Age-dependent changes in insulin action and body fat distribution are risk factors for the development of type 2 diabetes. To examine whether the accumulation of visceral fat (VF) could play a direct role in the pathophysiology of insulin resistance and type 2 diabetes, we monitored insulin action, glucose tolerance, and the expression of adipo-derived peptides after surgical removal of VF in aging (20-month-old) F344/Brown Norway (FBN) and in Zucker Diabetic Fatty (ZDF) rats. As expected, peripheral and hepatic insulin action were markedly impaired in aging FBN rats, and extraction of VF (accounting for ϳ18% of their total body fat) was sufficient to restore peripheral and hepatic insulin action to the levels of young rats. When examined at the mechanistic level, removal of VF in ZDF rats prevented the progressive decrease in insulin action and delayed the onset of diabetes, but VF extraction did not alter plasma free fatty acid levels. However, the expression of tumor necrosis factor-␣ and leptin in subcutaneous (SC) adipose tissue were markedly decreased after VF removal (by approximately three-and twofold, respectively). Finally, extracted VF retained ϳ15-fold higher resistin mRNA compared with SC fat. Our data suggest that insulin resistance and the development of diabetes can be significantly reduced in aging rats by preventing the age-dependent accumulation of VF. This study documents a cause-and-effect relationship between VF and major components of the metabolic syndrome. Diabetes 51: [2951][2952][2953][2954][2955][2956][2957][2958] 2002 A progressive increase in visceral adiposity is a common feature of aging, and epidemiological evidence supports its role as a prominent risk factor for insulin resistance, diabetes, and mortality from atherosclerotic cardiovascular disease (1-5). Among various body fat depots, the amount of visceral fat (VF) best correlates with insulin sensitivity in animal models and in humans. Insulin action is markedly impaired in individuals with visceral obesity (6,7), and epidemiological studies have shown that VF can account for most of the variability in insulin sensitivity in heterogeneous populations (2,4,6,7). However, these studies are associational in nature, and VF may be simply a "marker" of more complex endocrine and metabolic changes rather than playing a "causative" role in the pathogenesis of insulin resistance and its metabolic consequences. Putative mechanisms responsible for the modulation of insulin action by VF include increased portal release of free fatty acids (FFAs) (8,9) and/or abnormal expression and secretion of fat-derived peptides, such as resistin (10), leptin, ACRP30, and tumor necrosis factor-␣ (TNF-␣) (11).A consistent observation in the biology of aging is that chronic restriction of caloric intake in rodents markedly improves survival and prevents the onset of insulin resistance. We and others have hypothesized that the beneficial effects of caloric restriction (CR) on the metabolic alterations of aging are largely accounted for by its prevent...
Protein amide hydrogen exchange (HDX) is a convoluted process, whose kinetics is determined by both dynamics of the protein and the intrinsic exchange rate of labile hydrogen atoms fully exposed to solvent. Both processes are influenced by a variety of intrinsic and extrinsic factors. A mathematical formalism initially developed to rationalize exchange kinetics of individual amide hydrogen atoms is now often used to interpret global exchange kinetics (e.g., as measured in HDX MS experiments). One particularly important advantage of HDX MS is direct visualization of various protein states by observing distinct protein ion populations with different levels of isotope labeling under conditions favoring correlated exchange (the so-called EX1 exchange mechanism). However, mildly denaturing conditions often lead to a situation where the overall HDX kinetics cannot be clearly classified as either EX1 or EX2. The goal of this work is to develop a framework for a generalized exchange model that takes into account multiple processes leading to amide hydrogen exchange, and does not require that the exchange proceed strictly via EX1 or EX2 kinetics. To achieve this goal, we use a probabilistic approach that assigns a transition probability and a residual protection to each equilibrium state of the protein. When applied to a small protein chymotrypsin inhibitor 2, the algorithm allows complex HDX patterns observed experimentally to be modeled with remarkably good fidelity. On the basis of the model we are now in a position to begin to extract quantitative dynamic information from convoluted exchange kinetics.
The IL-6/GP130/STAT3 pathway is critical for the progression of multiple types of cancers. We report here the discovery of raloxifene and bazedoxifene as novel inhibitors of IL-6/GP130 protein-protein interactions (PPIs) using multiple ligand simultaneous docking (MLSD) and drug repositioning approaches. Multiple drug scaffolds were simultaneously docked into hot spots of GP130 D1 domain by MLSD to compete with the key interacting residues of IL-6, followed by tethering to generate virtual hit compounds. Similarity searches of virtual hits on drug databases identified raloxifene and bazedoxifene as potential inhibitors of IL-6/GP130 interaction. In cancer cell assays both compounds bind to GP130 and demonstrated selective inhibition of IL-6 induced STAT3 phosphorylation and were significantly more potent than the previously reported natural product inhibitor MDL-A. The identified drugs represent a new class of lead compounds with piperidine, benzothiophene, and indole scaffolds to inhibit IL-6 induced homodimerization of GP130. Besides potential direct usage for clinic trials, the two compounds can also serve as lead compounds for optimization to speed the development of drugs selectively targeting the IL-6/GP130/STAT3 cancer signaling pathway.
