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This figure summarizes the major differences observed between the two different models. Each specificity related to the organ of body fluid are depicted by a pictogram of the organ
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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...
Citations
... Other weight loss strategies, such as Pu-erh tea 36 , notoginsenoside Ft1 37 , resistant starch supplementation 38 and methionine-restriction diets 39 were also linked to increased serum levels of G/TDCA or G/TUDCA. Similarly, compared with lean wild-type littermates, ob/ob and db/db mice had lower serum levels of TDCA and TUDCA 40 . In addition, the gut microbial profile of the ob/ob mice presented higher abundances of L. murinus and L. reuteri 41 , both BSH-encoding microbes, which were positively associated with body weight and fasting glucose levels in our mouse study (Fig. 3h). ...
The low-carbohydrate ketogenic diet (KD) has long been practiced for weight loss, but the underlying mechanisms remain elusive. Gut microbiota and metabolites have been suggested to mediate the metabolic changes caused by KD consumption, although the particular gut microbes or metabolites involved are unclear. Here, we show that KD consumption enhances serum levels of taurodeoxycholic acid (TDCA) and tauroursodeoxycholic acid (TUDCA) in mice to decrease body weight and fasting glucose levels. Mechanistically, KD feeding decreases the abundance of a bile salt hydrolase (BSH)-coding gut bacterium, Lactobacillus murinus ASF361. The reduction of L. murinus ASF361 or inhibition of BSH activity increases the circulating levels of TDCA and TUDCA, thereby reducing energy absorption by inhibiting intestinal carbonic anhydrase 1 expression, which leads to weight loss. TDCA and TUDCA treatments have been found to protect against obesity and its complications in multiple mouse models. Additionally, the associations among the abovementioned bile acids, microbial BSH and metabolic traits were consistently observed both in an observational study of healthy human participants (n = 416) and in a low-carbohydrate KD interventional study of participants who were either overweight or with obesity (n = 25). In summary, we uncover a unique host–gut microbiota metabolic interaction mechanism for KD consumption to decrease body weight and fasting glucose levels. Our findings support TDCA and TUDCA as two promising drug candidates for obesity and its complications in addition to a KD.
... Studies have shown that db/db mice have leptin receptor deficiencies and exhibit characteristics associated with obesity and diabetes at the age of 3 to 4 weeks [7,45]. In these mice, at the age of 4 to 8 weeks, increased excessive blood sugar levels due to a severe depletion of insulin-producing β-cells lead to diabetes and increased gluconeogenesis. ...
Obesity is acknowledged as a significant risk factor for cardiovascular disease, often accompanied by increased inflammation and diabetes. Bioactive peptides derived from marine animal proteins show promise as safe and effective anti-obesity agents by regulating adipocyte differentiation through the AMPK signaling pathway. Therefore, this study aims to investigate the anti-obesity and anti-diabetic effects of bioactive compounds derived from a Meretrix lusoria Protamex enzymatic hydrolysate (MLP) fraction (≤1 kDa) through a 6-week treatment (150 mg/kg or 300 mg/kg, administered once daily) in leptin receptor-deficient db/db mice. The MLP treatment significantly decreased the body weight, serum total cholesterol, triglycerides, and LDL-cholesterol levels while also exhibiting a beneficial effect on hepatic and serum marker parameters in db/db mice. A histological analysis revealed a reduction in hepatic steatosis and epididymal fat following MLP treatment. Furthermore, poor glucose tolerance was improved, and hepatic antioxidant enzyme activities were elevated in MLP-treated mice compared to db/db control mice. Western blot analysis showed an increased expression of the AMPK protein after MLP treatment. In addition, the expression of lipogenic genes decreased in db/db mice. These findings indicate that bioactive peptides, which are known to regulate blood glucose levels, lipid metabolism, and adipogenesis, could be beneficial functional food additives and pharmaceuticals.
... Leptin receptor-defcient db/db mice are commonly used mice models mimicking the conditions of type 2 diabetes development. In addition to abnormal blood glucose, db/db mice also have obesity, insulin resistance, and chronic infammation [14], which are also the causes of testosterone defciency in men with type 2 diabetes [15]. Moreover, a previous study has reported impaired steroidogenesis in the testis of leptin-defcient mice (ob/ob −/−) [16], and leptin receptor expression is characteristic of mature Leydig cells [17]. ...
