title: Contrasting effects of different levels of food intake and adiposity on LH secretion and hypothalamic gene expression in sheep.
abstract: Body reserves (long-term) and food intake (short-term) both contribute nutritional feedback to the hypothalamus. Reproductive neuroendocrine output (GnRH/LH) is stimulated by increased food intake and not by high adiposity in sheep, but it is unknown whether appetite-regulating hypothalamic neurons show this differential response. Castrated male sheep (Scottish Blackface) with oestradiol implants were studied in two 4 week experiments. In Experiment 1, sheep were fed to maintain the initial body condition (BC) score of 2.0+/-0.00 (lower BC (LBC), n=7) or 2.9+/-0.09 (higher BC (HBC), n=9), and liveweight of 43+/-1.1 and 59+/-1.6 kg respectively. LBC and HBC sheep had similar mean plasma LH concentration, pulse frequency and amplitude, but HBC animals had higher mean plasma concentrations of insulin (P<0.01), leptin (P<0.01) and glucose (P<0.01). Gene expression (measured by in situ hybridisation) in the hypothalamic arcuate nucleus (ARC) was higher in LBC than HBC sheep for neuropeptide Y (NPY; 486% of HBC, P<0.01), agouti-related peptide (AGRP; 467%, P<0.05) and leptin receptor (OB-Rb; 141%, P<0.05), but lower for cocaine- and amphetamine-regulated transcript (CART; 92%, P<0.05) and similar between groups for pro-opiomelanocortin (POMC). In Experiment 2, sheep with initial mean BC score 2.4+/-0.03 and liveweight 55+/-0.8 kg were fed a liveweight-maintenance ration (low intake, LI, n=7) while sheep with initial mean BC score 2.0+/-0.03 and liveweight 43+/-1.4 kg were fed freely so that BC score increased to 2.5+/-0.00 and liveweight increased to 54+/-1.4 kg (high intake, HI, n=9). Compared with LI, HI sheep had higher mean plasma LH (P<0.05), baseline LH (P<0.01) and pulse amplitude (P<0.01) and showed a trend towards higher pulse frequency. Although there were no differences in final mean plasma concentrations, there were significant increases over time in mean concentrations of insulin (P<0.001), leptin (P<0.05) and glucose (P<0.001) in HI sheep. Gene expression for AGRP in the ARC was higher in HI than LI animals (453% of LI; P<0.05), but expression levels were similar for NPY, OB-Rb, CART and POMC. Thus, the hypothalamus shows differential responses to steady-state adiposity as opposed to an increase in food intake, in terms of both reproductive neuroendocrine activity and hypothalamic appetite-regulating pathways. Differences in hypothalamic gene expression were largely consistent with contemporary levels of systemic leptin and insulin feedback; however, increased nutritional feedback was stimulatory to GnRH/LH whereas constant high feedback was not. The hypothalamus therefore has the ability to retain a nutritional memory that can influence subsequent responses.
authors.affiliation: Molecular Neuroendocrinology Group, Aberdeen Centre for Energy Balance and Obesity, Rowett Research Institute, Bucksburn, UK. zaa@rri.sari.ac.uk
authors.forename: Z A
authors.initials: ZA
authors.lastname: Archer
authors.forename: S M
authors.initials: SM
authors.lastname: Rhind
authors.forename: P A
authors.initials: PA
authors.lastname: Findlay
authors.forename: C E
authors.initials: CE
authors.lastname: Kyle
authors.forename: L
authors.initials: L
authors.lastname: Thomas
authors.forename: M
authors.initials: M
authors.lastname: Marie
authors.forename: C L
authors.initials: CL
authors.lastname: Adam
mesh_terms: D000273:Adipose Tissue / Q000502:physiology*; D000818:Animals; D001345:Autoradiography; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight; D004435:Eating / Q000502:physiology*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D015870:Gene Expression / Q000235:genetics; D007031:Hypothalamus / Q000502:physiology*; D007328:Insulin / Q000097:blood; D020738:Leptin / Q000097:blood; D007986:Luteinizing Hormone / Q000378:metabolism*; D008297:Male; D009919:Orchiectomy; D012756:Sheep / Q000235:genetics / Q000502:physiology*
chemical_list: D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D020738:Leptin; D007986:Luteinizing Hormone