Obesity and type 2 diabetes are associated with significant health impacts and a decrease in quality of life. Ob/ob and db/db mice are frequently used to research these disorders. Ob/ob mice do not express leptin, a hormone released from fat cells, while db/db mice do not express its receptor. These mutations impair food intake and energy expenditure, which leads to fat mass gain. Despite targeting the same hormone-receptor pair, db/db mice are more diabetic than ob/ob mice. To investigate the mechanisms behind these differences, researchers recently examined the two lines in detail. They found that total fat mass was comparable but that fat mass distribution was different. They also found very distinct inflammatory profiles: ob/ob mice had more inflammation in the liver, whereas db/db mice had a higher inflammatory tone in the subcutaneous adipose tissue. Ob/ob and db/db mice also had very clear divergences in serum lipopolysaccharides concentration, hepatic bile acid content, and cecal short-chain fatty acids profile. Some of these differences could be explained by their very distinct fecal quantitative microbiome profiles. Together, these data show that these two mutant strains are not interchangeable experimental models.