McLaughlin, Tracey , MD
Adipose tissue response to overfeeding in insulin resistance-prone vs insulin sensitive humans
General Research Subject: Obesity
Focus: Adipocytes, Insulin Action\Insulin Resistance, Obesity\Pathogenesis
Type of Grant: Clinical Translational Research
Project Start Date: January 1, 2011
Project End Date: December 31, 2013
Metabolic/cardiovascular complications of obesity are likely related to the fact that obese individuals tend to be insulin resistant (IR). While insulin resistance correlates with adipose tissue mass, not all obese individuals are IR. Furthermore, while insulin sensitivity improves with weight loss, there is variability in this response as well. Given that fat mass per se does not fully explain insulin resistance, it is likely that differential adipose tissue function contributes. We hypothesize that in the setting of caloric excess, those individuals who can readily store excess calories in the subcutaneous fat depot will be protected from insulin resistance: those who cannot will develop insulin resistance via lipotoxicity, deposition of visceral/ectopic fat, and inflammation. Descriptions of normal and abnormal human adipose cell response to overfeeding are lacking. In order to address this gap in scientific knowledge we have designed an overfeeding study that will characterize differences in adipose tissue response in those with borderline IR (IR-prone) vs healthy (IS) controls.
1.Test the hypothesis that impaired adipogenesis and fat storage capacity are associated with insulin resistance by comparing changes in cell-size distribution, lipogenic gene expression, and preadipocyte differentiation in IR-prone vs IS individuals(in response to overfeeding).
2.Determine if circulating and ectopic fat are worsened to a greater degree in IR-prone vs IS individuals.
3.Determine whether inflammation or innate/adaptive immune response are associated with insulin resistance by comparing dendritic cell, T-cell, and inflammatory responses in IR-prone vs IS individuals.
4.Exploratory: Evaluate IR-prone vs IS individuals for differences in adipose tissue hypoxia and angiogenic response to overfeeding.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
This project will investigate the response of adipose tissue to caloric excess in individuals who are likely to have a healthy response versus those who are likely to develop metabolic complications of obesity. Because overweight/obesity is closely tied to diabetes risk, primarily through development of insulin resistance in at-risk individuals, the data generated from this project will shed light on the pathophysiologic link between excess body weight and insulin resistance. This information has potential to highlight targets for therapeutic interventions to prevent insulin resistance and diabetes in the setting of excess body weight, as well as to define which individuals are more likely to insulin resistance as a consequence of weight gain
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
This project ultimately has potential to define what 'goes wrong' in our fat tissue as a result of weight gain that predisposes us to diabetes. If we can figure out what is going wrong, there may be ways to modify this biological process, thereby minimizing the negative metabolic health consequences of obesity.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
I have been conducting diabetes research for many years and it is my passion. This award allows me to do what I consider the critical study to really understand what goes on at the level of adipocytes/adipose tissue when individuals are developing adverse metabolic consequences of excess body weight. The work I have done with several co-investigators over the years really points toward this study as a necessary project in order to test several hypotheses we have about why obesity can potentiate insulin resistance in some but not all individuals.
In what direction do you see the future of diabetes research going?
Obesity is a critical component of diabetes research. Right now many individuals are developing protocols to evaluate various aspects of obesity and adipose tissue. This is very important, and I hope it will continue to increase in scope in the arena of diabetes research.
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