Objective. The mechanism of steroidogenesis and spermatogenesis impairment in men with type 2 diabetes remains unclear. We aimed to explore the local changes of steroidogenesis and spermatogenesis in the testis of db/db mice. Research Design and Methods. We performed single-cell RNA sequencing analysis in the testis of db/db and C57BL/6J mice. The differentially expressed genes were then confirmed by real-time PCR. The histopathological characteristics of testis in db/db mice and C57BL/6J control were also performed. Results. The 20-week-old db/db mice had significantly higher blood glucose and body weight (both p<0.001). The serum testosterone levels (4.4 ± 0.8 vs. 9.8 ± 0.7 ng/ml, p=0.001) and weight of the testis (0.16 ± 0.01 vs. 0.24 ± 0.01 g, p<0.001) were significantly lower in db/db mice than that in C57BL/6J controls. db/db mice had a lower cross-sectional area of seminiferous tubules and thickness of the cell layer (both p<0.05). The numbers of Sertoli cells and Leydig cells decreased in db/db mice (both p<0.01). Single-cell RNA sequencing analysis showed that compared with the control group, the percentage of spermatogonia was significantly higher in the db/db mouse (p<0.001), while the proportions of spermatocytes, round and elongating spermatids, and sperms were all lower in the db/db mouse (p all<0.001). The most differentially expressed genes were found in round spermatids (n = 86), which were not found in spermatogonia, spermatocyte, and sperm. Igfbp5 was the most significantly decreased gene in Leydig cells of the db/db mouse, while the expression of Cd74, H2-Aa, and H2-Eb1 was elevated. Ccl7 and Ptgds were the most significantly increased and decreased genes in Sertoli cells of the db/db mouse. Conclusions. The present study indicates spermiogenesis and steroidogenesis defects in db/db mice. The mechanism of steroidogenesis impairment in the testis of db/db mice deserves further investigation.
... 3h-j). This observation aligns with studies utilizing leptin receptor-deficient db/db mice as models for T2DM 17 . Elevated circulating leptin concentrations, as observed in individuals with obesity, are often attributed to leptin resistance 18,19 , potentially implicating S1 is related with leptin resistance. ...
Type 2 Diabetes Mellitus (T2DM) is increasingly prevalent and significantly impacts patients' lives. However, the phenotypic and genetic heterogeneity of the preclinical stage of T2DM, along with the subsequent effects on various clinical outcomes, remain unclear, impeding progress in disease screening and prevention. To address this gap, we employed a robust machine learning algorithm (Subtype and Stage Inference, SuStaIn) with cross-sectional clinical data from the UK Biobank (20,305 preclinical-T2DM participants and 20,305 controls) to identify underlying subtypes and their progression trajectories for preclinical-T2DM. Our analysis revealed one subtype distinguished by elevated circulating leptin levels and decreased leptin receptor levels, coupled with increased BMI, diminished lipid metabolism, and heightened susceptibility to psychiatric conditions such as anxiety disorder, depression disorder, and bipolar disorder. Conversely, individuals in the second subtype manifested typical abnormalities in glucose metabolism, including rising glucose and HbA1c levels, with observed correlations with neurodegenerative disorders. Over ten-year follow-up observations of these individuals reveal differential deterioration in brain and heart organs, and statistically significant difference in disease risk and clinical outcomes between the two subtypes. Our findings indicate a heterogenous pathobiological basis underlying the progression of preclinical-T2DM, with clinical implications for understanding human health from a multiorgan perspective, and improving disease risk screening, prediction, and prevention efforts.
... Intermittent fasting has been proposed as a potential dietary strategy for weight management; however, the effect on microbiota and how it is associated with obesity needs to be further elucidated. (56). The research team determined that the gut microbiota of the db/db mice was modified by following an IF dietary pattern for 7 months. ...
