Recent studies suggest that obesity and its related disorders as part of the metabolic syndrome can be linked to a breakdown in normal adipocyte development and function. The association between obesity and insulin resistance is well established and several mechanisms play a role in the ability of fat cells to confer insulin resistance. First, it is known that fat cells have important endocrine functions and alterations in the production or secretion of fat specific hormones can result in insulin resistance. Inflammation in adipose tissue is also a profound contributor to insulin resistance. Moreover, several studies have shown that failure of adipocytes to store lipid properly results in ectopic lipid accumulation that significantly contributes to insulin resistance. A current hypothesis suggests that insulin resistance can be defined as an inability of fat cells to expand. Adipocyte dysfunction can be caused by an inability to store free fatty acids and by alterations in secreted hormones like adiponectin that lead to global metabolic dysregultion contributing to the development of metabolic syndrome. Thus it is reasonable to hypothesize that botanicals that promote safe lipid storage in adipose tissue, as well as increase adiponectin synthesis/release would be novel therapeutics to reduce ectopic lipid accumulation.  The reduction of ectopic lipid would attenuate insulin resistance in muscle and liver and delay the progression to metabolic syndrome. 

We propose to study botanicals which have been demonstrated by Center investigators to improve insulin sensitivity, i.e. selected Artemisia extracts and St. John’s Wort, a botanical that we have shown in preliminary studies to induce insulin resistance.

Specific Aims

• To identify the mechanism(s) involved in Artemisia-induced effects on adipogenesis and insulin action. We will perform in vitro and in vivo experiments to test the hypothesis that two related Artemisia species promote fat cell differentiation, induce a favorable pattern of adipokine secretion and increase insulin sensitivity. In addition, studies in this aim will include continued collaboration with the Botanical Core to identify active fractions and pure compounds in selected Artemisia extracts that have insulin sensitizing properties and to evaluate bioavailability and plasma appearance of the bioactive components.
• To identify the mechanism(s) involved in St. John's Wort induced insulin resistance. Overall, these studies will test our hypothesis that SJW, a ubiquitous commercially available and widely consumed botanical, impairs adipocyte development and induces insulin resistance in vitro and in vivo in adipocytes.
• To examine covalent modifications and protein-protein interactions in conditions of botanical mediated alterations in insulin sensitivity using targeted proteomic approaches. To date we have identified botanical extracts which have both favorable and unfavorable effects on adipocyte differentiation and function. We will work with the Integrative Biology Core to conduct mass spectrometry-based targeted proteomic studies to examine the expression and phosphorylation state of known players in insulin action following adipocyte treatment with active components from botanical extracts that we identified and characterize in Aims 1 and 2. We expect that our use of state-of-the-art proteomics methods will sresult in the identification of novel players in insulin sensitvity that are regulated under conditions of btoanical induced insulin resistance or insulin sensitivity.