Endothelial IGF-1 receptor mediates crosstalk with the gut wall to regulate microbiota in obesity.
Natalie J HaywoodCheukyau LukKatherine I BridgeMichael DrozdNatallia MakavaAnna SkromnaAmanda MaccannellClaire H OzberNele WarmkeChloe G WilkinsonNicole T WattJoanna Koch-PaszkowskiIrvin TehJordan H BoyleSean SmartJurgen E SchneiderNadira Y YuldashevaLee D RobertsDavid J BeechPiruthivi SukumarStephen B WheatcroftRichard M CubbonMark T KearneyPublished in: EMBO reports (2021)
Changes in composition of the intestinal microbiota are linked to the development of obesity and can lead to endothelial cell (EC) dysfunction. It is unknown whether EC can directly influence the microbiota. Insulin-like growth factor-1 (IGF-1) and its receptor (IGF-1R) are critical for coupling nutritional status and cellular growth; IGF-1R is expressed in multiple cell types including EC. The role of ECIGF-1R in the response to nutritional obesity is unexplored. To examine this, we use gene-modified mice with EC-specific overexpression of human IGF-1R (hIGFREO) and their wild-type littermates. After high-fat feeding, hIGFREO weigh less, have reduced adiposity and have improved glucose tolerance. hIGFREO show an altered gene expression and altered microbial diversity in the gut, including a relative increase in the beneficial genus Akkermansia. The depletion of gut microbiota with broad-spectrum antibiotics induces a loss of the favourable metabolic differences seen in hIGFREO mice. We show that IGF-1R facilitates crosstalk between the EC and the gut wall; this crosstalk protects against diet-induced obesity, as a result of an altered gut microbiota.
Keyphrases
- high fat diet induced
- insulin resistance
- binding protein
- growth hormone
- endothelial cells
- metabolic syndrome
- weight loss
- pi k akt
- wild type
- weight gain
- gene expression
- type diabetes
- adipose tissue
- dna methylation
- cell proliferation
- microbial community
- oxidative stress
- signaling pathway
- body mass index
- physical activity
- cell therapy
- vascular endothelial growth factor
- copy number
- room temperature
- bone marrow