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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,4,19]]},"abstract":"<jats:p>Augmentor \u03b1 and \u03b2 (Aug\u03b1 and Aug\u03b2) are newly discovered ligands of the receptor tyrosine kinases Alk and Ltk. Aug\u03b1 functions as a dimeric ligand that binds with high affinity and specificity to Alk and Ltk. However, a monomeric Aug\u03b1 fragment and monomeric Aug\u03b2 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\u03b1 and Aug\u03b2 are poorly understood. Here, we investigate the physiological roles of Aug\u03b1 and Aug\u03b2 by exploring mice deficient in each or both Aug ligands. Analysis of mutant mice showed that both Aug\u03b1 single knockout and double knockout of Aug\u03b1 and Aug\u03b2 exhibit a similar thinness phenotype and resistance to diet-induced obesity. In the Aug\u03b1-knockout mice, the leanness phenotype is coupled to increased physical activity. By contrast, Aug\u03b2-knockout mice showed similar weight curves as the littermate controls. Experiments are presented demonstrating that Aug\u03b1 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\u03b1 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.<\/jats:p>","DOI":"10.1073\/pnas.2200476119","type":"journal-article","created":{"date-parts":[[2022,4,13]],"date-time":"2022-04-13T05:53:06Z","timestamp":1649829186000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":25,"title":["A hypothalamic pathway for Augmentor \u03b1\u2013controlled body weight regulation"],"prefix":"10.1073","volume":"119","author":[{"given":"Mansoor","family":"Ahmed","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Yale School of Medicine, New Haven, CT 06520"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Navjot","family":"Kaur","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Yale School of Medicine, New Haven, CT 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