The term "diabesity" is a pandemic that is threatening populations worldwide and is the term is finding itself as a household name, fueling itself through the high-fat diet and sedentary lifestyle. As a result of these living choices, the population is suffering from lipotoxicity, the underlying cause of Type 2 Diabetes Mellitus (T2DM) and insulin resistance. Lipolytic control resides around the rate-limiting enzyme, adipose triglyceride lipase, which is normally downregulated in the insulin-stimulated state. This is the signal that is aberrant in patients who have T2DM and could be a significant factor in lipotoxicity. This state of lipotoxicity leads to many complications, increasing the risk of heart disease, heart attack, blindness, nephropathy, neuropathy, and stroke. Vasculature damage also can lead to poor perfusion of the lower extremities, increasing the risk of ulcer, gangrene, and amputation of the foot.
An area of research delving into this issue lies within the mammalian target of rapamycin complex 1 (mTORC1), as it mediates the antilipolytic signal and decreases ATGL expression. This discovery was further clarified when the Kandror lab identified the transcription factor early growth factor 1 (Egr1) as the protein that binds to the promoter region of ATGL and downregulates its transcription. Egr1 has also been thought to be a factor in the development of insulin resistance in the hyperinsulemic state.
To date, we have experimented upon murine 3T3-L1 and human adipocytes. We have developed a double transgenic mouse positive for reverse tetracycline transactivator (rtTA) and myc-tagged ras homolog enriched in brain (Rheb), which is a misnomer as it is located in adipose tissue (AT). With the mTORC1 axis hyperactive, we seek to show that Egr1 is a rich target in diabetes and lipotoxicity, regulating and inhibiting ATGL levels through mTORC1.
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/14674 |
| Date | 22 January 2016 |
| Creators | Thimmiah, Harun |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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