| First Author | Ahmed M | Year | 2022 |
| Journal | Proc Natl Acad Sci U S A | Volume | 119 |
| Issue | 16 | Pages | e2200476119 |
| PubMed ID | 35412887 | Mgi Jnum | J:324631 |
| Mgi Id | MGI:7280982 | Doi | 10.1073/pnas.2200476119 |
| Citation | Ahmed M, et al. (2022) A hypothalamic pathway for Augmentor alpha-controlled body weight regulation. Proc Natl Acad Sci U S A 119(16):e2200476119 |
| abstractText | Augmentor alpha and beta (Augalpha and Augbeta) are newly discovered ligands of the receptor tyrosine kinases Alk and Ltk. Augalpha functions as a dimeric ligand that binds with high affinity and specificity to Alk and Ltk. However, a monomeric Augalpha fragment and monomeric Augbeta 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 Augalpha and Augbeta are poorly understood. Here, we investigate the physiological roles of Augalpha and Augbeta by exploring mice deficient in each or both Aug ligands. Analysis of mutant mice showed that both Augalpha single knockout and double knockout of Augalpha and Augbeta exhibit a similar thinness phenotype and resistance to diet-induced obesity. In the Augalpha-knockout mice, the leanness phenotype is coupled to increased physical activity. By contrast, Augbeta-knockout mice showed similar weight curves as the littermate controls. Experiments are presented demonstrating that Augalpha 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 Augalpha 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. |
