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Body Composition and Metabolic Caging Analysis in High Fat Fed Mice
Published on: May 24, 2018
Early leptin blockade predisposes fat-fed rats to overweight and modifies hypothalamic microRNAs
Charlotte Benoit1, Hassina Ould-Hamouda, Delphine Crepin
1Neuroendocrinologie Moléculaire de la Prise Alimentaire, University of Paris-Sud, UMR 8195, Orsay F-91405, France.
Insights
Early leptin blockade in rats leads to adult obesity and insulin resistance. This impairment alters hypothalamic microRNA expression, potentially linking early life events to long-term metabolic dysfunction.
Area of Science:
- Endocrinology and Metabolism
- Developmental Biology
- Molecular Biology
Background:
- Perinatal leptin signaling is crucial for establishing long-term energy homeostasis.
- Disruptions in early leptin function can have lasting effects on body weight regulation.
- The precise mechanisms linking early leptin impairment to adult metabolic disorders remain unclear.
Purpose of the Study:
- To investigate the long-term consequences of early-life leptin blockade on energy balance and metabolic health in rats.
- To analyze the impact of early leptin antagonism on hypothalamic microRNA expression profiles.
- To explore the relationship between early leptin blockade, hypothalamic microRNAs, and the development of insulin and leptin resistance.
Main Methods:
- Newborn rats received daily injections of a pegylated rat leptin antagonist (pRLA) or saline from postnatal day 2 to 13.
- Body weight gain, insulin sensitivity, and leptin sensitivity were assessed at postnatal days 28, 90, and 153.
- Hypothalamic microRNA expression profiles were analyzed using high-throughput sequencing and quantitative RT-PCR.
- Gene expression of uncoupling proteins (UCPs) and adiponectin receptors (AdipoRs) was evaluated in muscle and liver tissues.
Main Results:
- Early pRLA treatment resulted in overweight conditions and promoted leptin and insulin resistance in the hypothalamus and liver of adult rats.
- Hypothalamic microRNA expression was significantly altered by pRLA treatment, with 34 miRNAs upregulated and 4 downregulated at day 28.
- Specific microRNAs (rno-miR-10a, rno-miR-200a, rno-miR-409-5p, rno-miR-125a-3p) showed altered expression following pRLA treatment and/or high-fat diet challenge.
- Expression of genes involved in energy homeostasis, including UCPs and AdipoRs, was modified in muscle and liver tissues of pRLA-treated rats.
Conclusions:
- Impairment of leptin action during the perinatal period can induce long-term insulin and leptin resistance.
- Early-life leptin blockade alters the hypothalamic microRNA expression pattern in adulthood.
- This study suggests a potential link between hypothalamic microRNA profiles and the development of insulin/leptin responsiveness, highlighting a critical window for metabolic programming.
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.
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