Mechanism of Decreased Iron Absorption in Obesity: Controlling Adiposity-related Inflammation

Study Overview
=================
Brief Summary
-----------------
The main iron regulatory protein in the human metabolism is hepcidin. In normal weight, healthy subjects, hepcidin is regulated through the iron status of the body: low iron status results in low hepcidin concentrations, which facilitates dietary iron absorption. In obesity, which is an inflammatory state, hepcidin concentrations are increased and iron absorption is reduced despite low iron stores, leading to iron deficiency over time. Whether lowering the chronic low-grade inflammation during a limited treatment period and thereby lowering hepcidin concentration can improve iron absorption is uncertain.

Detailed Description
-----------------
In states of high hepcidin concentration, intestinal iron absorption (through enterocytes) and recycling of iron (through macrophages) is reduced. The extent to which non-heme iron is absorbed from the diet is influenced by the composition of the diet. Ascorbic acid is a potent enhancer of non-heme iron absorption. It's mechanism of action is luminal reduction of dietary ferric iron (Fe3+) to more soluble ferrous iron (Fe2+). A study in the inestigator's laboratory showed that the enhancing effect of ascorbic acid on non-heme iron absorption is reduced in overweight and obese individuals. Possible explanations for this fact are the different sites of action of ascorbic acid and serum hepcidin on the enterocytes in dietary iron absorption. Increased hepcidin reduces iron efflux into the circulation at the basolateral membrane of the enterocyte. Therefore the improved iron transport into enterocytes through ascorbic acid at the luminal side (via the divalent metal transporter (DMT)-1), by reducing Fe3+ to Fe2+ seems to be less successful. To improve iron absorption in obese subjects, an intervention at the basolateral membrane of the enterocyte would be needed.

Official Title
-----------------
Mechanism of Decreased Iron Absorption in Obesity: Controlling Adiposity-related Inflammation

Conditions
-----------------
Obesity

Intervention / Treatment
-----------------
* Drug: Ibuprofen


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: normal-weight (BMI18.5-24.9kg/m2) or obesity (BMI 29-40kg/m2) pre-menopausal no chronic illness and no significant medical conditions that could influence iron or inflammatory status other than obesity no-smoking Exclusion Criteria: Diagnosed chronic disease or gastrointestinal disorders Metabolic disorders (e.g. diabetes) Regular use of medication (except oral contraceptives) Subject on a weight loss diet or planning to start a weight loss diet during the duration of the study Pregnancy or lactation

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: normal-weight<br>normal-weight women | Drug: Ibuprofen<br> <br> |
| Experimental: obesity<br>obese women | Drug: Ibuprofen<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fractional iron absorption | The fractional iron absorption from four test meals will be calculated based on the shift of the iron isotopic ratios in the collected blood samples 14 days after administration of the isotopically labeled meals. Calculation of fractional iron absorption will take into account the principles of isotope dilution and the fact that iron isotopic labels are not mono-isotopic. The investigators assumed iron incorporation into erythrocytes to be constant. Blood volume, needed for the calculation of fractional iron absorption will be estimated based on available data on blood volume estimations in obese women. | Days 15 and 45 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma ferritin |  | Days 1, 15, 30, 45 | 
| Hemoglobin |  | Days 1, 15, 30, 45 | 
| Transferrin receptor |  | Days 1, 15, 30, 45 | 
| Hepcidin |  | Days 1, 15, 30, 45 | 
| c-reactive protein |  | Days 1, 15, 30, 45 | 
| interleukin-6 |  | Days 1, 15, 30, 45 | 
| alpha-1-acid-glycoprotein |  | Days 1, 15, 30, 45 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Iron bioavailability, Inflammation, Hepcidin, Iron absorption