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

Abstract

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.

• Authors: Q Zheng, J Zhu, M Shanabrough, E Borok, S C Benoit, T L Horvath, D J Clegg, O Reizes
• Journal: Neuroscience (Neuroscience) Vol. 171 Issue 4 Pg. 1032-40 (Dec 29 2010) ISSN: 1873-7544 [Electronic] United States
• PMID: 20923696 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

Chemical References

• Agouti-Related Protein
• Agrp protein, mouse
• Neuropeptide Y
• Proto-Oncogene Proteins c-fos
• Sdc3 protein, mouse
• Syndecan-3
• alpha-MSH (4-10)amide, Ac-Nle(4)-cyclo(Asp(5)-Phe(7)-Lys(10))-
• alpha-MSH

Topics

• Agouti-Related Protein (metabolism)
• Analysis of Variance
• Animals
• Body Weight (drug effects, genetics)
• Dose-Response Relationship, Drug
• Eating (drug effects, genetics)
• Feeding Behavior (drug effects, physiology)
• Food Deprivation (physiology)
• Gene Expression Regulation (drug effects, genetics)
• Male
• Mice
• Mice, Knockout
• Neurons (drug effects, metabolism)
• Neuropeptide Y (pharmacology)
• Paraventricular Hypothalamic Nucleus (cytology, drug effects, metabolism)
• Proto-Oncogene Proteins c-fos (metabolism)
• Signal Transduction (drug effects, genetics, physiology)
• Syndecan-3 (deficiency)
• Time Factors
• alpha-MSH (analogs & derivatives, pharmacology)