Obesity is associated with a cluster of metabolic disorders, low-grade inflammation and altered gut microbiota. Whether host metabolism is controlled by intestinal innate immune system and the gut ...microbiota is unknown. Here we report that inducible intestinal epithelial cell-specific deletion of MyD88 partially protects against diet-induced obesity, diabetes and inflammation. This is associated with increased energy expenditure, an improved glucose homeostasis, reduced hepatic steatosis, fat mass and inflammation. Protection is transferred following gut microbiota transplantation to germ-free recipients. We also demonstrate that intestinal epithelial MyD88 deletion increases anti-inflammatory endocannabinoids, restores antimicrobial peptides production and increases intestinal regulatory T cells during diet-induced obesity. Targeting MyD88 after the onset of obesity reduces fat mass and inflammation. Our work thus identifies intestinal epithelial MyD88 as a sensor changing host metabolism according to the nutritional status and we show that targeting intestinal epithelial MyD88 constitutes a putative therapeutic target for obesity and related disorders.
Administration of Tolylsam, a MMP inhibitor with relative specificity for gelatinases, at a dose of 100 mg/kg/day to leptin-deficient (ob/ob) mice kept on high fat diet for 15 weeks, was associated ...with significantly reduced weight gain as compared to controls (p < 0.0005), resulting in lower body weight (p < 0.0005) at the end of the experiments. Food intake, physical activity and body temperature were not affected. Subcutaneous (SC) (2.9 ± 0.1g vs. 3.4 ± 0.2g in controls; p < 0.05) and gonadal (GON) (3.4 ± 0.1g vs. 3.7 ± 0.1g in controls; p = NS) fat mass were reduced by Tolylsam treatment. Reduced MMP-2 (gelatinase A) activity in adipose tissue extracts was confirmed by zymography. Mild adipocyte hypotrophy was observed in treated SC and GON adipose tissues. Blood vessel density was significantly reduced in Tolylsam treated SC (p < 0.05) and GON (p < 0.005) adipose tissues. Sirius red staining revealed comparable collagen content in both SC and GON fat of treated mice, whereas collagen disorganization (ratio thick/thin fibers) was also similar. Thus, gelatinase inhibition in mice with leptin deficiency resulted in lower body and fat pad weights, associated with mild adipocyte hypotrophy. This indicates that MMP inhibition may impair adipose tissue development independently of leptin.
The field of the gut microbiota is still a relatively young science area, yet many studies have already highlighted the translational potential of microbiome research in the context of human health ...and disease. However, like in many new fields, discoveries are occurring at a fast pace and have provided new hope for the development of novel clinical applications in many different medical conditions, not in the least in metabolic disorders. This rapid progress has left the field vulnerable to premature claims, misconceptions and criticism, both from within and outside the sector. Tackling these issues requires a broad collaborative effort within the research field and is only possible by acknowledging the difficulties and challenges that are faced and that are currently hindering clinical implementation. These issues include: the primarily descriptive nature of evidence, methodological concerns, disagreements in analysis techniques, lack of causality, and a rather limited molecular-based understanding of underlying mechanisms. In this review, we discuss various studies and models that helped identifying the microbiota as an attractive tool or target for developing various translational applications. We also discuss some of the limitations and try to clarify some common misconceptions that are still prevalent in the field.
Gut microorganisms are vital for many aspects of human health, and the commensal bacterium Akkermansia muciniphila has repeatedly been identified as a key component of intestinal microbiota. ...Reductions in A. muciniphila abundance are associated with increased prevalence of metabolic disorders such as obesity and type 2 diabetes. It was recently discovered that administration of A. muciniphila has beneficial effects and that these are not diminished, but rather enhanced after pasteurization. Pasteurized A. muciniphila is proposed for use as a food ingredient, and was therefore subjected to a nonclinical safety assessment, comprising genotoxicity assays (bacterial reverse mutation and in vitro mammalian cell micronucleus tests) and a 90‐day toxicity study. For the latter, Han Wistar rats were administered with the vehicle or pasteurized A. muciniphila at doses of 75, 375 or 1500 mg/kg body weight/day (equivalent to 4.8 × 109, 2.4 × 1010, or 9.6 × 1010 A. muciniphila cells/kg body weight/day) by oral gavage for 90 consecutive days. The study assessed potential effects on clinical observations (including detailed arena observations and a modified Irwin test), body weight, food and water consumption, clinical pathology, organ weights, and macroscopic and microscopic pathology. The results of both in vitro genotoxicity studies were negative. No test item‐related adverse effects were observed in the 90‐day study; therefore, 1500 mg/kg body weight/day (the highest dose tested, equivalent to 9.6 × 1010 A. muciniphila cells/kg body weight/day) was established as the no‐observed‐adverse‐effect‐level. These results support that pasteurized A. muciniphila is safe for use as a food ingredient.
