Lipolysis in Health and Disease: Pathways, Regulation, and Metabolic Consequences

Lipolysis regulates lipid distribution, energy availability, and metabolic homeostasis in organisms that store triacylglycerols. In multicellular organisms, adipose tissue evolved as a specialized organ that centralizes lipid storage and release, buffers nutrient fluctuations, and protects non-adipose tissues from lipid overload. Dysregulated adipocyte lipolysis occurs across diverse metabolic conditions, including obesity, diabetes, lipodystrophy, and inflammatory states. This review synthesizes evidence that defective suppression of basal lipolysis and impaired responsiveness to physiological stimuli disrupt lipid partitioning, promote insulin resistance, and drive ectopic lipid accumulation. Research shows that metabolic dysfunction arises in both obese and non-obese settings and correlates more closely with impaired control of fatty acid flux than with adiposity itself. Higher expression of lipolytic receptors, including those targeted by weight-loss medications, together with genes that regulate lipolysis through insulin signaling, is associated with greater weight loss and improved systemic metabolic health. In this review, we highlight canonical and noncanonical mechanisms governing lipolytic regulation and contrast pathological lipolysis with the tightly controlled lipolysis observed during weight loss. Together, these findings reframe lipolysis as a central determinant of metabolic health and a therapeutic target when precisely regulated.