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

Abstract

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.

Three of a Kind: Control of the Expression of Liver-Expressed Antimicrobial Peptide 2 (LEAP2) by the Endocannabinoidome and the Gut Microbiome

“…This finding may suggest that LEAP2 is overproduced by the ileum to counteract glucose intolerance induced by an HFHS diet or hyperphagia. Since the ileum of HFHS and of ob/ob and db/db mice presents with inter-related alterations in gut eCBome signaling (present results and [ 23 ]) and microbiota composition [ 23 , 42 , 43 ], we hypothesized a role of either system in the modulation of Leap2 expression. However, also, in this case, the only potential eCBome signaling pathway that changed in a manner similar to Leap2 expression following HFHS and in ob/ob and db/db mice was that mediated by PPARα and/or its ligands.…”

Intestinal Barrier in Human Health and Disease

“…A high fat diet (HFD) promotes gut leakiness through dysbiosis, since antibiotic treatment has been shown to be effective in improving intestinal permeability and glucose homeostasis in HFD-fed mice [ 128 ]. However, in an experimental model of leptin-deficient mice, obesity per se was associated with increased intestinal permeability, due to reduced expression of occludin, ZO1, and mucin synthesis, regardless of diet [ 142 , 143 ].…”

“…Recent studies on mice with defective leptin pathways show how obese mutant mice are featured by major defects in bile acid synthesis and conjugation, together with higher expression of liver cholic acid [ 142 , 153 ].…”

CXCR1/2 Inhibitor Ladarixin Ameliorates the Insulin Resistance of 3T3-L1 Adipocytes by Inhibiting Inflammation and Improving Insulin Signaling

“…Recent data have shown that, along with CXCL5, circulating levels of CXCL1, with high affinity to CXCR2, are markedly increased in the db/db mice and correlate with obesity development [ 43 , 44 ]. KC, the human orthologue of CXCL1 (IL-8), is an important member of the chemokine family of pro-inflammatory chemotactic cytokines and it is also involved in systemic immunity and macrophages infiltration and activation in adipose tissue [ 45 ].…”