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

Ladyman, Sharon R; Fieldwick, Diana; Grattan, David R.

doi:10.1530/rep-12-0112

Cited by 66 publications

(77 citation statements)

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“…We also showed that this increase induced by leptin was absent following pre-treatment with PA, indicating that PA can impair the leptin signaling pathway in the PVN. A previous study has also reported that mice resistant to leptin during pregnancy have defective leptin JAK2-STAT3 signaling in the PVN [45]. SOCS3 is a leptin-inducible inhibitor of leptin JAK2-STAT3 signaling, and it has been suggested to mediate central leptin resistance in obesity [46].…”

Section: Discussionmentioning

confidence: 95%

Palmitic acid induces central leptin resistance and impairs hepatic glucose and lipid metabolism in male mice

Cheng

Szabo

et al. 2015

The Journal of Nutritional Biochemistry

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X. (2015). Palmitic acid induces central leptin resistance and impairs hepatic glucose and lipid metabolism in male mice. Journal of Nutritional Biochemistry, 26 (5), 541-548. Palmitic acid induces central leptin resistance and impairs hepatic glucose and lipid metabolism in male mice AbstractThe consumption of diets rich in saturated fat largely contributes to the development of obesity in modern societies. A diet high in saturated fats can induce inflammation and impair leptin signaling in the hypothalamus. However, the role of saturated fatty acids on hypothalamic leptin signaling, and hepatic glucose and lipid metabolism remains largely undiscovered. In this study, we investigated the effects of intracerebroventricular (icv) administration of a saturated fatty acid, palmitic acid (PA, C16:0), on central leptin sensitivity, hypothalamic leptin signaling, inflammatory molecules and hepatic energy metabolism in C57BL/6 J male mice. We found that the icv administration of PA led to central leptin resistance, evidenced by the inhibition of central leptin's suppression of food intake. Central leptin resistance was concomitant with impaired hypothalamic leptin signaling ( JAK2-STAT3, PKB/Akt-FOXO1) and a pro-inflammatory response (TNF-α, IL1-β, IL-6 and pIκBa) in the mediobasal hypothalamus and paraventricular hypothalamic nuclei. Furthermore, the pre-administration of icv PA blunted the effect of leptin-induced decreases in mRNA expression related to gluconeogenesis (G6Pase and PEPCK), glucose transportation (GLUT2) and lipogenesis (FAS and SCD1) in the liver of mice. Therefore, elevated central PA concentrations can induce pro-inflammatory responses and leptin resistance, which are associated with disorders of energy homeostasis in the liver as a result of diet-induced obesity. Abstract:The consumption of diets rich in saturated fat largely contributes to the development of obesity in modern societies. A diet high in saturated fats can induce inflammation and impair leptin signaling in the hypothalamus. However, the role of saturated fatty acids on hypothalamic leptin signaling, and hepatic glucose and lipid metabolism remains largely undiscovered. In this study, we investigated the effects of intracerebroventricular (icv) administration of a saturated fatty acid, palmitic acid (PA, C16:0), on central leptin sensitivity, hypothalamic leptin signaling, inflammatory molecules, and hepatic energy metabolism in C57BL/6J male mice. We found that the icv administration of PA led to central leptin resistance, evidenced by the inhibition of central leptin's suppression of food intake. Central leptin resistance was concomitant with impaired hypothalamic leptin signaling (JAK2-STAT3, PKB/Akt-FOXO1), and a pro-inflammatory response (TNF-α, IL1-β, IL-6, and pIκBa) in the mediobasal hypothalamus and paraventricular hypothalamic nuclei.Furthermore, the pre-administration of icv PA blunted the effect of leptin-induced decreases in mRNA expression related to gluconeogenesis (G6Pase and PEPCK), glucose transportation (GLUT2), ...

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Section: Discussionmentioning

confidence: 95%

Palmitic acid induces central leptin resistance and impairs hepatic glucose and lipid metabolism in male mice

Cheng

Szabo

et al. 2015

The Journal of Nutritional Biochemistry

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“…Still, GH (Furigo et al 2016) or leptin could contribute to the pSTAT5-ir observed in pregnant females, although the high levels of PLs likely account for most (if not all) of the pSTAT5 immunolabelling observed. Regarding leptin, STAT3 is the main STAT member associated with the leptin receptor (Ladyman et al 2012), whereas STAT5 phosphorylation associated with leptin signalling has been reported only in the arcuate nucleus (Gong et al 2007;Mütze et al 2007) and has not been replicated in all studies (Vaisse et al 1996). As for GH, regions of the brain showing high levels of expression of GH receptors and responsiveness to GH (detected by pSTAT5-ir; Furigo et al 2016), such as the hippocampus and dentate gyrus (Burton et al 1992) or layers 2, 3, and 5, and especially, layer 6 of the cerebral cortex (Lobie et al 1993), show no pSTAT5 labelling in any of our mice, neither in virgin nor in pregnant or lactating females.…”

