Lumeng, Carey , MD, PhD
Hematopoietic origins of obesity-induced inflammation
General Research Subject: Obesity
Focus: Immunology, Integrated Physiology, Integrated Physiology\Insulin Resistance, Obesity, Obesity\Animal Models
Type of Grant: Career Development
Project Start Date: July 1, 2012
Project End Date: June 30, 2017
Inflammation is an important link between obesity and diseases such as diabetes and atherosclerosis. Inflammatory cells known as macrophages and monocytes link obesity to the development of disease. However, the reasons why macrophages are induced by obesity are unknown. This proposal will investigate the novel hypothesis that the broad activation of macrophages and in obesity may be caused by the effects of obesity on bone marrow hematopoietic stem cells from which macrophages are derived. Experiments will investigate the mechanisms by which obesity alters macrophage function in mouse models of obesity. We will also examine if the effects of obesity on bone marrow stem cells in young animals may influence their response to obesity in adulthood to explain the associations between childhood obesity and future morbidities. These studies will advance our understanding of how inflammation is generated in obesity, the mechanisms by which diabetes complications are generated, and how childhood obesity influences adult health.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
My lab is interested in why obesity obesity has negative effects on health in adults and children. A major advance in the field is the understanding that obesity leads to chronic low-grade inflammation. This inflammation appears to play a pivotal role in the development of Type 2 diabetes and metabolic syndrome. Our lab has focused on how cells called macrophages respond to the obese environment in fat tissue. These cells partner with other cells to generate inflammation within obese fat tissue that disrupts its normal function.
We lack a basic understanding of how and why these macrophages are activated in fat. We also know that macrophage activation is associated with disease in other organs such as the heart and liver. This project has the goal of understanding how obesity may cause fundamental alterations in the ability of the body to produce macrophages with pro-inflammatory properties.
If we are successful, we feel that our findings could lead to a paradigm shift in our understanding of the origins of obesity-induced inflammation. This work hopes to open the door for new therapeutic strategies to break the link between obesity and Type 2 diabetes by targeting inflammation. In addition, we hope that our work may lead to novel ways to identify those most at risk for the negative health effects of being overweight to better target our treatments.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
The impact of the new research on inflammation and obesity has been fascinating for several reasons. It has led to the development of new anti-inflammatory medications currently in clinical trials for the treatment of Type 2 Diabetes. More interesting to me is that it has led us to revisit how older diabetes treatments work. We now understand that many existing diabetes treatments have potent anti-inflammatory effects on macrophages that may underlie how they work.
This project has the possibility identifying how inflammation is triggered by obesity. With this knowledge, we can then identify the dietary, lifestyle, and medical interventions that can block the generation of excess inflammatory cells and ultimately improve health. In addition, our studies can provide valuable new tools to monitor disease in those with pre-diabetes and identify those who may be at risk. We also feel that these inflammatory changes may play a pivotal role in the impaired wound healing and risk of infections seen with diabetes and our research can lead to new way to treat and prevent these conditions.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
As a Pediatrician I am alarmed at the high rates of childhood obesity and the increasing frequency by which diabetes is diagnosed in children and young adults. I have seen the rise of childhood obesity in my everyday practice and am worried about the health of my patients as they become adults. I take care of many children with diabetes and can see the negative impact this has upon their health and quality of life. I am very worried that the current epidemic of obesity will effect multiple generations to come.
While there is excellent work going on in the ways to prevent and treat obesity - my goal is to find ways to disrupt the connections between and obesity and disease at a basic level. This award will allow me to continue to investigate and identify new ways to think about the causes of diabetes and will support the efforts of a team of young researchers singularly focused on this goal. The award comes at an important time in the development of my laboratory as we have built a unique team with expertise in metabolism, endocrinology, immunology, and cell biology to attack this problem from multiple angles. This support will ensure that we can continue to think creatively and bring new perspectives on a growing health problem.
In what direction do you see the future of diabetes research going?
I see that the future of diabetes research lies in understanding the interplay between glucose metabolism and other biologic systems not traditionally thought to impact diabetes. Inflammation is one of these new areas that is just now starting to capture the interest and imagination of a new range of researchers. Exciting research that relates to this topic extend into the relationship between microbes in the gut, the immune system, and diabetes. In addition, the pace of research on the biology of adipose tissue has been rapidly increasing and I think that research on how the non-fat cells in fat will lead to new studies and discoveries important to obesity and diabetes research.
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