Leptin Rapidly Induces the Expression of Metabolic and Myokine Genes in C2C12 Muscle Cells to Regulate Nutrient Partition and Oxidation

Nozhenko, Yuriy; Rodríguez, Ana; Palou, Andreu

doi:10.1159/000369678

Cited by 15 publications

(17 citation statements)

References 39 publications

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“…Recapitulating, the time‐sequential in vitro model used in the present work shows that leptin is able to transitorily promote PGC1α acetylation and thus regulate its co‐transcriptional activity. Moreover, leptin has several sequential effects on gene expression in muscular cells as described previously (Nozhenko et al, ), but we also describe here the induction of Mfn2, a key mitochondrial‐dynamic marker (Zorzano et al, ). These effects may be explained, at least in part, by leptin modulation of AMPK and Akt activities and may have a physiological meaning considering the nutrient environment of the cells.…”

Section: Discussionsupporting

confidence: 72%

“…We do not know the exact reason for the discrepancy, but the differences in the culture medium used may be part of the explanation of the different results, since we used a high‐glucose serum‐free medium in our experiment. With respect to PGC1α protein levels, we have previously described that leptin (50 ng/ml) rapidly induces PGC1α mRNA very early on (30 min) and such an increase is later reflected in increased protein levels (at 24 h) (Nozhenko et al, ). Nevertheless, in the present experiment the gradual time‐dependent increase in PGC1α protein levels does not reach statistical significance.…”

Section: Discussionmentioning

confidence: 99%

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Leptin Effect on Acetylation and Phosphorylation of Pgc1α in Muscle Cells Associated With Ampk and Akt Activation in High‐Glucose Medium

García-Carrizo

Nozhenko

Palou

et al. 2015

Journal Cellular Physiology

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Leptin is crucial in energy metabolism, including muscle regulation. Peroxisome proliferator activated receptor gamma co-activator 1α (PGC1α) orchestrates energy metabolism and is tightly controlled by post-translational covalent modifications such as phosphorylation and acetylation. We aimed to further the knowledge of PGC1α control by leptin (at physiological levels) in muscle cells by time-sequentially analysing the activation of AMP activated protein kinase (AMPK), P38 mitogen-activated protein kinase (P38 MAPK) and Akt (Protein kinase B)--all known to phosphorylate PGC1α and to be involved in the regulation of its acetylation status--in C2C12 myotubes placed in a high-glucose serum-free medium. We also studied the protein levels of PGC1α, Sirtuin 1, adiponectin, COX IV, mitofusin 2 (Mfn2), and pyruvate dehydrogenase kinase 4 (PDK4). Our main findings suggest an important role of leptin regulating AMPK and Akt phosphorylation, Mfn2 induction and PGC1α acetylation status, with the novelty that the latter in transitorily increased in response to leptin, an effect dependent, at least in part, on AMPK regulation. These post-translational reversible changes in PGC1α in response to leptin, especially the increase in acetylation status, may be related to the physiological role of the hormone in modulating muscle cell response to the physiological/nutritional status.

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Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Leptin Effect on Acetylation and Phosphorylation of Pgc1α in Muscle Cells Associated With Ampk and Akt Activation in High‐Glucose Medium

García-Carrizo

Nozhenko

Palou

et al. 2015

Journal Cellular Physiology

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“…The association between hyperleptinemia and UCP2 up‐regulation has been already documented in engineered rats overexpressing leptin as well as in models of exogenous transitory hyperleptinemia, and diet‐induced obesity . In the case of UCP3, exogenous leptin has been reported to reduce its expression in skeletal muscle, although a more recent study has reported the opposite . In any case, data regarding UCP3 regulation by leptin in cardiac tissue are, to our knowledge, lacking.…”

Section: Discussionmentioning

confidence: 98%

“…[31,50] In the case of UCP3, exogenous leptin has been reported to reduce its expression in skeletal muscle, [51] although a more recent study has reported the opposite. [52] In any case, data regarding UCP3 regulation by leptin in cardiac tissue are, to our knowledge, lacking.…”

Section: Discussionmentioning

confidence: 99%

Potential Role of Leptin in Cardiac Steatosis Induced by Highly Saturated Fat Intake during Adolescence

