Weight loss in response to caloric restriction is variable. Because skeletal muscle mitochondrial proton leak may account for a large proportion of resting metabolic rate, we compared proton leak in diet-resistant and dietresponsive overweight women and compared the expression and gene characteristics of uncoupling protein (UCP)2 and UCP3. Of 1,129 overweight women who completed the University of Ottawa Weight Management Clinic program, 353 met compliance criteria and were free of medical conditions that could affect weight loss. Subjects were ranked according to percent body weight loss during the first 6 weeks of a 900-kcal meal replacement protocol. The highest and lowest quintiles of weight loss were defined as diet responsive and diet resistant, respectively. After body weight had been stable for at least 10 weeks, 12 of 70 subjects from each group consented to muscle biopsy and blood sampling for determinations of proton leak, UCP mRNA expression, and genetic studies. Despite similar baseline weight and age, weight loss was 43% greater, mitochondrial proton leak-dependent (state 4) respiration was 51% higher (P ‫؍‬ 0.0062), and expression of UCP3 mRNA abundance was 25% greater (P < 0.001) in diet-responsive than in diet-resistant subjects. There were no differences in UCP2 mRNA abundance. None of the known polymorphisms in UCP3 or its 5 flanking sequence were associated with weight loss or UCP3 mRNA abundance. Thus, proton leak and the expression of UCP3 correlate with weight loss success and may be candidates for pharmacological regulation of fat oxidation in obese diet-resistant subjects. Diabetes 51: 2459 -2466, 2002 A t the Weight Management Program at the University of Ottawa, we have documented a 10-fold variation in the rate of weight loss in 353 highly compliant women on a standard exercise program and standard 900-kcal meal replacement protocol. These women were ranked according to percent body weight loss, and highest and lowest quintiles were defined as diet responsive and diet resistant, respectively. Regression analyses demonstrated that the known variables regulating energy requirements, including initial weight, age, and plasma free triiodothyronine (T3) concentrations, accounted for only half of this variability (1), leading us to search for novel molecular determinants of weight loss success.Variable responses to overfeeding have been reported. Rodent studies have demonstrated that genetic factors not only regulate weight gain in response to high-fat highcalorie diets but also determine the susceptibility to obesity when energy intake is controlled (2). In response to the ingestion of hypercaloric diets, the majority of subjects gain less weight than anticipated, and a process of adaptive thermogenesis appears to play a role in the defense against obesity (3). Several studies have demonstrated marked interindividual variability in the susceptibility to weight gain in response to overfeeding (4), and identical twins show marked similarity in this regard, suggesting an important genetic cont...

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Sterol regulatory element binding proteins (SREBPs) are a family of membrane-bound transcription factors that play a unique and fundamental role in both cholesterol and fatty acid metabolism, relevant to human disease. There are three SREBPs that regulate the expression of over 30 genes. SREBPs are subject to regulation at three levels: proteolytic cleavage, rapid degradation by the ubiquitin-proteasome pathway, and sumoylation. Recently, there have been exciting advances in our understanding of the molecular mechanism of SREBP trafficking and processing with new information on the role of insulin-induced genes and the differential role and regulation of SREBP-1c and -2, which may ultimately lead to novel strategies for the treatment of dyslipidemia and insulin resistance.

The ␣ 2 -macroglobulin receptor/low density lipoprotein receptor-related protein (LRP) is a large multifunctional receptor that interacts with a variety of molecules. It is implicated in biologically important processes such as lipoprotein metabolism, neurological function, tissue remodeling, protease complex clearance, and cell signal transduction. However, the regulation of LRP gene expression remains largely unknown. In this study, we have analyzed 2 kb of the 5-flanking region of the LRP gene and identified a predicted peroxisome proliferator response element (PPRE) from ؊1185 to ؊1173. Peroxisome proliferator-activated receptor ␥ (PPAR␥) ligands such as fatty acids and rosiglitazone increased functional cell surface LRP by 1.5-2.0-fold in primary human adipocytes and in the SW872 human liposarcoma cell line as assessed by activated ␣ 2 -macroglobulin binding and degradation. These agents were found to increase LRP transcription. Gel shift analysis of the putative PPRE demonstrated direct binding of PPAR␥/retinoid X receptor ␣ heterodimers to the PPRE in the LRP gene. Furthermore, these heterodimers could no longer interact with a mutated PPRE probe. The isolated promoter was functional in SW872 cells, and its activity was increased by 1.5-fold with the addition of rosiglitazone. Furthermore, the isolated response element was similarly responsive to rosiglitazone when placed upstream of an ideal promoter. Mutagenesis of the predicted PPRE abolished the ability of this construct to respond to rosiglitazone. These data demonstrate that fatty acids and rosiglitazone directly stimulate transcription of the LRP gene through activation of PPAR␥ and increase functional LRP expression.The ␣ 2 -macroglobulin receptor/low density lipoprotein receptor-related protein (LRP) 1 is a 600-kDa multifunctional endocytic receptor that belongs to the low density lipoprotein receptor gene family (1). LRP binds and internalizes a broad range of biologically diverse ligands. These include proteases of the fibrinolytic pathway (2) and serpin-enzyme complexes (3) as well as proteins important in lipoprotein metabolism such as lipoprotein lipase, hepatic lipase, lipoprotein(a), and apoE-rich lipoproteins (4 -9). Targeted deletion of LRP in the mouse results in early embryonic death, demonstrating a critical function for LRP in prenatal development (10). LRP has also been shown to have a dual role in ␤-amyloid metabolism by enhancing ␤-amyloid precursor protein conversion to ␤-amyloid (11) and mediating the clearance of ␤-amyloid (12, 13). These data support a potentially complex role for LRP in the pathogenesis of Alzheimer's disease (14). In addition, LRP mediates signal transduction by interacting with cytosolic adaptor and scaffold proteins including DAB-1, JIP-2, and PSD-95 (15). A 39-kDa receptor-associated protein (RAP) is an endoplasmic reticulumresident protein that functions intracellularly as a molecular chaperone for LRP and regulates its ligand binding activity (16 -18). RAP is required for the proper folding and export...