Evidence that undernutrition increases AgRP signaling to arcuate kisspeptin neurons in male and female lambs.

“Evidence that undernutrition increases AgRP signaling to arcuate kisspeptin neurons in male and female lambs. Boney SS(1), Renwick AN(2), Harlow KK(3), Sommer JR(4), McCosh RB(5)(6), Kennedy A(7), Nestor CC(5)(6). Author information: (1)Mechanistic Toxicology Branch, Division of Translational Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA. (2)Department of Biological Sciences, Kent State University, Kent, OH 44242, USA. (3)Animal Biosciences and Biotechnology Laboratory, Beltsville Agricultural Research Center, Agricultural Research Service, United States Department of Agriculture, Beltsville, MD 20705, USA. (4)Department of Animal Science, North Carolina State University, Raleigh, NC 27695, USA. (5)Department of Biomedical Sciences, Colorado State University, Fort Collins, CO 80523, USA. (6)Animal Reproduction and Biotechnology Laboratory, Colorado State University, CO 80521, USA. (7)Department of Molecular and Structural Biochemistry, North Carolina State University, Raleigh NC 27695, USA. Proper energy balance is important for reproductive success, but the central mechanism whereby undernutrition inhibits reproduction remains to be fully elucidated. Given that arcuate (ARC) kisspeptin (Kiss1) neurons express melanocortin receptors, orexigenic neurons that produce agouti-related peptide (AgRP), an endogenous antagonist/inverse agonist to melanocortin receptors, may play a role in relaying energy status to the reproductive axis. We hypothesized undernutrition would increase AgRP input to Kiss1 neurons and inhibit Kiss1 expression in melanocortin receptor expressing neurons in lambs. Using ARC tissue from male and female lambs that were fed to maintain body weight (FM; n = 6/sex) or feed-restricted (FR; n = 8/sex), we conducted dual-label immunofluorescence to assess Kiss1 and AgRP protein expression as well as RNAscope to assess mRNA content for Kiss1 and MC3R. Immunofluorescence revealed significantly more AgRP close-contacts onto ARC Kiss1 neurons in FR animals than in FM animals. RNAscope analysis revealed no significant difference in total MC3R-expressing cells between FR and FM males, while we observed significantly fewer total MC3R-expressing cells in FM females compared to FR females. Furthermore, we observed that the integrated density for Kiss1 in MC3R cells was significantly lower in FR animals compared to FM animals. Taken together, these findings support the conclusion that AgRP neurons inhibit arcuate Kiss1 neurons during undernutrition and play a key role in relaying negative energy status to reduce GnRH/LH secretion to ultimately impair reproduction in male and female sheep.”