title: Early leptin blockade predisposes fat-fed rats to overweight and modifies hypothalamic microRNAs.
abstract: Perinatal leptin impairment has long-term consequences on energy homeostasis leading to body weight gain. The underlying mechanisms are still not clearly established. We aimed to analyze the long-term effects of early leptin blockade. In this study, newborn rats received daily injection of a pegylated rat leptin antagonist (pRLA) or saline from day 2 (d2) to d13 and then body weight gain, insulin/leptin sensitivity, and expression profile of microRNAs (miRNAs) at the hypothalamic level were determined at d28, d90, or d153 (following 1 month of high-fat diet (HFD) challenge). We show that pRLA treatment predisposes rats to overweight and promotes leptin/insulin resistance in both hypothalamus and liver at adulthood. pRLA treatment also modifies the hypothalamic miRNA expression profile at d28 leading to the upregulation of 34 miRNAs and the downregulation of four miRNAs. For quantitative RT-PCR confirmation, we show the upregulation of rno-miR-10a at d28 and rno-miR-200a, rno-miR-409-5p, and rno-miR-125a-3p following HFD challenge. Finally, pRLA treatment modifies the expression of genes involved in energy homeostasis control such as UCPs and AdipoRs. In pRLA rat muscle, Ucp2/3 and Adipor1/r2 are upregulated at d90. In liver, pRLA treatment upregulates Adipor1/r2 following HFD challenge. These genes are known to be involved in insulin resistance and type 2 diabetes. In conclusion, we demonstrate that the impairment of leptin action in early life promotes insulin/leptin resistance and modifies the hypothalamic miRNA expression pattern in adulthood, and finally, this study highlights the potential link between hypothalamic miRNA expression pattern and insulin/leptin responsiveness.
authors.affiliation: Neuroendocrinologie Moléculaire de la Prise Alimentaire, University of Paris-Sud, UMR 8195, Orsay F-91405, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Benoit
authors.forename: Hassina
authors.initials: H
authors.lastname: Ould-Hamouda
authors.forename: Delphine
authors.initials: D
authors.lastname: Crepin
authors.forename: Arieh
authors.initials: A
authors.lastname: Gertler
authors.forename: Laurence
authors.initials: L
authors.lastname: Amar
authors.forename: Mohammed
authors.initials: M
authors.lastname: Taouis
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D059305:Diet, High-Fat / Q000009:adverse effects; D015536:Down-Regulation / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D020869:Gene Expression Profiling; D006727:Hormone Antagonists / Q000633:toxicity; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D007333:Insulin Resistance; D020738:Leptin / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D050177:Overweight / Q000139:chemically induced / Q000209:etiology* / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D054411:Receptors, Leptin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011994:Recombinant Proteins / Q000633:toxicity; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D006727:Hormone Antagonists; D020738:Leptin; D035683:MicroRNAs; D054411:Receptors, Leptin; D011994:Recombinant Proteins
keywords: high-fat diet; insulin  resistance; leptin  resistance; microRNA; overweight; postnatal leptin