A hypothalamic pathway for Augmentor alpha-controlled body weight regulation

Augmentor alpha and beta (Aug alpha and Aug beta) are newly discovered ligands of the receptor tyrosine kinases Alk and Ltk. Auga functions as a dimeric ligand that binds with high affinity and specificity to Alk and Ltk. However, a monomeric Aug alpha fragment and monomeric Aug beta also bind to Alk and potently stimulate cellular responses. While previous studies demonstrated that oncogenic Alk mutants function as important drivers of a variety of human cancers, the physiological roles of Aug alpha and Aug beta are poorly understood. Here, we investigate the physiological roles of Aug alpha and Aug beta by exploring mice deficient in each or both Aug ligands. Analysis of mutant mice showed that both Aug alpha single knockout and double knockout of Aug alpha and Aug beta exhibit a similar thinness phenotype and resistance to diet-induced obesity. In the Aug alpha-knockout mice, the leanness phenotype is coupled to increased physical activity. By contrast, Aug beta-knockout mice showed similar weight curves as the littermate controls. Experiments are presented demonstrating that Aug alpha is robustly expressed and metabolically regulated in agouti-related peptide (AgRP) neurons, cells that control whole-body energy homeostasis in part via their projections to the paraventricular nucleus (PVN). Moreover, both Alk and melanocortin receptor-4 are expressed in discrete neuronal populations in the PVN and are regulated by projections containing Aug alpha and AgRP, respectively, demonstrating that two distinct mechanisms that regulate pigmentation operate in the hypothalamus to control body weight. These experiments show that Alk-driven cancers were co-opted from a neuronal pathway in control of body weight, offering therapeutic opportunities for metabolic diseases and cancer.