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Brain Control of Sexually Dimorphic Liver Function and Disease: The Endocrine Connection

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Abstract

A multistep signaling cascade originates in brain centers that regulate hypothalamic growth hormone-releasing hormone (Ghrh) and somatostatin expression levels and release to control the pattern of GH secretion. This process is sexually fine-tuned, and relays important information to the liver where GH receptors can be found. The temporal pattern of pituitary GH secretion, which is sex-specific in many species (episodic in males and more stable in females), represents a major component in establishing and maintaining the sexual dimorphism of hepatic gene transcription. The liver is sexually dimorphic exhibiting major differences in the profile of more than 1000 liver genes related to steroid, lipid, and foreign compound metabolism. Approximately, 90% of these sex-specific liver genes were shown to be primarily dependent on sexually dimorphic GH secretory patterns. This proposes an interesting scenario in which the central nervous system, indirectly setting GH profiles through GHRH and somatostatin control, regulates sexual dimorphism of liver activity in accordance with the need for sex-specific steroid metabolism and performance. We describe the influence of the loss of sexual dimorphism in liver gene expression due to altered brain function. Among other many factors, abnormal brain sexual differentiation, xenoestrogen exposure and D2R ablation from neurons dysregulate the GHRH–GH axis, and ultimately modify the liver capacity for adaptive mechanisms. We, therefore, propose that an inefficient brain control of the endocrine growth axis may underlie alterations in several metabolic processes through an indirect influence of sexual dimorphism of liver genes.

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Acknowledgements

This work was supported by Grants from Agencia Nacional de Promoción Científica y Tecnológica, Argentina: PICT 330-2013; PICT 1343-2015; PICT 526-2016, Fundación Rene Barón, Fundación Williams, Consejo Nacional de Investigaciones Científicas y Técnicas; Pfizer 2015 Latin America ASPIRE Endo.

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  1. Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Vuelta de Obligado 2490, 1428, Buenos Aires, Argentina

    Belen Brie, Catalina De Winne, Felicitas Lopez Vicchi, Eleonora Sorianello, Ana María Ornstein & Damasia Becu-Villalobos

  2. Amgen México, Av. Vasco de Quiroga 3000 piso 4, Santa Fe, Ciudad De México, Mexico

    Maria Cecilia Ramirez

  3. Departament of Micro y Nanotechnology, Instituto de Nanociencia y Nanotecnología, Comisión Nacional de Energia Atomica-Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina

    Luis Villarruel & Paolo Catalano

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  1. Belen Brie
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DB was the main contributor (writing, searching, editing). BB, MCR, LV, PC, AMO, E S, and FLV, discussed ideas, helped in the outline of the review, and corrected the text.

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Correspondence to Damasia Becu-Villalobos.

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Paolo Catalano was a recipient of Pfizer 2015 Latin America ASPIRE Endo for young investigators. The rest of the authors have nothing to disclose.

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Brie, B., Ramirez, M.C., De Winne, C. et al. Brain Control of Sexually Dimorphic Liver Function and Disease: The Endocrine Connection. Cell Mol Neurobiol 39, 169–180 (2019). https://doi.org/10.1007/s10571-019-00652-0

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  • DOI: https://doi.org/10.1007/s10571-019-00652-0

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