Endocrine Abstracts

Agouti-related protein (AgRP) and neuropeptide Y (NPY) are co-localised in hypothalamic arcuate nucleus neurons that have been implicated in the regulation of energy balance. Both AgRP and NPY stimulate food intake when administered into the third ventricle and are up-regulated in states of negative energy balance e.g. fasting. AgRP/NPY neurones are thought to play a role in the integration of information received from circulating satiety factors and signals of energy store status. Interestingly, mice with targeted deletion of either NPY or AgRP or both do not have obvious perturbations in energy homeostasis. Mice lacking both AgRP and NPY have however recently been shown not to respond to exogenously administered ghrelin, a gut hormone known to increase food intake.

We have used bacterial artificial chromosome (BAC) transgenesis to target the expression of a mutant form of the ataxin-3 protein, which causes neuronal degeneration, to AgRP expressing neurones in the arcuate nucleus. Successfully targeted expression of mutant ataxin-3 resulted in an approximate 50% loss of AgRP neurons. This was associated with significantly reduced body weight, 28.63plus/minus0.59 grams Tg v. 34.67plus/minus0.67 grams WT (p<0.001) for 16 week old male mice, and reduced average daily food intake, 3.6plus/minus0.12 grams Tg v. 5.01plus/minus0.24 grams WT (p<0.001) in male mice aged between 14 and 16 weeks of age. Neuronal loss also resulted in significantly reduced total fat content, plasma insulin (0.48plus/minus0.14 nanograms per millilitre Tg v. 1.02plus/minus0.13 nanograms per millilitre WT, p<0.05) and a trend for reduced plasma leptin. Fasted glucose levels were no different between wild type and age matched controls despite significantly reduced plasma insulin, suggesting transgenic mice are more insulin sensitive. This suggests that loss of AgRP/NPY neurons leads to a lean, hypophagic phenotype. This work demonstrates that AgRP/NPY neurones play an important role in the control of appetite and body weight.