Novel mechanism for coupling of leptin and estrogen signals in metabolism
General Research Subject: Obesity
Focus: Integrated Physiology, Integrated Physiology\Regulation of Food Intake, Obesity, Obesity\Animal Models, Signal Transduction (Non-Insulin Action), Signal Transduction (Non-Insulin Action)\Hormones
In the field of obesity and diabetes, one important question to be answered is why women with menopause have much higher risk to develop obesity and metabolic syndrome. In previous experiments, we generated a mutant line of mice that eat less but become fat, by genetically deleting Shp2, a signaling molecule, in forebrain region of mice. We have found that this molecule acts to amplify the neuronal signal elicited by leptin, a hormone that is secreted by adipose tissue but acts in the hypothalamus to control food intake and energy balance. Therefore, removal of Shp2 from the brain causes early-onset obesity. This observation also suggests that pharmaceutical activation of Shp2 activity in the brain may enhance leptin signaling and overcome obesity.
To provide a proof of principle, we generated a transgenic mouse line expressing a dominant active mutant of Shp2 in forebrain neurons. Surprisingly, we have found that expression of this engineered molecule confers resistance to obesity only in female but not in male mice. This unexpected result has allowed us to find a potentially important mechanism for connection of leptin and estrogen, a sex hormone. Completion of proposed experiments will explain why estrogen has leptin-like effect and why postmenopausal women have dramatically increased risk to develop obesity. Therefore we can find a better therapeutic strategy to treat obesity and associated metabolic syndrome in women with menopause.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating, and curing diabetes?
The goal of our project is to elucidate why estrogen, a sex hormone, has leptin-like effect in control of metabolism and energy balance in the brain. In postmenopausal women, estrogen deficiency is associated with increased probability of obesity and type 2 diabetes, but the underlying biochemical and biological mechanisms remain to be unlocked. Success of this project will provide better understanding of the association of obesity and diabetes in women, especially in women with menopause, and will allow us to develop better strategies for hormone treatment in postmenopausal women for prevention of obesity progression, enhancement of insulin sensitivity and glucose tolerance.
Based on the current life-span expectation, women can spend, on average, a third of their lives in the menopause state. Therefore, the public health impacts of postmenopausal diseases are enormous.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
We will be able to help subjects suffering from diabetes, obesity and metabolic complications in three different ways.
a) Based on the experimental results, we can suggest or recommend better recipes or guidelines for better life style or food compositions for men and women at different ages, to cope with treatment of diabetes, or at least slow down diabetes development.
b) The new scientific data from our proposed experiments, expected or unexpected, will identify new drug targets and facilitate the development of better therapeutic strategies for type 2 diabetes, especially those associated with obesity, in the era of personalized medicine.
c) More specifically, success of our project will provide better strategies for pharmaceutical intervention of accelerated development of diabetes, obesity and cardiovascular disorders in postmenopausal women, which will definitely improve the quality of their life, to live not only longer, but also healthy and happy!
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your efforts?
Quite a few of my extended family members and relatives are suffering from diabetes, metabolic and cardiovascular diseases. One can also see the increasing health costs for diabetes patients in the US and other countries around the globe. I am a molecular biologist and is extremely interested in contributing to the advancement in research, prevention and cure of diabetes using my knowledge and research capability.
I must point out that at the very beginning of my research career as an independent investigator, the first grant received to support this laboratory was a career development award from the American Diabetes Association (1995-1997). Now, the current ADA basic science research award provides timely and required funding to a major project with ongoing experiments in this laboratory aimed at addressing an unsolved issue, i.e. why postmenopausal women have the tendency to develop obesity and diabetes. An answer to this open question will allow us to address this health concern that affect so many in the world. Without this award, we will have to discontinue the research project with high health impact.
In what direction do you see the future of diabetes research going?
Despite the large efforts and investment in diabetes research, the number of patients suffering from this and other associated metabolic diseases are increasing but not decreasing. Evidently, there is a need to rethink and debate whether we are in the right direction or not in this field. From my point of view, diabetes research must take multidisciplinary approaches. I am a PhD research scientist and am eager to have more crosstalk and collaboration with physicians who have direct contacts with diabetes patients on the daily basis. This will shorten the distance of the gap between basic research and clinical treatment. The value of animal models in diabetes research cannot be over-emphasized, but it is important to recognize the difference between human patients and animal models.
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