Abstract
Obesity represents a multifactorial disorder rooted in genetic, developmental, and environmental influences. Its persistence and heterogeneity warrant deeper understanding of pathology beyond genetic determinism. This Perspective synthesizes a conceptual model that draws from fundamental concepts, establishes cellular and organ levels of pathology, and provides a functional hierarchy of molecular signals in energy regulation. At the cellular level, DNA, RNA, and epigenetic regulators act as scripts, playwrights, and directors shaping metabolic behavior, establishing a "metabolic memory" that influences lifelong vulnerability, whereas peptides, proteins and other functional molecules are the actors. At the organ level, a four-organ model of hunger-the stomach (initiator), brain (executor), pancreas, and gut (regulators)-explains how hunger arises as a transient deviation from satiety, the body's homeostatic baseline. These organs communicate through rapid neural and slower chemical routes, integrating homeostatic and hedonic signals of food intake. At the molecular level, signaling molecules can be organized by size and function: small neurotransmitters that perform rapid communications, medium-sized peptides (ghrelin and incretins) that denote the messages to be conveyed and larger molecules like leptin that establish long-term tone. Recognizing this relationship clarifies why incretin therapies, though transformative, remain symptomatic rather than curative. These insights highlight the need for therapies that reprogram metabolic memory and restore durable equilibrium. Integrating these insights in research and practice would align obesity management with its true biological complexity.