Charge Characteristics of Agouti-Related Protein Implicate Potent Involvement of Heparan Sulfate Proteoglycans in Metabolic Function

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, AgRP increased ad libitum feeding and operant responding for food in mice, decreased oxygen consumption, and lowered 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. 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.