Obesity rates in Croatia are among the highest in the European Union with over 57% of overweight adults. Although this has rendered a significant proportion of the population insulin resistant (IR), a small subset of obese individuals remains insulin sensitive (IS). Dysfunctional adipose tissue has a central role in the development of IR. Dysregulated lipid metabolism, impaired mitochondrial function, and chronic inflammation are closely associated with oxidative stress and subsequent peroxidation of polyunsaturated fatty acids (PUFAs), yielding reactive aldehydes. Work from our team suggests that adipose tissue macrophages are responsible for the oxidation of lipids and formation of reactive aldehydes, which accumulate in adipocytes and account for altered redox homeostasis, impaired adipogenesis, and induction of IR. Reactive aldehydes also regulate mitochondrial function and energy production triggering a shift in bioenergetics of adipocytes. Most of these pathways converge at lipid droplets, long neglected fat storage organelles with emerging roles in the regulation of redox and mitochondrial metabolism as well as PUFA lipotoxicity. Using novel approaches and relevant cellular models, including patient adipose tissue-derived cells, we aim to identify the major molecular pathways underlying the elusive relationship between dysregulated lipid accumulation, mitochondrial function, and lipid peroxidation (LPO). This work will also provide a deeper understanding of the altered adipocyte-macrophage crosstalk modulated by LPO. The study of the interplay between the two organelles crucial for controlling cellular lipid composition, energy and redox metabolism, combined with the analyses of patient samples, will pinpoint molecular targets responsible for the IR/IS phenotype differences and pave the path for novel therapeutic strategies for treating obesity and associated IR, and limit obesity-associated morbidity and mortality in the Croatia and worldwide.