AgRP and NPY Expression in the Human Hypothalamic Infundibular Nucleus Correlate with Body Mass Index, Whereas Changes in alpha MSH Are Related to Type 2 Diabetes

Context: Rodent data show that altered hypothalamic signaling contributes to the development of obesity and insulin resistance. Objective: To determine differences in hypothalamic expression levels of neuropeptide Y (NPY), agouti-related peptide (AgRP), and alpha MSH in the infundibular nucleus, the human equivalent of the arcuate nucleus, in relation to body mass index (BMI). In addition, the expression in the infundibular nucleus of eight subjects diagnosed with type 2 diabetes was measured to determine possible interference of type 2 diabetes with the association observed between neuropeptides and BMI. Design: We studied AgRP, NPY, and alpha MSH expression by means of quantitative immunocytochemistry in postmortem hypothalami of 30 subjects with known BMI. In separate experiments, we compared neuropeptide expression in eight subjects with type 2 diabetes with eight matched controls. Results: We found that AgRP immunoreactivity showed a U-shaped correlation with BMI. No evidence was found for possible influences of corticosteroid treatment. NPY immunoreactivity was significantly lower in overweight and obese subjects. alpha MSH did not correlate with BMI but was significantly lower in subjects with type 2 diabetes compared with controls. By contrast, NPY and AgRP expression was not affected in type 2 diabetes. Conclusion: Our results indicate that the expression of AgRP and NPY are correlated with body weight changes, rather than the presence of type 2 diabetes, whereas changes in alpha MSH immunoreactivity are related to the presence of type 2 diabetes, indicating separate hypothalamic mechanisms. (J Clin Endocrinol Metab 97: E925-E933, 2012)