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Nutritional Influences on Reproductive Neuroendocrine Output: Insulin, Leptin, and Orexigenic Neuropeptide Signaling in the Ovine Hypothalamus

Obesity and Metabolic Health Division (J.L.H., E.J.B., P.A.F., C.L.A.), Rowett Research Institute, Aberdeen Centre for Energy Regulation and Obesity, Aberdeen AB21 9SB, United Kingdom; Sustainable Livestock Systems Group (D.W.M., E.J.B.), Scottish Agricultural College, Aberdeen AB21 9YA, United Kingdom; and Integrative Physiology Group, School of Biological Sciences (J.L.H.), University of Aberdeen, Aberdeen AB24 2TZ, United Kingdom

Address all correspondence and requests for reprints to: Dr. Clare Adam, Obesity and Metabolic Health Division, Rowett Research Institute, Bucksburn, Aberdeen AB21 9SB, United Kingdom. E-mail: cla{at}rowett.ac.uk.

This study investigated how changing nutritional status may alter reproductive neuroendocrine (LH) output via circulating leptin and insulin signaling through orexigenic hypothalamic pathways. Thin sheep were given an increasing nutritional plane (INP), sheep with intermediate adiposity a static nutritional plane (SNP), and fat sheep a decreasing nutritional plane (DNP) for 6 wk. Mean group adiposities converged by wk 6, LH output increased in INP, remained unchanged in SNP, and decreased in DNP sheep. Plasma and cerebrospinal fluid (CSF) insulin and plasma leptin concentrations increased in INP but did not change in the SNP and DNP groups. In INP sheep, LH output correlated positively with adiposity and plasma and CSF insulin concentrations and negatively with orexigenic neuropeptide Y gene expression in the hypothalamic arcuate nucleus (ARC). In DNP sheep, LH output correlated positively with adiposity, CSF leptin concentrations, and ARC proopiomelanocortin gene expression and negatively with leptin receptor (OB-Rb) and agouti-related peptide gene expression in the ARC. These data are consistent with the feedback response to an increasing nutritional plane being mediated by increasing circulating insulin entering the brain and stimulating LH via inhibition of hypothalamic neuropeptide Y and the response to a decreasing nutritional plane being mediated by altered hypothalamic leptin signaling brought about by increased OB-Rb expression and decreased melanocortin signaling. Because end point adiposity was similar yet LH output was different, the hypothalamus apparently retains a nutritional memory, based on changes in orexigenic neuropeptide expression, that influences contemporary neuroendocrine responses.