Purpose and Objectives:
The project aims to address a fundamental gap in our understanding of relevance to obesity-related diseases, including type 2 diabetes. Namely, how is vitamin C transported into human fat cells (adipocytes) and is this compromised in obesity, making adipocytes “vitamin C resistant”.
It builds on epidemiology showing that circulating vitamin C levels are low in people living with obesity, and that people with low vitamin C levels are at increased risk of developing type 2 diabetes, and the established causative links between adipocyte dysfunction, insulin resistance and type 2 diabetes, and our published and unpublished findings demonstrating that vitamin C protects human adipocytes from obesity-induced dysregulation.
Overarching hypothesis:
Increasing vitamin C levels in adipocytes will reduce obesity-induced adipocyte dysfunction, promote enhanced insulin sensitivity, and improve outcomes in people living with type 2 diabetes.
Specific aims:
1. Identify the vitamin C transporter(s) responsible for vitamin C uptake in human adipocytes
2. Characterize the effects of obesity-induced stress on vitamin C uptake and availability in human adipocytes
3. Determine the effects of vitamin C supplementation on the function of human adipocytes under control (healthy) and stressed (obese) conditions.
Experimental approaches:
This is a fundamental, lab-based research project that will use human adipocytes cultured under defined conditions allowing us to manipulate important variables including:
(i) vitamin C levels, to mimic levels found in the circulation of people with very low (deficient) or very high (saturated) levels
(ii) factors that recapitulate the obese environment - we typically use a cocktail of inflammatory factors and fatty acids
(iii) specific chemical inhibitors that will block the uptake of vitamin C into adipocytes by known as well as putative vitamin C transporters.
Use of state-of-the-art techniques involving biofluorescent reporter probes alongside classic biochemical approaches will allow us to measure vitamin C uptake, availability, and activity in the adipocytes at a level of resolution never seen before.
Anticipated findings:
These studies will allow us to determine how vitamin C gets into human adipocytes, to what extent this process may be impaired in obesity, and whether increasing vitamin C levels in adipocytes can prevent obesity-induced adipocyte stress and dysfunction. Such new understanding may identify novel therapeutic targets to improve adipocyte function, insulin sensitivity, and type 2 diabetes.
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