PYR-41 Liver metabolic programming begins in
Liver metabolic programming begins in utero. Aiming to find a reason for the decreased lipid catabolism enzyme expression observed in fetuses and offspring from SFD rats, we studied the effect of leptin on liver catabolism in fetuses from control and SFD rats. Livers from control fetuses responded to leptin-activating lipid catabolism, decreasing lipid levels and increasing the expression of genes of catabolic enzymes. In contrast, livers of fetuses from SFD rats showed no changes in lipid catabolism after the culture with leptin. ACO and CPT1 showed no response to leptin in fetal livers and were down-regulated in the subsequent developmental stages studied in the offspring from SFD rats. This suggests that leptin resistance may continue later in life and cause the alterations in lipid levels and enzyme expression observed in young and adult offspring. Other researchers have suggested liver leptin resistance in rats with fatty livers . Here we provide data denoting that liver leptin resistance might be programmed during intrauterine life, conditioning the liver lipid metabolism of the offspring in the future.
We have previously shown that fetuses from SFD rats are hyperleptinemic . Aiming to establish a role for fetal leptinemia, we mimicked the fetal hyperleptinemia observed in fetuses from SFD rats, in fetuses from control rats. Therefore, we assessed the expression of the genes involved in lipid catabolism in livers from control fetuses administered daily with leptin. The expression of ACO was down-regulated by leptin administration to male fetuses. The same down-regulated expression was observed in male fetuses from SFD rats. As hyperleptinemia is a common feature of SFD and control leptin-injected fetuses, we speculate that hyperleptinemia could be inducing impaired leptin receptor signaling, causing the down-regulation of ACO in livers from male SFD fetuses , . Nevertheless, the other alterations observed in gene expression in livers from SFD fetuses could not be explained by our experiment of fetal leptin administration. Thus, further research is needed to clarify this point.
In summary, we found lipid overaccumulation and abnormal expression of lipid catabolic PYR-41 in the livers from fetuses and offspring from rats fed a diet enriched in saturated fat. We also found liver leptin resistance in fetuses from the SFD mothers, suggesting that liver lipid homeostasis impairments observed in the offspring from SFD rats might be programmed by in utero leptin resistance.
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Funding This study was supported by the Agencia de Promoción Científica y Tecnológica de Argentina and GlaxoSmithKline (grant number PICTO GLAXO 2012-00054), the Ministry of Science and Technology of Argentina (grant number AU1218) and the Agencia de Promoción Científica y Tecnológica de Argentina (grant number PICT 2010-00034).
Introduction Current production systems involve high-producing dairy cows that face great metabolic demands and environmental stresses that finally compromise their reproductive efficiency [, , ]. One of the most important dysfunctions associated with high-yielding dairy cows is cystic ovarian disease (COD), a disease that compromises normal ovarian cyclicity . In addition to imbalances in different hormones such as insulin, adiponectin, and leptin, several metabolites such as glucose, non-esterified fatty acids (NEFA) and amino acids have been proposed to participate in cyst formation . Therefore, the nutritional and metabolic state of the animal could affect the ovulation process [, , ]. During early lactation, food intake is generally insufficient to meet the demand for nutrients, especially glucose, required to support the extremely high levels of milk production . A nutritional imbalance leads the cow to a state of negative energy balance, in which NEFA from lipid stores of adipose tissue are mobilized and then captured by the liver and oxidized to produce ketone bodies. Beta-hydroxybutyrate (BHB) is the predominant ketone body in blood and its concentration is an index of increased fatty acid oxidation, so it is also considered as a marker of an excessive negative energy balance . Several studies have shown that high levels of NEFA may adversely affect follicular growth and development, resulting cytotoxic and potentially leading to COD [11,12]. This cytotoxicity can lead to an alteration throughout folliculogenesis, which prevents recovery from of the disease and favors recidivism in COD presentation. In addition, fatty acids are mainly metabolized by beta-oxidation, a process that includes a series of metabolic reactions with highly regulated enzymes such as carnitine palmitoyltransferase-1 (CPT1) in mitochondria and acyl-coenzyme A oxidase 1 (ACOX1) in peroxisomes [13,14].