Friday, May 16, 2025
5/16/2025
Effect of TRB3 and Leucine Supplement on Beige Fat Formation - Obesity is an alarming signal for the risk of Type 2 diabetes, cardiovascular disease, and metabolic diseases in humans. Obesity results from an energy imbalance, and therefore stimulating adaptive thermogenesis has been proposed to prevent and/or treat obesity and Type 2 diabetes. Although the identification of heat- producing white adipocytes, beige fat, has drawn considerable attention, and this type of fat is thought to increase energy expenditure, the mechanism and signaling molecules involved in the development of beige fat have not yet been fully understood. Furthermore, effective medication or dietary supplement are not currently available. Our goal is to identify novel molecule(s) that regulates beige fat formation and activity. We hypothesize in this study that Leucine supplement improves beige fat formation by suppressing TRB3, and that transplantation of beige fat from Leucine fed mice prevents mice from high fat diet-induced obesity and diabetes. This hypothesis has been formulated on the basis of our preliminary data showing that knockout of TRB3 promotes beige fat formation. Furthermore, Leucine, a branched-chain amino acid effectively suppresses TRB3 expression in adipose tissue. We will test the hypothesis by pursing three specific aims. In Aim 1, we will determine the mechanism(s) by which Leucine promotes beige fat formation. In Aim 2, we will determine if Leucine supplement augments exercise training- and cold exposure-induced beige fat formation. We expect that Leucine decreases TRB3 expression, which in turn promotes beige fat formation. Leucine decreases TRB3 expression by suppressing ER stress. In Aim 3, we will determine if transplantation of beige fat from Leucine fed mice protects against high fat diet-induced weight gain and insulin resistance. We anticipate Leucine fed mice will resist high fat diet-induced weight gain and insulin resistance and promotes beige fat formation. Transplantation of beige fat from Leucine fed mice will improve whole-body metabolism. The proposed research will establish the function of TRB3 and Leucine in the beige fat formation and identify a new approach for treating obesity and metabolic diseases. The study will be innovative in 1) investigating the underlying mechanism by which Leucine promotes beige fat formation and metabolism; 2) studying the role of TRB3 and Leucine in beige fat, which has not yet been studied; 3) utilizing beige fat transplantation technique to assess the tissue effect on whole body metabolism; and 4) attempting to identify TRB3 inhibition- and/or Leucine supplement-induced adipokines from beige fat improving whole body glucose metabolism. The proposed study will be also significant in providing new insights into the development of treatment strategies for obesity and Type 2 diabetes. The study will provide an opportunity for African America and/or underrepresented students to be trained as independent researchers.
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