Enhanced anorexigenic signaling in lean obesity resistant syndecan-3 null mice.

Obesity is associated with increased risk of diabetes, cardiovascular disease and several types of cancers. The hypothalamus is a region of the brain critical in the regulation of body weight. One of the critical and best studied hypothalamic circuits is comprised of the melanocortinergic orexigenic agouti-related protein (AgRP) and anorexigenic α-melanocyte stimulating hormone (α-MSH) neurons. These neurons project axons to the same hypothalamic target neurons and balance each other's activity leading to body weight regulation. We previously showed that the brain proteoglycan syndecan-3 regulates feeding behavior and body weight, and syndecan-3 null (SDC-3(-/-)) mice are lean and obesity resistant. Here we show that the melanocortin agonist Melanotan II (MTII) potently suppresses food intake and activates the hypothalamic paraventricular nuclei (PVN) in SDC-3(-/-) mice based on c-fos immunoreactivity. Interestingly, we determined that the AgRP neuropeptide is reduced in the PVN of SDC-3(-/-) mice compared to wild type mice. In contrast, neuropeptide Y, coexpressed in the AgRP neuron, is not differentially expressed nor is the counteracting neuropeptide α-MSH. These findings are unprecedented and indicate that AgRP protein localization can be selectively regulated within the hypothalamus resulting in altered neuropeptide response and tone.