Many animal studies on obesity and diabetes utilize a model of feeding animals a high-fat diet (HFD) to induce obesity or diabetes. Despite the wealth of information obtained from these animal-based HFD studies, the mechanisms regulating the interplay between obesity and insulin resistance in humans remain unclear. Dietary modification in rodents may not translate to a better understanding of treatments for human obesity and diabetes. This review article outlines the potential reasons for this translational discrepancy.

The underlying mechanism linking obesity with insulin resistance is widely thought to be impaired adipogenesis, which results in enlarged adipocytes. When larger adipocytes can no longer expand, the excess lipid is thought to be shunted to non-adipose tissues (skeletal muscle, liver, heart, and pancreas), where it disrupts insulin signaling and causes insulin resistance. This concept was tested in humans by overfeeding men by 40 percent for eight weeks, then measuring the changes in insulin sensitivity and adipocyte size and the lipid accumulation in the liver and muscle. The study caused a 7.6 kilogram weight gain (55 percent fat), and insulin sensitivity decreased 18 percent. Liver fat increased 46 percent, but skeletal muscle lipid content did not change. There was no association between adipocyte size and ectopic lipid accumulation. Despite similar weight gain, subjects with smaller fat cells at baseline had a greater decrease in insulin sensitivity. This study suggests that the presence of larger adipocytes does not promote ectopic lipid accumulation; however, smaller fat cells were associated with a worsened metabolic response to overfeeding.