1. At baseline and again at weeks 12 and 36, subcutaneous fat biopsies will be obtained from the lateral aspect of one thigh by a surgeon as described (8) for determination of ER stress markers. In brief, the skin will be cleaned with betadine and anesthetized with 1% lidocaine without epinephrine in a field block pattern (at 2 X 3 in). (We have found that injection of lidocaine too close to the biopsy site interfered with the measurement of acetyl-CoA). After an incision (~ 1 in.) will be made through the skin, ~ 300 mg of fat will be mobilized and excised. The fat will be dropped immediately into isopentane, kept at its freezing point (-160°C) by liquid nitrogen. The frozen fat will be stored at -70°. To screen for changes in unfolded protein response (UPR) genes, we will first perform an UPR PCR microarray (SA Biosciences, Frederick, MD) using pooled fat biopsy extracts. This array profiles expression of 84 key genes recognizing and responding to misfolded protein accumulation in the ER. Significant changes (> 1.5 fold comparing post vs. pre drug biopsies) will then be confirmed by real time RT-PCR of the UPR mRNAs. Thus, mRNAs of the identified UPR markers (for instance, GRP78, XBP-1s, ATF4, ATF6, PDI, calreticulin, calnexin) will be measured by real time RT-PCR in triplicate and normalized against 18s and β-actin mRNAs and will be expressed as arbitrary units. The respective proteins will be analyzed by Western blots.