Obesity, a public health challenge, arises from a complex interplay of factors such as dietary habits and genetic predisposition. Alterations in gut microbiota, characterized by an imbalance between Firmicutes and Bacteroidetes, further exacerbate metabolic dysregulation, promoting inflammation and metabolic disturbances. Intermittent fasting (IF) emerges as a promising dietary strategy showing efficacy in weight management and favoring fat utilization. Studies have used mice as animal models to demonstrate the impact of IF on gut microbiota composition, highlighting enhanced metabolism and reduced inflammation. In humans, preliminary evidence suggests that IF promotes a healthy microbiota profile, with increased richness and abundance of beneficial bacterial strains like Lactobacillus and Akkermansia. However, further clinical trials are necessary to validate these findings and elucidate the long-term effects of IF on microbiota and obesity. Future research should focus on specific tissues and cells, the use of advanced -omics techniques, and exploring the interaction of IF with other dietary patterns, to analyze microbiota composition, gene expression, and potential synergistic effects for enhanced metabolic health. While preliminary evidence supports the potential benefits of IF in obesity management and microbiota regulation, further research with diverse populations and robust methodologies is necessary to understand its implications and optimize personalized dietary interventions. This review explores the potential impact of IF on gut microbiota and its intricate relationship with obesity. Specifically, we will focus on elucidating the underlying mechanisms through which IF affects microbiota composition, as well as its subsequent effects on obesity.
... Considering the gender differences in elucidating the regulatory effect of DAPA in promoting the "browning" of adipose tissue on metabolic disorders is also meaningful. Additionally, the application of various obesity models, such as ob/ob mice [30], is equally important in clarifying the role of DAPA in adipose tissue. However, it is undeniable that our study using a high-fat diet-induced obese male mouse model excluded the influence of gender and genetic factors on adipose tissue, making it more convincing to preliminarily clarify the role of DAPA in the "browning" of adipose tissue. ...
Background
Obesity is associated with a wide variety of metabolic disorders that impose significant burdens on patients and society. The “browning” phenomenon in white adipose tissue (WAT) has emerged as a promising therapeutic strategy to combat metabolic disturbances. However, though the anti-diabetic drug dapagliflozin (DAPA) is thought to promote “browning,” the specific mechanism of this was previously unclear.
Methods
In this study, C57BL/6 J male mice were used to establish an obesity model by high-fat diet feeding, and 3T3-L1 cells were used to induce mature adipocytes and to explore the role and mechanism of DAPA in “browning” through a combination of in vitro and in vivo experiments.
Results
The results show that DAPA promotes WAT "browning" and improves metabolic disorders. Furthermore, we discovered that DAPA activated "browning" through the fibroblast growth factor receptors 1-liver kinase B1-adenosine monophosphate-activated protein kinase signaling pathway.
Conclusion
These findings provide a rational basis for the use of DAPA in treating obesity by promoting the browning of white adipose tissue.
... Intestinal flora has long been shown to induce metabolic endotoxaemia by releasing endotoxins, promoting systemic hypo-inflammation and insulin resistance [55,56]. As a result, increased LPS can lead to inflammation, weight gain, and diabetes. ...
Endotoxin is a general term for toxic substances in Gram-negative bacteria, whose damaging effects are mainly derived from the lipopolysaccharides (LPS) in the cell walls of Gram-negative bacteria, and is a strong pyrogen. Obesity is a chronic, low-grade inflammatory condition, and LPS are thought to trigger and exacerbate it. The gut flora is the largest source of LPS in the body, and it is increasingly believed that altered intestinal microorganisms can play an essential role in the pathology of different diseases. Today, the complex axis linking gut flora to inflammatory states and adiposity has not been well elucidated. This review summarises the evidence for an interconnection between LPS, obesity, and gut flora, further expanding our understanding of LPS as a mediator of low-grade inflammatory disease and contributing to lessening the effects of obesity and related metabolic disorders. As well as providing targets associated with LPS, obesity, and gut flora, it is hoped that interventions that combine targets with gut flora address the individual differences in gut flora treatment.
... [27][28][29] The elevation in the level of FBG, C-peptide, HOMA-IR, TG, and TC observed in the DB group, indicates the outbreak of metabolic disorder. The insulin resistance (IR) is related to the hepatic lipid accumulation, the elevation of plasma inflammatory cytokines, [30][31][32][33] and the reductions in plasma IAA and IL-22, which are related to a bidirectional relationship between T2DM-associated dysbiosis and impaired glucose metabolism. [34][35][36][37] It is reported that the precise mechanism underlying the contribution of modulated gut microbiota or hyperglycemia to increased gut permeability and lipid accumulation remains elusive. ...
