Inter-Organ Lipid Trafficking in Obesity-Induced Diabetes: From Adipose Overflow to Lipotoxic Organ Crosstalk

Kabazzi Douglas T.

Department of Pharmaceutics Kampala International University Uganda

Email: t.kabazzi@studwc.kiu.ac.ug

ABSTRACT

Obesity-induced type 2 diabetes (T2D) is not simply a problem of “too much fat” but of where lipid ends up and how it moves between organs. Under physiological conditions, subcutaneous adipose tissue (AT) serves as a safe reservoir that buffers postprandial lipid flux, limiting exposure of non-adipose organs to toxic lipid intermediates. In obesity, however, AT becomes inflamed, fibrotic, and relatively non-expandable, leading to adipose overflow: excess fatty acids and triglyceride-rich lipoproteins spill into the circulation and are deposited as ectopic fat in liver, skeletal muscle, pancreas, heart, and kidney.Within these organs, neutral triglyceride storage in lipid droplets coexists with accumulation of bioactive lipids such as diacylglycerols (DAGs) and ceramides that interfere with insulin signaling, mitochondrial function, and cell survival, a process termed lipotoxicity. Lipid-induced stress triggers maladaptive inter-organ crosstalk mediated by adipokines, hepatokines, myokines, and extracellular vesicles, amplifying insulin resistance and β-cell failure. This review frames obesity-induced diabetes as a network disease of disordered lipid trafficking. We first outline the adipose tissue expandability and overflow hypotheses, then detail how ectopic lipid accumulation and lipotoxic intermediates drive insulin resistance and dysfunction in liver, muscle, pancreas, and heart. We next highlight emerging roles for organokines and extracellular vesicles in lipid-related signaling between tissues. Finally, we discuss therapeutic strategies that re-route lipid flux through improving adipose storage capacity, targeting ceramide and DAG synthesis, or altering lipoprotein handling and future biomarker and fluxomic approaches that may enable precision management of lipotoxic diabetes.

Keywords: lipotoxicity; ectopic fat; adipose tissue overflow; ceramides; organ crosstalk

CITE AS: Kabazzi Douglas T. (2026). Inter-Organ Lipid Trafficking in Obesity-Induced Diabetes: From Adipose Overflow to Lipotoxic Organ Crosstalk. RESEARCH INVENTION JOURNAL OF SCIENTIFIC AND EXPERIMENTAL SCIENCES 6(1):101-108. https://doi.org/10.59298/RIJSES/2026/61101108