Obesity often leads to insulin resistance and an increased risk of type 2 diabetes. However, not all individuals with obesity are similarly affected. Given the same weight gain, individuals may be either protected from or predisposed to metabolic dysfunction. This variability has been attributed to individual differences in the characteristics of the excess adipose tissue. However, there remains a lack of understanding of the specific adipose tissue properties that underlie differential responses to weight gain and obesity. The aim of the present project is to understand the adipose tissue mechanisms that either protect from or predispose to insulin resistance and type 2 diabetes. The project builds on human genetic findings made in large populations and applies a range of approaches to connect the genetic variants to adipose tissue biology. The new understanding emerging from the project may point towards more effective ways to treat insulin resistance and type 2 diabetes.