Charge Characteristics of Agouti-Related Protein Implicate Potent Involvement of Heparan Sulfate Proteoglycans in Metabolic Function
Jihuan Chen,
Valerie Chen,
Tomoya Kawamura,
Ivy Hoang,
Yang Yang,
Ashley Tess Wong,
Ryan McBride,
Vez Repunte-Canonigo,
Glenn L. Millhauser,
Pietro Paolo Sanna
Affiliations
Jihuan Chen
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA
Valerie Chen
Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA 95064, USA
Tomoya Kawamura
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA
Ivy Hoang
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA
Yang Yang
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA
Ashley Tess Wong
Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA 95064, USA
Ryan McBride
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA; Genomics Core, The Scripps Research Institute, La Jolla, CA 92037, USA
Vez Repunte-Canonigo
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA
Glenn L. Millhauser
Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA 95064, USA; Corresponding author
Pietro Paolo Sanna
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA; Corresponding author
Summary: The endogenous melanocortin peptide agouti-related protein (AgRP) plays a well-known role in foraging, but its contribution to metabolic regulation is less understood. Mature AgRP(83-132) has distinct residues for melanocortin receptor binding and heparan sulfate interactions. Here, we show that AgRP increases ad libitum feeding and operant responding for food in mice, decreases oxygen consumption, and lowers body temperature and activity, indicating lower energy expenditure. AgRP increased the respiratory exchange ratio, indicating a reduction of fat oxidation and a shift toward carbohydrates as the primary fuel source. The duration and intensity of AgRP's effects depended on the density of its positively charged amino acids, suggesting that its orexigenic and metabolic effects depend on its affinity for heparan sulfate. These findings may have major clinical implications by unveiling the critical involvement of interactions between AgRP and heparan sulfate to the central regulation of energy expenditure, fat utilization, and possibly their contribution to metabolic disease. : Obesity Medicine; Physiology Subject Areas: Obesity Medicine, Physiology