Plaza

Antonazzi

Blanco‐Urgoiti

et al. 2019

Molecular Nutrition Food Res

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Scope To identify the age‐dependent effect of diets containing elevated amounts of either saturated or unsaturated fatty acids on cardiac steatosis in mice. Methods and Results Five‐ and eight‐week‐old C57BL/6J mice cohorts are given free access to either a saturated or an unsaturated fatty‐acid‐enriched diet during 8 weeks. Body weight (BW) and food intake are monitored during this period. Cardiac lipid content, carnitine palmitoyltransferase‐I (CPT‐I) activity, and the amount of uncoupling proteins 2 and 3 (UCP2 and UCP3) are analyzed and correlated with blood leptin concentration. Leptin and PPARγ gene expression is quantified in white adipose tissue (WAT). Both diets have a similar effect on food intake, BW, and adiposity, independently of the age. Nevertheless, cardiac steatosis is specifically identified in adolescent mice consuming the saturated diet. These animals also display lower activity of cardiac CPT‐I, a down‐regulation of cardiac UCP2, together with lower concentration of plasma leptin. Accordingly, leptin gene expression is reduced in the visceral WAT. Conclusion Consumption of diets containing elevated amounts of saturated fat during adolescence and early adult life promotes cardiac steatosis in mice. An insufficient endocrine activity of WAT, in terms of leptin production, may account for such an effect.

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“…Subsequently, other studies demonstrated that FGF21 is modulated by key metabolic transcription factors such as PPARα and PPARγ [16][17][18] which are also induced by leptin [19]. Leptin is also known to promote metabolic health by notably increasing fat oxidation in muscle cells [20] and decreasing inflammation [21]. In the present study, we first investigated whether leptin may regulate FGF21 expression in vivo in Wistar rats.…”

Section: Introductionmentioning

confidence: 87%

Leptin as a Potential Regulator of FGF21

Asrih

Veyrat-Durebex

Poher

et al. 2016

Cell Physiol Biochem

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Background/Aims: Fibroblast growth factor 21 (FGF21), a potent metabolic regulator, has been shown to improve insulin sensitivity in animal models of insulin resistance. Several studies have focused on identifying mediators of FGF21 effects. However, the identification of factors involved in FGF21 regulation is far from complete. As leptin is a potent metabolic modulator as well, we aimed at characterizing whether leptin may regulate FGF21. Methods: We investigated a potential regulation of FGF21 by leptin in vivo in Wistar rats and in vitro using human derived hepatocarcinoma HepG2 cells. This model was chosen as the liver is considered the main FGF21 expression site. Results: We found that leptin injections increased plasma FGF21 levels in adult Wistar rats. This was confirmed in vitro, as leptin increased FGF21 expression in HepG2 cells. We also showed that the leptin effect on FGF21 expression was mediated by STAT3 activation in HepG2 cells. Conclusion: New findings regarding a leptin-STAT3-FGF21 axis were provided in this study, although investigating the exact mechanisms linking leptin and FGF21 are still needed. These results are of great interest in the context of identifying potential new clinical approaches to treat metabolic diseases associated with insulin resistance, such as obesity and type 2 diabetes.

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Leptin Rapidly Induces the Expression of Metabolic and Myokine Genes in C2C12 Muscle Cells to Regulate Nutrient Partition and Oxidation

Abstract: Leptin rapidly induces the expression of genes important for its own response and the control of metabolic fuels, with the rapid responses of the genes encoding the master regulator PGC1α, mCPT1, UCP3, PDK4 and the signaling secretory molecule IL6 particularly interesting.

Cited by 15 publications

References 39 publications

Leptin Effect on Acetylation and Phosphorylation of Pgc1α in Muscle Cells Associated With Ampk and Akt Activation in High‐Glucose Medium

Leptin Effect on Acetylation and Phosphorylation of Pgc1α in Muscle Cells Associated With Ampk and Akt Activation in High‐Glucose Medium

Potential Role of Leptin in Cardiac Steatosis Induced by Highly Saturated Fat Intake during Adolescence

Leptin as a Potential Regulator of FGF21

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