Obesity and its comorbidities account for the largest proportion of preventable deaths. Obese patients develop chronic, systemic inflammation that leads to various comorbidities, such as type 2 diabetes (T2D). The active crosstalk between dysfunctional adipose tissue (AT) and the liver, has been suggested to underpin chronic inflammation and impair the function and metabolism of immune cells. In particular, the T helper (Th)2-dominant immune landscape in lean people transitions to an aberrant Th1-biased pro-inflammatory signature in obese patients. This shift has emerged as a key contributing factor to disease progression and increased susceptibility to infections and cancer. Therefore, understanding the fundamental mechanisms underlying the Th2-to-Th1 switch and defective Th1-immunity during obesity will offer an opportunity to alleviate the burden of comorbidities associated with the obesity epidemic. Natural killer (NK) cells are innate lymphocytes residing in different organs including the liver and the AT, there they acquire distinct phenotypic, metabolic, and functional features. Besides their protective role, NK cells are central to the maintenance of healthy tissue function and metabolism at steady state. In obese patients and in mice fed a high-fat diet (HFD), NK cells are reduced in frequency, show altered cellular metabolism and are impaired in their ability to produce effector cytokines (TNF-α and IFN-γ) and kill target cells. To date, the obesity-related factors and metabolites driving NK cells into dysfunction are yet to be fully elucidated. Our preliminary data show that human NK cell subsets rely on lipid droplet biogenesis to support cytokine production and cytotoxicity. Our findings suggest a prominent role of lipid metabolism in shaping NK cell biology. Given the crucial role of NK cells in tissue function and host protection, we plan to determine their role in obesity and how they contribute to the development of comorbidities and promote the susceptibility to influenza and cancer.