Effects of ZD7114, a selective beta3-adrenoceptor agonist, on neuroendocrine mechanisms controlling energy balance

Selective beta3-adrenoceptor agonists increase energy expenditure by increasing non-shivering thermogenesis in brown adipose tissue. The aim of this study was to investigate how changes in energy balance affect energy intake and interaction of peripheral metabolic feedback signals with central neuroendocrine mechanisms participating in the control of body energy balance. Expression of preproneuropeptide Y (preproNPY) mRNA in the arcuate nucleus and preprocorticotropin-releasing factor (CRF) mRNA in the paraventricular nucleus were measured by in situ hybridisation technique after 1 day, 1 and 5 weeks of treatment with ZD7114 ((S)-4-[2-[(2-hydroxy-3-phenoxypropyl)amino]ethoxy]-N-(2-methoxyet hyl)phenoxyacetamide, 3 mg kg(-1) day(-1) in drinking water) in obese fa/fa Zucker rats. In addition, expression of leptin mRNA in epididymal fat and serum levels of leptin were analysed. Food intake, body weights, binding of GDP to brown adipose tissue mitochondria, plasma insulin and glucose were also measured. Treatment with ZD7114 significantly reduced weight gain and activated brown adipose tissue thermogenesis, but had no effect on food intake. Expressions 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 preproNPY and preproCRF mRNA expressions and brown fat thermogenic activity and plasma insulin levels in the ZD7114 treated rats, but not in the control rats. It is concluded that treatment with ZD7114 markedly activated brown fat thermogenesis, but did not affect neuropeptide Y (NPY) 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 neuroendocrine mechanisms integrating body energy balance.