Organelle contact sites as spatial regulators of lipid fate in adipose tissue metabolic disease.

Abstract

Adipose tissue protects metabolic homeostasis by storing excess fatty acids, releasing fuels during energy demand and coordinating endocrine and inflammatory signals. These functions are often described as linear pathways of lipogenesis, lipolysis, fatty acid oxidation and thermogenesis. However, lipid handling in adipocytes is spatially organized by organelle contact sites. The endoplasmic reticulum (ER), lipid droplets (LDs), mitochondria, peroxisomes and lysosomes form dynamic interfaces that determine whether fatty acids are stored safely, mobilized for oxidation, processed into specialized lipid species or redirected toward lipotoxic intermediates. In this review, we synthesize evidence that ER-LD and LD-mitochondria contacts coordinate lipid storage and oxidative use, whereas peroxisome-centred contacts connect lipolysis, very-long-chain and branched-chain fatty acid processing, plasmalogen metabolism and mitochondrial remodelling. We further discuss how autophagy and lysosomal pathways maintain adipocyte quality control by regulating LD turnover, mitophagy and membrane renewal. Finally, we propose that obesity, insulin resistance, ectopic lipid deposition, lipodystrophy and adipose inflammation can be viewed as different manifestations of impaired spatial lipid routing. This framework does not replace classical metabolic models, but provides a mechanistic layer that may help identify contact-site-dependent vulnerabilities in metabolic disease.