The adipose tissue is an incredibly dynamic tissue which stores excess energy as fat and, when energy is scarce, releases fat to be utilised as fuel by other tissues. Beyond its role in energy storage, adipose has endocrine functions by releasing metabolites, hormones and cytokines which regulate whole-body metabolism. Furthermore, brown or subcutaneous adipocytes have beneficial effects by dissipating energy as heat. By utilizing mouse models of diverse genetic backgrounds, we have recently observed profound genetically-encoded differences in adipose expansion1. For example, when fed a high fat diet, certain inbred mouse strains show a propensity for adipocytes to expand in size (hypertrophy), whereas others show a propensity for making new adipocytes (hyperplasia). This has important implications because large adipocytes are believed to be insulin resistant and inflammatory, leading to insulin resistance in other tissues such as muscle via inflammatory cytokine signalling or accumulation of ectopic lipids. It is well-accepted that, in mice that have been made obese with high fat diet feeding, the adipose tissue develops insulin resistance, i.e. lower insulin-stimulated glucose uptake on a per-gram basis. However, we have observed that when the glucose uptake is normalised to account for the overall expansion of the fat pad, in many cases there is no defect. We hypothesise that adipose ‘insulin resistance’ is often a function of expanded adipocyte volume, marked by an upregulation of a subset of structural proteins, but not other metabolic proteins such as the insulin-responsive glucose transporter GLUT4, resulting in fewer molecules per cell membrane area. For example, we observe the A/J mouse strain has very large ‘insulin-resistant’ adipocytes and low GLUT4 expression normalised to total protein, yet this strain’s skeletal muscle remains insulin sensitive. Therefore, I will share our findings from our ongoing interrogations of the relationship between adipocyte size, function and metabolic health.