The lipid and metabolic disturbances associated with human immunodeficiency virus (HIV) protease inhibitor therapy in AIDS have stimulated interest in developing new agents that minimize these side effects in the clinic. The underlying explanation of mechanism remains enigmatic, but a recently described link between endoplasmic reticulum (ER) stress and dysregulation of lipid metabolism suggests a provocative integration of existing and emerging data. We provide new evidence from in vitro models indicating that proteasome inhibition and differential glucose transport blockade by protease inhibitors are proximal events eliciting an ER stress transcriptional response that can regulate lipogenic pathways in hepatocytes or adipocytes. Proteasome activity was inhibited in vitro by several protease inhibitors at clinically relevant (micromolar) levels. In the intact cells, protease inhibitors rapidly elicited a pattern of gene expression diagnostic of intracellular proteasome inhibition and activation of an ER stress response. This included induction of transcription factors GADD153, ATF4, and ATF3; amino acid metabolic enzymes; proteasome components; and certain ER chaperones. In hepatocyte lines, the ER stress response was closely linked to moderate increases in lipogenic and cholesterogenic gene expression. However, in adipocytes where GLUT4 was directly inhibited by some protease inhibitors, timedependent suppression of lipogenic genes and triglyceride synthesis was observed in coordination with the ER stress response. These results further link ER stress to dyslipidemia and contribute to a unifying mechanism for the pathophysiology of protease inhibitor-associated lipodystrophy, helping explain differences in clinical metabolic profiles among protease inhibitors.The development and clinical use of HIV protease inhibitors have contributed greatly to treatment of HIV-AIDS as a critical component of highly active antiretroviral therapy (HAART) regimens. With this efficacy has come recognition of an associated syndrome of metabolic side effects that is relevant in evaluating the long-term risk/benefit of treatment options (Calza et al., 2004). The constellation of metabolic problems with protease inhibitors includes hyperlipidemia, insulin resistance, peripheral lipoatrophy, central fat accumulation, and hepatic steatosis. Despite several hypotheses to explain clinical findings, the cellular and molecular mechanisms underlying this lipodystrophy-like syndrome are incompletely understood. Recent clinical studies in patients (Woerle et al., 2003;Calza et al., 2004) and in normal subjects (Purnell et al., 2000;Noor et al., 2002Noor et al., , 2004 have confirmed a direct connection between some protease inhibitors and metabolic effects, despite the complexity of multidrug therapy and virological and immunological responses during HAART. The recent emergence of a newer generation of protease inhibitor that exhibits antiviral efficacy without adverse affects on lipid or glucose parameters in the clinic (Haas et al

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In search of potent and selective human beta(3) agonists as potential drugs for the treatment of human obesity and type II diabetes, a series of (4-piperidin-1-yl)phenyl amides was prepared and evaluated for their biological activity on the human beta(3)-adrenergic receptor. The leucine derivative 26e and the reverse amide 33b were found to be the two most potent and selective compounds in this study. With EC(50) values of 0.008 and 0.009 microM, respectively, at the beta(3) receptor, nearly completely abolished intrinsic activity at either the beta(1) or beta(2) receptor, and significant thermogenesis effects on human beta(3)-adrenergic receptor transgenic mice, 26e and33b are among the most potent and selective human beta(3) agonists known to date.