Central leptin action improves skeletal muscle AKT, AMPK, and PGC1α activation by hypothalamic PI3K-dependent mechanism

Roman, Erika; Reis, Daniel G.; Romanatto, Talita; Maimoni, Denis; Ferreira, Eduardo André; Santos, Givanildo Alves dos; Torsoni, Adriana Souza; Velloso, Lı́cio A.; Torsoni, Márcio Alberto

doi:10.1016/j.mce.2009.08.007

Cited by 66 publications

(55 citation statements)

References 61 publications

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“…For example, an icv injection of leptin activates hypothalamic Akt and improves glucose tolerance in skeletal muscle [47]. Akt can phosphorylate and inactivate FOXO1, a transcriptional factor in the hypothalamus [32].…”

Section: Discussionmentioning

confidence: 99%

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: 99%

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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“…These results revealed the close relationship between NPY and PI3K in the regulation of food intake. The PI3K activates downstream targets, such as Akt, which in turn may convey and coordinate the STAT3 to induce NPY or POMC gene expression (Roman et al, 2010;Sahu, 2011). Thus, we tested the prediction that PI3K-STAT3 signalling was involved in regulating the NPY-and POMC-mediated appetite suppression in amphetamine-treated rats.…”

Section: Introductionmentioning

confidence: 99%

Involvement of hypothalamic PI3K–STAT3 signalling in regulating appetite suppression mediated by amphetamine

Chu

Chen

Hsieh

et al. 2014

British J Pharmacology

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BACKGROUND AND PURPOSEAppetite suppression induced by amphetamine has been attributed to its inhibition of neuropeptide Y (NPY) neurons and activation of pro-opiomelanocortin (POMC) neurons in the hypothalamus. This study examined whether STAT3 was involved in these actions of amphetamine. EXPERIMENTAL APPROACHRats were given amphetamine daily for 4 days. Changes in the expression of NPY, POMC, melanocortin MC3 receptors, PI3K and STAT3 in the hypothalamus were assessed by RT-PCR and Western blotting. Antisense oligonucleotides to STAT3 were also used. KEY RESULTSExpression of NPY decreased with a maximum effect day 2 of amphetamine treatment. Expression of POMC, MC3 receptors, PI3K and STAT3 increased with a maximum response on day 2. Moreover, phosphorylation of STAT3 and its DNA binding activity increased and was expressed in a similar pattern. Infusion (i.c.v.) of STAT3 antisense at 60 min before amphetamine treatment, partly blocked amphetamine-induced anorexia and modulated expression of NPY, POMC, MC3 receptors and PI3K, indicating the involvement of STAT3 in amphetamine-treated rats. CONCLUSIONS AND IMPLICATIONSHypothalamic PI3K-STAT3 signalling participated in the regulation of NPY-and POMC-mediated appetite suppression. These findings may contribute to a better understanding of anorectic drugs.

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“…UCP1 expression in brown fat is also regulated by ␤-adrenergic activation (46), but we found no evidence that downstream factors in the ␤-adrenergic signaling pathway, including either phosphorylated ACC or PGC-1␣, were downregulated in fetal PAT in the PIUN group. Indeed, the abundance of total phosphorylated AMPK in the PCUN group and PDK4 abun- dance in the PIUN group was upregulated rather than downregulated (40,49,52). One possibility is that exposure to poor maternal nutrition in early embryonic life results in an epigenetic downregulation of UCP1 within the progenitors of brown adipocytes as an adaptation to decreased energy utilization within brown adipocytes in later life.…”

Section: Preimplantation Undernutrition and Ucp1 Expression In Fetal mentioning

confidence: 97%

Impact of embryo number and periconceptional undernutrition on factors regulating adipogenesis, lipogenesis, and metabolism in adipose tissuein the sheep fetus

Lie

Morrison

Williams-Wyss

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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-Maternal undernutrition around the time of conception is associated with an increased risk of insulin resistance in adulthood. We hypothesized that maternal undernutrition during the periconceptional (PCUN: Ϫ60 to 7 days) and/or preimplantation (PIUN: 0 -7 days) periods would result in a decrease in UCP1 expression and the abundance of insulin signaling molecules and an increase in the abundance of factors that regulate adipogenesis and lipogenesis in fetal perirenal adipose tissue (PAT) and that these effects would be different in singletons and twins. Maternal PCUN and PIUN resulted in a decrease in UCP1 expression in PAT, and PIUN resulted in higher circulating insulin concentrations, an increased abundance of pPKC and PDK4, and a decreased abundance of Akt1, phosphorylated mTOR, and PPAR␥ in PAT in singleton and twin fetuses. In singletons, there was also a decrease in the abundance of p110␤ in PAT in the PCUN and PIUN groups and an increase in total AMPK␣ in PAT in the PIUN group. In twins, however, there was an increase in the abundance of mTOR in the PCUN group and an increase in PDK2 and decrease in total AMPK␣ in the PIUN group. Thus exposure to periconceptional undernutrition programs changes in the thermogenic capacity and the insulin and fatty acid oxidation signaling pathway in visceral fat, and these effects are different in singletons and twins. These findings are important, as the thermogenic capacity of brown fat and the insulin sensitivity of visceral fat are important determinants of the risk of developing obesity and an insulin resistance phenotype in later life. pregnancy; nutrition; programming; metabolism A RANGE OF EXPERIMENTAL AND CLINICAL STUDIES has shown that poor maternal nutrition experienced around the time of conception or during pregnancy, placental insufficiency, and being of low birth weight are each associated with an increase in visceral fat mass in postnatal life (5,9,11,17,21,27,30,31). Interestingly, exposure to a poor nutrient supply in early pregnancy, such as which occurred in the Dutch Winter Famine of 1944Famine of -1945, in the absence of a change in birth weight resulted in increased adiposity in later life (38, 39). Maternal undernutrition around the time of conception has also been shown to result in glucose intolerance and insulin resistance in the human and in the sheep (36,41,47). However, the impact of maternal undernutrition during the periconceptional period on the factors that regulate adipogenesis, lipogenesis, and insulin sensitivity in visceral fat is not known.In the sheep fetus, fat is deposited at a rate of ϳ0.8 g·kg body wt Ϫ1 ·day Ϫ1 in late gestation, and the proportion of body fat at term is between 0.3 and 2.0%. The perirenal adipose tissue (PAT) is the major fat depot present in the sheep fetus and is comprised predominantly of brown fat cells that express adipogenic and lipogenic factors, including peroxisome proliferator-activated receptor-␥ (PPAR␥), lipoprotein lipase (LPL), and the adipokines leptin and adiponectin (10,28,54). Brown fat i...

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Central leptin action improves skeletal muscle AKT, AMPK, and PGC1α activation by hypothalamic PI3K-dependent mechanism

Cited by 66 publications

References 61 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

Involvement of hypothalamic PI3K–STAT3 signalling in regulating appetite suppression mediated by amphetamine

Impact of embryo number and periconceptional undernutrition on factors regulating adipogenesis, lipogenesis, and metabolism in adipose tissuein the sheep fetus

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