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Background  Leptin-deficient  ob/ob  mice and leptin receptor-deficient  db/db  mice are commonly used mice models mimicking the conditions of obesity and type 2 diabetes development. However, although  ob/ob  and  db/db  mice are similarly gaining weight and developing massive obesity,  db/db  mice are more diabetic than  ob/ob  mice. It remains still unclear why targeting the same pathway—leptin signaling—leads to the development of two different phenotypes. Given that gut microbes dialogue with the host via different metabolites (e.g., short-chain fatty acids) but also contribute to the regulation of bile acids metabolism, we investigated whether inflammatory markers, bacterial components, bile acids, short-chain fatty acids, and gut microbes could contribute to explain the specific phenotype discriminating the onset of an obese and/or a diabetic state in  ob/ob  and  db/db  mice.    Results  Six-week-old  ob/ob  and  db/db  mice were followed for 7 weeks; they had comparable body weight, fat mass, and lean mass gain, confirming their severely obese status. However, as expected, the glucose metabolism and the glucose-induced insulin secretion were significantly different between  ob/ob  and  db/db  mice. Strikingly, the fat distribution was different, with  db/db  mice having more subcutaneous and  ob/ob  mice having more epididymal fat. In addition, liver steatosis was more pronounced in the  ob/ob  mice than in  db/db  mice. We also found very distinct inflammatory profiles between  ob/ob  and  db/db  mice, with a more pronounced inflammatory tone in the liver for  ob/ob  mice as compared to a higher inflammatory tone in the (subcutaneous) adipose tissue for  db/db  mice. When analyzing the gut microbiota composition, we found that the quantity of 19 microbial taxa was in some way affected by the genotype. Furthermore, we also show that serum LPS concentration, hepatic bile acid content, and cecal short-chain fatty acid profiles were differently affected by the two genotypes.    Conclusion  Taken together, our results elucidate potential mechanisms implicated in the development of an obese or a diabetic state in two genetic models characterized by an altered leptin signaling. We propose that these differences could be linked to specific inflammatory tones, serum LPS concentration, bile acid metabolism, short-chain fatty acid profile, and gut microbiota composition.Video abstract.Supplementary Information  The online version contains supplementary material available at 10.1186/s40168-021-01097-8.

Novel insights into the genetically obese (ob/ob) and diabetic (db/db) mice: two sides of the same coin