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The role of intestinal iron absorption machinery in regulating gut hormone secretion and systemic metabolism [Duodenum]

ABSTRACT: Bariatric surgeries remain the most effective treatments for sustained weight loss and remission of type 2 diabetes. In addition to decreased body weight and improved glucose regulation, these procedures also dramatically increase secretion of several gut hormones including GLP-1. Despite these benefits, there are deleterious side effects to these procedures that include an increased incidence of iron-deficiency related anemias. The transcription factor HIF2a is heavily expressed in the duodenum and regulates the molecular machinery of iron absorption from the lumen. Lower iron levels after both gastric bypass and sleeve gastrectomy procedures occur despite dramatic upregulation of HIF2a signaling in the duodenum and are likely the result of increased hepcidin levels. Low iron diets also stimulate increased HIF2a signaling in the duodenum and produce effects similar to bariatric surgery that include reduced body weight/fat, improved glucose regulation and increased secretion of the GLP-1. Gut-specific deletion of VHL results in a constitutive upregulation of HIF2a signaling in the small intestine and produces a dramatic phenotype that includes reduced body weight/fat, improved glucose tolerance and increased GLP-1 secretion from the intestine. These data demonstrate an important role of HIF2a signaling in the duodenum to regulate multiple aspects of systemic metabolism and gut hormone secretion pointing towards critical cross-talk between the systems that regulate iron and other aspects of systemic physiology important to prevalent metabolic diseases.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE169402 | GEO | 2022/02/03

REPOSITORIES: GEO

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Project description:Obesity is associated with multiple diseases. Bariatric surgery is the most effective therapy for severe obesity that can reduce body weight and obesity-associated morbidity. The metabolic alterations associated with obesity and respective changes after bariatric surgery are incompletely understood.We comprehensively assessed metabolic alterations associated with severe obesity and distinct bariatric procedures. In our longitudinal observational study, we applied a (1)H-nuclear magnetic resonance-based global, untargeted metabolomics strategy on human serum samples that were collected before and repeatedly <=1 y after distinct bariatric procedures [i.e., a sleeve gastrectomy, proximal Roux-en Y gastric bypass (RYGB), and distal RYGB]. For comparison, we also analyzed serum samples from normal-weight and less-obese subjects who were matched for 1-y postoperative body mass index (BMI) values of the surgical groups. We identified a metabolomic fingerprint in obese subjects that was clearly discriminated from that of normal-weight subjects. Furthermore, we showed that bariatric surgery (sleeve gastrectomy and proximal and distal RYGB) dynamically affected this fingerprint in a procedure-dependent manner, thereby establishing new fingerprints that could be discriminated from those of BMI-matched and normal-weight control subjects. Metabolites that largely contributed to the metabolomic fingerprints of severe obesity were aromatic and branched-chain amino acids (elevated), metabolites related to energy metabolism (pyruvate and citrate; elevated), and metabolites suggested to be derived from gut microbiota (formate, methanol, and isopropanol; all elevated). Our data indicate that bariatric surgery, irrespective of the specific kind of procedure used, reverses most of the metabolic alterations associated with obesity and suggest profound changes in gut microbiome-host interactions after the surgery. This trial was registered at clinicaltrials.gov as NCT02480322.

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The role of intestinal iron absorption machinery in regulating gut hormone secretion and systemic metabolism [Duodenum]

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