PROJECT SUMMARY Twentieth-century Danish physiologist August Krogh wrote that, “for such a large number of problems there will be some animal of choice, or a few such animals, on which it can be most conveniently studied.” Formalized as “Krogh's Principle” by biochemist Hans Krebs nearly 50 years later, this approach has become a guiding tenant for many scientific fields such as comparative physiology, neuroethology, and functional genomics. Investigations in such distantly-related model organisms provide great value to biomedical research specifically because they possess unique features that allow unprecedented insight to functions and dysfunctions that occur in humans. We invoke Krogh's principle to advance the mouth-brooding cichlid fish Astatotilapia burtoni as an innovative animal model for the study of metabolic regulation and dysregulation. In humans, the inappropriate decoupling of feeding behavior and metabolic rate is clearly maladaptive, severely compromising patient quality of life and even survival outcome without medical intervention. A. burtoni females undergo self induced starvation for as long as 30 days while brooding their young in their mouths - a prerequisite of reproduction - and yet recover to resume feeding and reenter the reproductive cycle after their young have achieved independence. In contrast to the human state, these fish provide an animal model in which the underlying mechanisms have been shaped by natural selection and can be conveniently studied. The synergistic aims of this proposal span physiological, gene regulatory networks, protein-expression, tissue histology, regulatory neural circuit analysis, and pharmacology to establish Astatotilapia burtoni as an animal model suited to the study of anorexia and, more broadly, appetite/metabolic regulation. Following metabolic measures and histology, neural and peripheral circuits are anatomically defined and functionally addressed through expression of activity markers, autoradiography, and pharmacology. Finally, we use a hypothesis-driven approach to test candidate neural and peripheral mechanisms with qPCR to complement a discovery-based Tag-Seq analysis of neural transcriptomes from identified brain nuclei in the feeding circuit, thereby identifying conserved and novel mechanisms of feeding regulation and lean tissue catabolism. Mechanisms of appetite regulation appear to be largely conserved between the teleost and mammalian lineages, allowing for many direct comparisons. However, sufficient phylogenetic distance and difference in selective pressures predict mechanistic adaptations in A. burtoni that are not present in mammals. These similarities and differences can inform both novel therapeutic approaches to devastating human disorders.