Pasteurized A. muciniphila is proposed for use as a food ingredient and was therefore subjected to in vitro genotoxicity tests and a 90‐day oral (gavage) toxicity study in rats. There was no evidence of genotoxicity, and the highest dose tested in the 90‐day study (1500 mg/kg body weight/day, equivalent to 9.6 × 1010 A. muciniphila cells/kg body weight/day) was established as the no‐observed‐adverse‐effect‐level. These results support the safety of pasteurized A. muciniphila for use as a food ingredient.
Obesity is a pandemic disease associated with many metabolic alterations and involves several organs and systems. The endocannabinoid system (ECS) appears to be a key regulator of energy homeostasis ...and metabolism. Here we show that specific deletion of the ECS synthesizing enzyme, NAPE-PLD, in adipocytes induces obesity, glucose intolerance, adipose tissue inflammation and altered lipid metabolism. We report that Napepld-deleted mice present an altered browning programme and are less responsive to cold-induced browning, highlighting the essential role of NAPE-PLD in regulating energy homeostasis and metabolism in the physiological state. Our results indicate that these alterations are mediated by a shift in gut microbiota composition that can partially transfer the phenotype to germ-free mice. Together, our findings uncover a role of adipose tissue NAPE-PLD on whole-body metabolism and provide support for targeting NAPE-PLD-derived bioactive lipids to treat obesity and related metabolic disorders.
Expression of thrombospondin‐2 (TSP‐2), a matricellular protein with anti‐angiogenic properties, is modulated in developing adipose tissue. To investigate a potential functional role of TSP‐2 in ...adipose tissue angiogenesis and growth, TSP‐2 deficient (TSP‐2−/−) and wild‐type littermate (TSP‐2+/+) mice were kept on normal chow (standard fat diet (SFD)) or on high fat diet (HFD) for 15 weeks. TSP‐2−/− mice kept on HFD had a significantly lower total body weight throughout the experimental period. Subcutaneous (SC) and gonadal (GON) fat mass were, however, not different, and their composition in terms of size and density of adipocytes and blood vessels was also comparable in both genotypes. Macrophage infiltration in SC or GON adipose tissues was not affected by TSP‐2 deficiency. TSP‐2 deficiency had no effect on adipose tissue mRNA expression of gelatinase A (MMP‐2), whereas gelatinase B (MMP‐9) was downregulated in SC and GON adipose tissues of TSP‐2−/− mice on HFD. Glucose tolerance and insulin resistance tests were comparable for TSP‐2+/+ and TSP‐2−/− mice. TSP‐2 deficiency was not compensated by increased expression of TSP‐1 in the TSP‐2−/− mice. These data suggest that TSP‐2, despite its reported anti‐angiogenic properties, does not play an important functional role in adipose tissue related angiogenesis or associated fat development in mice.
Dietary fibers are essential components of a balanced diet and have beneficial effects on metabolic functions. To gain insight into their impact on host physiology and gut microbiota, we performed a ...direct comparison of two specific prebiotic fibers in mice. During an 8-wk follow up, mice fed a high-fat diet (HFD) were compared with mice on a normal diet (basal condition, controls) and to mice fed the HFD but treated with one of the following prebiotics: fructooligosaccharides (FOS) or soluble corn fiber (SCF). Both prebiotic fibers led to a similar reduction of body weight and fat mass, lower inflammation and improved metabolic parameters. However, these health benefits were the result of different actions of the fibers, as SCF impacted energy excretion, whereas FOS did not. Interestingly, both fibers had very distinct gut microbial signatures with different short-chain fatty acid profiles, indicating that they do not favor the growth of the same bacterial communities. Although the prebiotic potential of different fibers may seem physiologically equivalent, our data show that the underlying mechanisms of action are different, and this by targeting different gut microbes. Altogether, our data provide evidence that beneficial health effects of specific dietary fibers must be documented to be considered a prebiotic and that studies devoted to understanding how structures relate to specific microbiota modulation and metabolic effects are warranted.
Obesity and obesity-related disorders, such as type 2 diabetes have been progressively increasing worldwide and treatments have failed to counteract their progression. Growing evidence have ...demonstrated that gut microbiota is associated with the incidence of these pathologies. Hence, the identification of new nutritional compounds, able to improve health through a modulation of gut microbiota, is gaining interest. In this context, the aim of this study was to investigate the gut-driving effects of rhubarb extract in a context of diet-induced obesity and diabetes. Eight weeks old C57BL6/J male mice were fed a control diet (CTRL), a high fat and high sucrose diet (HFHS) or a HFHS diet supplemented with 0.3% (g/g) of rhubarb extract for eight weeks. Rhubarb supplementation fully prevented HFHS-induced obesity, diabetes, visceral adiposity, adipose tissue inflammation and liver triglyceride accumulation, without any modification in food intake. By combining sequencing and qPCR methods, we found that all these effects were associated with a blooming of
, which is strongly correlated with increased expression of
in the colon. Our data showed that rhubarb supplementation is sufficient to protect against metabolic disorders induced by a diet rich in lipid and carbohydrates in association with a reciprocal interaction between
and Reg3γ.
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