Signaling Pathways Regulating the Activity of ChREBP by Glucose

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DESCRIPTION (provided by applicant): Project Summary The overarching goal of the proposed project is to better understand the intracellular and extracellular signals that regulate fat storage in the mature animal. From an evolutionary perspective, the ability of an organism to store energy in the form of fat when resources are plentiful is critical for its survival in ensuing times when resources are scarce. However, inappropriate fat storage can lead to multiple metabolic problems in man, including both common diseases such as obesity and type 2 diabetes as well as rarer disorders such as the lipodystrophies. The carbohydrate response-element binding protein (ChREBP) is a protein recently identified as playing a critical role in conversion of carbohydrate into fats. This factor responds to changes in serum glucose levels by activating cellular programs of lipid synthesis and storage, and mice lacking ChREBP exhibit significant alterations in lipid and glucose metabolism. AMP-dependent protein kinase (AMPK) is another well-characterized protein that senses intracellular energy and glucose but appears to function in a manner opposite to ChREBP. We and others have previously reported that the commonly used diabetes medication metformin relies on AMPK for exerting its beneficial effect on blood glucose. We wish to test the hypothesis that AMPK plays either a direct or indirect role as a negative regulator of ChREBP and that elevation in glucose uptake reduces AMPK activity and thus circumvents the negative regulation. The aims of this proposed project are to first identify the specific modifications on ChREBP induced by changes in serum glucose and then to investigate whether these modifications are consistent with the known activity of AMPK. These modifications will be identified using the technique of mass spectrometry, an emerging technology with which our laboratory has proven expertise. We also will test whether conditions that either enhance or inhibit AMPK activity lead to functional changes in ChREBP within the cell. We will then test whether genetic disruption of AMPK function, both in cultured cells as well as in mice, leads to changes in ChREBP activity. Relevance Type 2 diabetes and obesity are growing public health concerns both characterized by disordered fat metabolism. Identification of the specific molecules controlling fat synthesis and storage will provide new insights into these disorders and may potentially produce novel pharmacologic targets for treatment.