The gut microbiota plays a pivotal role in metabolic disorders, notably type 2 diabetes mellitus (T2DM). In this study, we investigated the synergistic potential of combining the effects of Bifidobacterium longum NBM7–1 (CKD1) with anti-diabetic medicines, LobeglitazoneⓇ (LO), SitagliptinⓇ (SI), and MetforminⓇ (Met), to alleviate hyperglycemia in a diabetic mouse model. CKD1 effectively mitigated insulin resistance, hepatic steatosis, and enhanced pancreatic β-cell function, as well as fortifying gut-tight junction integrity. In the same way, SI-CKD1 and Met- CKD1 synergistically improved insulin sensitivity and prevented hepatic steatosis, as evidenced by the modulation of key genes associated with insulin signaling, β-oxidation, gluconeogenesis, adipogenesis, and inflammation by qRT-PCR. The comprehensive impact on modulating gut microbiota composition was observed, particularly when combined with MetforminⓇ. This combination induced an increase in the abundance of Rikenellaceae and Alistipes related negatively to the T2DM incidence while reducing the causative species of Cryptosporangium, Staphylococcaceae, and Muribaculaceae. These alterations intervene in gut microbiota metabolites to modulate the level of butyrate, indole-3-acetic acid, propionate, and inflammatory cytokines and to activate the IL-22 pathway. However, it is meaningful that the combination of B. longum NBM7–1(CKD1) reduced the medicines’ dose to the level of the maximal inhibitory concentrations (IC50). This study advances our understanding of the intricate relationship between gut microbiota and metabolic disorders. We expect this study to contribute to developing a prospective therapeutic strategy modulating the gut microbiota.
... The db/db mice have been instrumental in exploring the pathogenesis of common human T2DM complications, such as, susceptibility to infection and wound healing impairment (76)(77)(78)(79)(116)(117)(118). However, a limitation of db/db mouse model is its inability to fully reproduce the diabetic conditions in humans (34,81). For example, the db/db mice primarily heal their wounds through contraction, which is in contrast with the reepithelialization that is seen in humans, although this limitation can be overcome using splinted wound models (81,82,99). ...
... However, a limitation of db/db mouse model is its inability to fully reproduce the diabetic conditions in humans (34,81). For example, the db/db mice primarily heal their wounds through contraction, which is in contrast with the reepithelialization that is seen in humans, although this limitation can be overcome using splinted wound models (81,82,99). Another limitation is that homozygous db/db mice are sterile and the maintenance of db/db mice requires breeding between heterozygous (db/+) pairs, thus adding to the cost and effort (83,84). ...
... In these mice, the islets of Langerhans are hypertrophied, which leads to an increase in insulin content and a general state of insulin resistance (34,122). The limitations with the ob/ob mouse model are like db/db mice (34,81,82). It is worth noting that although ob/ob males can occasionally reproduce if maintained on a restricted diet, ob/ob females are always sterile, but their sterility can be corrected through repeated treatment with leptin (86). ...
Diabetes mellitus, commonly referred to as diabetes, is a group of metabolic disorders characterized by chronic elevation in blood glucose levels, resulting from inadequate insulin production, defective cellular response to extracellular insulin, and/or impaired glucose metabolism. The two main types that account for most diabetics are type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM), each with their own pathophysiological features. T1D is an autoimmune condition where the body’s immune system attacks and destroys the insulin-producing beta cells in the pancreas. This leads to lack of insulin, a vital hormone for regulating blood sugar levels and cellular glucose uptake. As a result, those with T1D depend on lifelong insulin therapy to control their blood glucose level. In contrast, T2DM is characterized by insulin resistance, where the body’s cells do not respond effectively to insulin, coupled with a relative insulin deficiency. This form of diabetes is often associated with obesity, sedentary lifestyle, and/or genetic factors, and it is managed with lifestyle changes and oral medications. Animal models play a crucial role in diabetes research. However, given the distinct differences between T1DM and T2DM, it is imperative for researchers to employ specific animal models tailored to each condition for a better understanding of the impaired mechanisms underlying each condition, and for assessing the efficacy of new therapeutics. In this review, we discuss the distinct animal models used in type 1 and type 2 diabetes mellitus research and discuss their strengths and limitations.
... Notably, Suriano et al. [64] found that differences in the metabolic profile of db/db and ob/ ob mice were determined by their intestinal environment, including intestinal flora composition, intestinal flora fractions (e.g., LPS), intestinal-derived metabolites (e.g., SCFAs), and bile acid profile. In addition to metabolic profiles, inflammatory profiles also differ significantly. ...
