efficiency. Measures of circulating leptin reveal that the increased adiposity is matched by increased circulating leptin. By infusing voles with exogenous leptin, we have demonstrated that SD voles are leptin sensitive (reducing both body mass and food intake), whereas LD animals are leptin resistant. Voles may therefore be a useful model for understanding the process of leptin resistance. The change in leptin sensitivity in voles was not associated with changes in the levels of gene expression of the orexogenic or anorexogenic neuropeptides, such as neuropeptide Y, agouti-related peptide, POMC and cocaine-and amphetamine-regulated transcript, measured in the hypothalamic arcuate nucleus (ARC). During the phase that body mass was increasing, however, there was a transient increase in the ARC expression of suppressor of cytokine signalling-3 (SOCS3). These data suggest that the changes in the expression of SOCS3 in the ARC may be involved in leptin resistance. However, the mechanism by which these changes may be linked to alterations in digestive efficiency that underpin the changes in adiposity, or how the differences are signalled by changes in photoperiod, remains unclear.

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“…Consistent with this, a leptin-activated autoinhibitory action in vivo has recently been suggested for Tyr 985 in the l/l mice expressing a mutant leptin receptor where Tyr 985 was replaced with leucine (10). However, whereas elevated hypothalamic expression of SOCS3 has been reported to occur in aged rodents (36) or in mice with diet-induced obesity (18,42), it has yet to be understood whether Ob-Rb Tyr 985 -mediated mechanisms are physiologically connected to altered SOCS3 expression, particularly in the face of aging or high dietary fat intake. Moreover, direct in vivo evidence also has been lacking with respect to whether there exist potential interplays between Ob-Rb Tyr 985 signaling and other Ob-Rb tyrosine-dependent mechanisms, which act to influence the homeostatic control of energy balance.…”

Section: Leptin Regulates Energy Homeostasis Through Central Activatimentioning

confidence: 99%

Signaling through Tyr⁹⁸⁵ of Leptin Receptor as an Age/Diet-Dependent Switch in the Regulation of Energy Balance

You

Jiang

et al. 2010

Molecular and Cellular Biology

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Leptin regulates energy homeostasis through central activation of multiple signaling pathways mediated byOb-Rb, the long form of leptin receptor. Leptin resistance underlies the pathogenic development of obesity, which is closely associated with environmental factors. To further understand the physiological function of leptin signaling mechanisms, we generated a knock-in line of mice (Y985F) expressing a mutant Ob-Rb with a phenylalanine substitution for Tyr 985 , one of the three intracellular tyrosines that mediate leptin's signaling actions. Surprisingly, whereas young homozygous Y985F animals were slightly leaner, they exhibit adult-onset or diet-induced obesity. Importantly, both age-dependent and diet-induced deterioration of energy balance was paralleled with pronounced leptin resistance, which was largely attributable to attenuation of leptin-responsive hypothalamic STAT3 activation as well as prominently elevated expression of hypothalamic SOCS3, a key negative regulator of leptin signaling. Thus, these results unmask distinct binary roles for Try 985 -mediated signaling in energy metabolism, acting as an age/diet-dependent regulatory switch to counteract age-associated or diet-induced obesity.As a component of the metabolic syndrome, obesity is closely associated with increased risk for the development of type 2 diabetes and cardiovascular disorders (16). Arising from a chronic imbalance between energy intake and expenditure, the pathogenic progression of obesity is attributable to the complex interactions between genetic factors and environmental influences. In mammals, energy balance is maintained through multiple homeostatic mechanisms that operate coordinately in response to hormonal and nutritional cues. Leptin is an adipose-secreted hormone (43) that plays a pivotal role in the regulation of energy metabolism. Acting through its activeform receptor Ob-Rb in distinct classes of leptin-responsive neurons (11,14,34), leptin activates multiple signaling pathways in the hypothalamus to regulate food intake and energy expenditure. Mice with deficiency in leptin (ob/ob) or its functional receptor (db/db) develop morbid obesity, hyperphagia, and diabetes (20). Impaired leptin responsiveness, i.e., leptin resistance (33), is a key characteristic of the metabolic defects that are responsible for disrupted energy control, presumably underlying the pathogenic development of human obesity (29). Although diminished leptin signaling has been found to occur in association with aging (21, 39) or feeding of a high-fat diet (HFD) (17, 18), the exact physiological mechanisms linking the environmental factors to the impairment in leptin-mediated regulation of energy metabolism remain largely elusive.Leptin binds to Ob-Rb and elicits an array of subsequent intracellular signaling cascades (7, 22) via Jak2 phosphorylation. The mouse Ob-Rb comprises three cytoplasmic tyrosine residues, Tyr 985 , Tyr 1077 , and Tyr 1138 , which are known to be phosphorylated and mediate leptin's physiological functions (22,26). The phosp...

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Ageing increases SOCS-3 expression in rat hypothalamus: effects of food restriction

Cited by 82 publications

References 15 publications

Suppression of leptin-induced hypothalamic JAK/STAT signalling and feeding response during pregnancy in the mouse

Suppression of leptin-induced hypothalamic JAK/STAT signalling and feeding response during pregnancy in the mouse

Regulation of body mass and adiposity in the field vole, Microtus agrestis: a model of leptin resistance

Signaling through Tyr⁹⁸⁵ of Leptin Receptor as an Age/Diet-Dependent Switch in the Regulation of Energy Balance

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Ageing increases SOCS-3 expression in rat hypothalamus: effects of food restriction

Cited by 82 publications

References 15 publications

Suppression of leptin-induced hypothalamic JAK/STAT signalling and feeding response during pregnancy in the mouse

Suppression of leptin-induced hypothalamic JAK/STAT signalling and feeding response during pregnancy in the mouse

Regulation of body mass and adiposity in the field vole, Microtus agrestis: a model of leptin resistance

Signaling through Tyr985 of Leptin Receptor as an Age/Diet-Dependent Switch in the Regulation of Energy Balance

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Signaling through Tyr⁹⁸⁵ of Leptin Receptor as an Age/Diet-Dependent Switch in the Regulation of Energy Balance