Person:
Benito De Las Heras, Manuel R.

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First Name
Manuel R.
Last Name
Benito De Las Heras
URI
https://hdl.handle.net/20.500.14352/77703
Affiliation
Universidad Complutense de Madrid
Faculty / Institute
Farmacia
Department
Bioquímica y Biología Molecular
Area
Bioquímica y Biología Molecular
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2020 - 20212
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    Severe Hepatic Insulin Resistance Induces Vascular Dysfunction: Improvement by Liver-Specific Insulin Receptor Isoform A Gene Therapy in a Murine Diabetic Model
    (Cells, 2021) Gómez Hernández, María De La Almudena; Heras Jiménez, Natalia De Las; López-Pastor, Andrea R.; García-Gómez, Gema; Infante-Menéndez, Jorge; González-López, Paula; González-Illanes, Tamara; Lahera Julia, Vicente; Benito De Las Heras, Manuel R.; Escribano Illanes, Óscar
    Background: Cardiovascular dysfunction is linked to insulin-resistant states. In this paper, we analyzed whether the severe hepatic insulin resistance of an inducible liver-specific insulin receptor knockout (iLIRKO) might generate vascular insulin resistance and dysfunction, and whether insulin receptor (IR) isoforms gene therapy might revert it. Methods: We studied in vivo insulin signaling in aorta artery and heart from iLIRKO. Vascular reactivity and the mRNA levels of genes involved in vascular dysfunction were analyzed in thoracic aorta rings by qRT-PCR. Finally, iLIRKO mice were treated with hepatic-specific gene therapy to analyze vascular dysfunction improvement. Results: Our results suggest that severe hepatic insulin resistance was expanded to cardiovascular tissues. This vascular insulin resistance observed in aorta artery from iLIRKO mice correlated with a reduction in both PI3K/AKT/eNOS and p42/44 MAPK pathways, and it might be implicated in their vascular alterations characterized by endothelial dysfunction, hypercontractility and eNOS/iNOS levels’ imbalance. Finally, regarding long-term hepatic expression of IR isoforms, IRA was more efficient than IRB in the improvement of vascular dysfunction observed in iLIRKO mice. Conclusion: Severe hepatic insulin resistance is sufficient to produce cardiovascular insulin resistance and dysfunction. Long-term hepatic expression of IRA restored the vascular damage observed in iLIRKO mice.
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    Specific knockout of p85α in brown adipose tissue induces resistance to high-fat diet–induced obesity and its metabolic complications in male mice
    (Molecular metabolism, 2020) Gómez Hernández, María De La Almudena; Raposo López-Pastor, Andrea; Rubio-Longas, Carlota; Majewski, Patrik; Beneit, Nuria; Viana-Huete, Vanesa; García-Gómez, Gema; Fernandez, Silvia; Hribal, Marta Letizia; Sesti, Giorgio; Escribano Illanes, Óscar; Benito De Las Heras, Manuel R.
    Objective: An increase in mass and/or brown adipose tissue (BAT) functionality leads to an increase in energy expenditure, which may be beneficial for the prevention and treatment of obesity. Moreover, distinct class I PI3K isoforms can participate in metabolic control as well as in systemic dysfunctions associated with obesity. In this regard, we analyzed in vivo whether the lack of p85a in BAT (BATp85aKO) could modulate the activity and insulin signaling of this tissue, thereby improving diet-induced obesity and its associated metabolic complications. Methods: We generated BATp85aKO mice using Cre-LoxP technology, specifically deleting p85a in a conditional manner. To characterize this new mouse model, we used mice of 6 and 12 months of age. In addition, BATp85aKO mice were submitted to a high-fat diet (HFD) to challenge BAT functionality. Results: Our results suggest that the loss of p85a in BAT improves its thermogenic functionality, high-fat dieteinduced adiposity and body weight, insulin resistance, and liver steatosis. The potential mechanisms involved in the improvement of obesity include (1) increased insulin signaling and lower activation of JNK in BAT, (2) enhanced insulin receptor isoform B (IRB) expression and association with IRS-1 in BAT, (3) lower production of proinflammatory cytokines by the adipose organ, (4) increased iWAT browning, and (5) improved liver steatosis. Conclusions: Our results provide new mechanisms involved in the resistance to obesity development, supporting the hypothesis that the gain of BAT activity induced by the lack of p85a has a direct impact on the prevention of diet-induced obesity and its associated metabolic complications