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  • br Acknowledgements We thank Jeus Perez Clausell from the


    Acknowledgements We thank Jeus Perez-Clausell from the Department of Cell Biology, School of Biology, University of Barcelona, Felipe Casanueva\'s group from the Department of Molecular Endocrinology and Carlos Diéguez\'s group from the Department of Physiology, School of Medicine, University of Santiago de Compostela for their support in stereotaxis Hydrocortisone experiments, to Olga Jaúregui from the Scientific-Technical Services of the University of Barcelona for her technical assistance in the LC–MS/MS analysis. We also thank Biomol-Informatics SL ( for bioinformatics consulting. This study was supported by Grant SAF2007-61926 and by grant CTQ2006-13249 from the Ministerio de Educación y Ciencia, Spain; by grant C3/08 from the Fondo de Investigación Sanitaria of the Instituto de Salud Carlos III; by the Activities Program among R&D groups of the Comunidad de Madrid in Biosciences (S-BIO-0260/2006-COMBACT) and by the Ajut de Suport als Grups de Recerca de Catalunya (2005SGR-00733), Spain. Financial support of “Fundación Ramón Areces” to CBMSO is also acknowledged. A.G.C. and D.S. were recipients of fellowships from the University of Barcelona, and A.B. and C.G. from the Ministerio de Educación y Ciencia, Spain.
    Introduction Currently, the great offer of unhealthy diets, rich in saturated fat, increases the prevalence of metabolic disorders [1], [2], [3]. The metabolic syndrome is already established in the worldwide population and is not limited to overweight or obese persons. This disorder refers to a group of metabolic anomalies as dyslipidemias, Hydrocortisone intolerance, among others, which have a direct relationship with an increase in the risk of developing diabetes, cancer, cardiovascular diseases and other health complications [4], [5], [6]. A worrying fact is the increase in the incidence of overweight, metabolic syndrome and related metabolic alterations in young people from neonates to teenagers ( [7], [8], [9], [10]. This fact predicts an unhealthy adulthood and an old age with many needs for clinical and pharmacological therapies [6], [7], [9], [11]. It has been well established that the burden of metabolic complications can be perinatally originated [12], [13], [14], [15], [16]. The Barker hypothesis states that neonates born small for gestational age are prone to develop cardiovascular diseases later in life. Since then, many investigations have demonstrated that maternal overweight also induces metabolic alterations from fetal life to adulthood in the offspring [9], [14], [16], [17]. We and others have described metabolic abnormal outcomes in fetuses from rats fed with different approaches of diets rich in saturated fat, with increases in caloric input [18], [19], [20]. Many metabolic alterations have been described in fetuses and offspring from mothers with metabolic impairments [21], [22], [23], [24]. Lipid metabolic alterations harm the liver, which is an important organ for lipid homeostasis and lipid trafficking through the organism. Studies in humans and animal models have shown that perinatal exposure to a lipid enriched environment may develop fatty liver disease later in life [25], [26], [27], [28], [29]. Liver fat depots are unlikely to persist and induce fatty liver disease in the adult offspring unless specific alterations in the mechanisms that control liver lipid metabolism are programmed in utero. Animal models allow the researcher to control the nutrition for long periods of time, and many works have shown different liver metabolic alterations in healthy nourished offspring born to obese mothers, suggesting that the maternal environment alters the offspring’s liver lipid metabolism permanently [25], [26], [30]. Leptin is an adipokine that activates lipid catabolism in peripheral tissue like adipocytes, muscle and liver [31], [32], [33]. This adipokine increases fatty acid oxidation in mitochondria and peroxisomes [34], [35], [36]. The binding of leptin to its receptor triggers intracellular signaling mechanisms that involve phosphorylation and activation of several proteins, such as Janus kinase 2, AMP-activated protein kinase, the signal transducer and activator of transcription STAT-3 and the peroxisome proliferator-activated receptor PPARα. The transcription factors PPARα and STAT-3 mediate the expression of leptin-induced lipid catabolic enzymes [32], [37], such as the acetyl-CoA oxidase ACO and the carnitine palmitoyl transferase CPT1 [38], [39]. We have shown that fetuses from rats fed a saturated-fat-rich diet through pregnancy and lactation display hyperleptinemia and liver lipid overaccumulation [24].