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Curr Biol. 2019 May 29. pii: S0960-9822(19)30556-1. doi: 10.1016/j.cub.2019.05.021. [Epub ahead of print]

Agouti-Related Protein 2 Is a New Player in the Teleost Stress Response System.

Author information

1
School of Neurobiology, Biochemistry and Biophysics, The George S. Wise Faculty of Life Sciences, Tel-Aviv University, 6997801 Tel Aviv, Israel. Electronic address: inbal.shainer@gmail.com.
2
Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA; Institute of Zoology, University of Cologne, 50674 Cologne, Germany.
3
Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892, USA; Neuroscience and Cognitive Science Program, University of Maryland, College Park, MD 20742, USA.
4
Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892, USA.
5
Department of Marine Biotechnology, Institute of Marine and Environmental Technology, University of Maryland Baltimore County, Baltimore, MD 21202, USA.
6
School of Neurobiology, Biochemistry and Biophysics, The George S. Wise Faculty of Life Sciences, Tel-Aviv University, 6997801 Tel Aviv, Israel.
7
Department Genes - Circuits - Behavior, Max Planck Institute of Neurobiology, 82152 Martinsried, Germany.
8
Department of Animal Sciences, The Robert H. Smith Faculty of Agriculture, Food, and Environment, Hebrew University of Jerusalem, 76100 Rehovot, Israel.
9
Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
10
School of Neurobiology, Biochemistry and Biophysics, The George S. Wise Faculty of Life Sciences, Tel-Aviv University, 6997801 Tel Aviv, Israel; Sagol School of Neuroscience, Tel-Aviv University, 6997801 Tel Aviv, Israel. Electronic address: yoavgothilf@gmail.com.

Abstract

Agouti-related protein (AgRP) is a hypothalamic regulator of food consumption in mammals. However, AgRP has also been detected in circulation, but a possible endocrine role has not been examined. Zebrafish possess two agrp genes: hypothalamically expressed agrp1, considered functionally equivalent to the single mammalian agrp, and agrp2, which is expressed in pre-optic neurons and uncharacterized pineal gland cells and whose function is not well understood. By ablation of AgRP1-expressing neurons and knockout of the agrp1 gene, we show that AgRP1 stimulates food consumption in the zebrafish larvae. Single-cell sequencing of pineal agrp2-expressing cells revealed molecular resemblance to retinal-pigment epithelium cells, and anatomic analysis shows that these cells secrete peptides, possibly into the cerebrospinal fluid. Additionally, based on AgRP2 peptide localization and gene knockout analysis, we demonstrate that pre-optic AgRP2 is a neuroendocrine regulator of the stress axis that reduces cortisol secretion. We therefore suggest that the ancestral role of AgRP was functionally partitioned in zebrafish by the two AgRPs, with AgRP1 centrally regulating food consumption and AgRP2 acting as a neuroendocrine factor regulating the stress axis.

KEYWORDS:

circadian clock; cortisol; food consumption; gene knockout; hypothalamus; neuronal ablation; pineal gland; single-cell RNA sequencing; transgenesis; zebrafish

PMID:
31178320
DOI:
10.1016/j.cub.2019.05.021

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