TY - JOUR
T1 - Early leptin blockade predisposes fat-fed rats to overweight and modifies hypothalamic microRNAs
AU - Benoit, Charlotte
AU - Ould-Hamouda, Hassina
AU - Crepin, Delphine
AU - Gertler, Arieh
AU - Amar, Laurence
AU - Taouis, Mohammed
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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.
KW - High-fat diet
KW - Insulin resistance
KW - Leptin resistance
KW - MicroRNA
KW - Overweight
KW - Postnatal leptin
UR - http://www.scopus.com/inward/record.url?scp=84878778711&partnerID=8YFLogxK
U2 - 10.1530/JOE-12-0561
DO - 10.1530/JOE-12-0561
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C2 - 23576026
AN - SCOPUS:84878778711
SN - 0022-0795
VL - 218
SP - 35
EP - 47
JO - Journal of Endocrinology
JF - Journal of Endocrinology
IS - 1
ER -