Section: Immunohistochemical Detection Of Pstat5 As a Measure Of Centmentioning

confidence: 99%

Tuning the brain for motherhood: prolactin-like central signalling in virgin, pregnant, and lactating female mice

et al. 2016

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Prolactin is fundamental for the expression of maternal behaviour. In virgin female rats, prolactin administered upon steroid hormone priming accelerates the onset of maternal care. By contrast, the role of prolactin in mice maternal behaviour remains unclear. This study aims at characterizing central prolactin activity patterns in female mice and their variation through pregnancy and lactation. This was revealed by immunoreactivity of phosphorylated (active) signal transducer and activator of transcription 5 (pSTAT5-ir), a key molecule in the signalling cascade of prolactin receptors. We also evaluated non-hypophyseal lactogenic activity during pregnancy by administering bromocriptine, which suppresses hypophyseal prolactin release. Late-pregnant and lactating females showed significantly increased pSTAT5-ir resulting in a widespread pattern of immunostaining with minor variations between pregnant and lactating animals, which comprises nuclei of the sociosexual and maternal brain, including telencephalic (septum, nucleus of the stria terminalis, and amygdala), hypothalamic (preoptic, paraventricular, supraoptic, and ventromedial), and midbrain (periaqueductal grey) regions. During late pregnancy, this pattern was not affected by the administration of bromocriptine, suggesting it to be elicited mostly by non-hypophyseal lactogenic agents, likely placental lactogens. Virgin females displayed, instead, a variable pattern of pSTAT5-ir restricted to a subset of the brain nuclei labelled in pregnant and lactating mice. A hormonal substitution experiment confirmed that estradiol and progesterone contribute to the variability found in virgin females. Our results reflect how the shaping of the maternal brain takes place prior to parturition and suggest that lactogenic agents are important candidates in the development of maternal behaviours already during pregnancy.

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“…This suggests that a pregnancy-associated state of partial leptin resistance may exist within the hypothalamus. Recently, resistance to the central effects of leptin during pregnancy and its effect on food intake has been verified in mice (Ladyman et al, 2012). Grattan et al (2007) have demonstrated that intra cerebro-ventricular leptin is unable to suppress food intake in pregnant rats, as it does in non-pregnant animals.…”

Section: Correlation Between Leptin Level and Body Weight During Pregnamentioning

confidence: 99%

Leptin Gene Expression in Rabbits During Pregnancy and Fetal Life

Kirat¹,

Hamid²,

Mohamed³

et al. 2015

IJB

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Leptin may act as the critical link between adipose tissue and reproduction. Although considerable progress has been achieved in understanding the reproductive actions of leptin, much work is needed for understanding its physiological role. Till now, no data has been published about the distribution and expression levels of leptin in the rabbit maternal adipose tissue, placenta, and various fetal rabbit tissues during pregnancy and postpartum. Our results indicated that circulating leptin levels in rabbit serum during pregnancy were significantly higher than in postpartum and non pregnant rabbits. Furthermore, leptin showed positive correlations with body weight and estrogen and negative correlation with progesterone in pregnant and postpartum rabbits. RT-PCR verified the presence of RNAs encoding leptin in the rabbit maternal perirenal adipose tissue, placenta, and several fetal tissues; including brain, liver, adipose tissue, and bone. The relative abundance of leptin RNA in rabbit maternal adipose was significantly higher at 20 th day of pregnancy than that of non pregnant rabbits, while it was significantly decreased at 2 nd day after parturition. No significant changes in the placental leptin RNA levels were noticed in pregnant rabbits at 10 th , 20 th , and 30 th day of pregnancy. The relative abundance of fetal leptin transcripts at day 30 th of pregnancy was in the order of liver> bone ≥ adipose tissue > brain. The present study provides new evidence for the distribution and expression levels of leptin in the rabbit maternal and fetal tissues during pregnancy and supports the importance of leptin in reproductive physiology and fetal development.

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

Cited by 66 publications

References 40 publications

Palmitic acid induces central leptin resistance and impairs hepatic glucose and lipid metabolism in male mice

Palmitic acid induces central leptin resistance and impairs hepatic glucose and lipid metabolism in male mice

Tuning the brain for motherhood: prolactin-like central signalling in virgin, pregnant, and lactating female mice

Leptin Gene Expression in Rabbits During Pregnancy and Fetal Life

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