EFFECTS OF ZD7114, A SELECTIVE BETA(3)-ADRENOCEPTOR AGONIST, ON NEUROENDOCRINE MECHANISMS CONTROLLING ENERGY-BALANCE

Selective beta(3)-adrenoceptor agonists increase energy expenditure by increasing non-shivering thermogenesis in brown adipose tissue. The a im of this study was to investigate how changes in energy balance affe ct energy intake and interaction of peripheral metabolic feedback sign als with central neuroendocrine mechanisms participating in the contro l of body energy balance. Expression of preproneuropeptide Y (preproNP Y) mRNA in the arcuate nucleus and preprocorticotropin-releasing facto r (CRF) mRNA in the paraventricular nucleus were measured by in situ h ybridisation technique after 1 day, 1 and 5 weeks of treatment with ZD 7114 )amino]ethoxy]-N-(2-methoxyethyl)phenoxyacetamide, 3 mg kg(-1) da y(-1) in drinking water) in obese fa/fa Zucker rats. In addition, expr ession of leptin mRNA in epididymal fat and serum levels of leptin wer e analysed. Food intake, body weights, binding of GDP to brown adipose tissue mitochondria, plasma insulin and glucose were also measured. T reatment with ZD7114 significantly reduced weight gain and activated b rown adipose tissue thermogenesis, but had no effect on food intake. E xpressions of preproNPY or preproCRF mRNAs were similarly not changed by treatment with ZD7114. Furthermore, ZD7114 had no effect on plasma insulin or leptin and the expression of leptin mRNA in epididymal fat. However, statistically significant correlations were found between pr eproNPY and preproCRF mRNA expressions and brown fat thermogenic activ ity and plasma insulin levels in the ZD7114 treated rats, but not in t he control rats. It is concluded that treatment with ZD7114 markedly a ctivated brown fat thermogenesis, but did not affect neuropeptide Y (N PY) and CRF gene expression per se. However, the correlation analyses suggest that ZD7114 may modulate feedback connections of brown adipose tissue thermogenesis and plasma insulin with the hypothalamic neuroen docrine mechanisms integrating body energy balance. (C) 1998 Elsevier Science B.V.