Increased fat mass, abdominal adiposity, and insulin resistance are typical findings in aging mammals and are frequently associated with leptin resistance and increased plasma leptin levels. To examine whether leptin's failure in aging is due to aging per se or to changes in body fat mass or distribution, we studied aging rats that underwent calorie restriction throughout their lives, maintaining their youthful body fat pattern and metabolic profile. Leptin's action was assessed by measuring its ability to regulate food intake, fat mass and its distribution, peripheral and hepatic insulin action, and its own gene expression in fat. Our results show that leptin's action is markedly diminished in aging rats, independently of their body fat pattern. Leptin's failure in this model suggests its causative role in the metabolic decline seen with aging. Diabetes 51: 1016 -1021, 2002 A ging is associated with a metabolic decline characterized by the development of changes in fat distribution, obesity, and insulin resistance (1-3). All these metabolic alterations are associated with a variety of age-related diseases that subsequently result in increased mortality (4 -9). It has been recently demonstrated that leptin, a 16-kDa fat-derived peptide, can modulate many of the metabolic alterations characteristic of aging (10 -12). Chronic administration of leptin decreases food intake and induces reduction in fat mass (FM) and visceral fat (VF), with a parallel significant improvement in hepatic and peripheral insulin action (10 -14). This finding suggests that alterations in leptin action may play a role in the metabolic phenotype of aging. Indeed, the dramatic increase in plasma leptin levels in aging animal models and in humans suggests a leptinresistant state (15-18). Although the increase in plasma leptin concentration in aging may be partially attributed to the development of obesity (which is associated with leptin resistance [19]), the increase in plasma leptin level during aging is often disproportionate to the increase in the amount of fat (16 -19). We therefore hypothesize that aging per se is associated with a failure in leptin's action, independent of obesity or changes in body fat distribution. Thus, leptin resistance of aging may represent a perpetuating factor in developing and maintaining obesity and its clinical consequences.Because aging is frequently associated with obesity, it is difficult to identify whether leptin failure is due to obesity, the process of aging per se, or both. To overcome this difficulty, we used caloric restriction throughout aging in a rodent model and prevented the typical age-related changes in body composition. We reasoned that aging rats would remain leptin resistant even when kept relatively lean and "metabolically young" by calorie restriction. RESEARCH DESIGN AND METHODS Animals.A total of 36 male Sprague-Dawley rats (Charles River Laboratories, Wilmington, MA) were housed in individual cages and subjected to a standard light (6:00 A.M. to 6:00 P.M) to dark (6:00 P.M. to 6:0...
Tip60 (Tat-interactive protein, 60 kDa), a cellular protein with intrinsic histone acetyltransferase activity, is involved in DNA damage repair and apoptosis. Recent studies have suggested that Tip60 acts either as a coactivator or a co-repressor to modulate transcription. In this study, we demonstrate that Tip60 represses reporter gene expression when it is fused to the Gal4 DNA binding domain. We also show that Tip60 associates with histone deacetylase 7 (HDAC7) through its N-terminal zinc finger-containing region and that HDAC7 activity is required for the repressive effect of Tip60. Because endogenous Tip60 interacts with STAT3, we hypothesized that Tip60 might complex with STAT3 and HDAC7 and modulate STAT3-mediated trans-activation. Consistent with this hypothesis, the overexpression of Tip60 represses STAT3-driven reporter gene expression, which can be further potentiated by the co-transfection of HDAC7. Furthermore, interleukin-9-induced c-myc expression, which depends on STAT3 activity, is abrogated by exogenous expression of Tip60. This is the first demonstration of which Tip60 represses STAT3 activity in part through the recruitment of HDAC7. Tip601 (Tat-interactive protein, 60 kDa) is a member of the MYST family of proteins, which are highly conserved from yeast to human and play diverse physiological functions (1). Several members among this family, such as SAS3 (Something About Silencing), Esa1 (Essential sas2-related acetyltransferase), and Tip60, possess intrinsic histone acetyltransferase (HAT) activity (2-4), suggesting their potential roles in chromatin remodeling and gene regulation. Tip60 is expressed in a variety of tissues and cell lines, and its homologues have been identified in chicken, mouse, and human (5-7). Tip60 is mainly localized in the nucleus; however, cytoplasmic and perinuclear localization has been reported previously (4, 8 -11). Tip60 forms stable nuclear complexes, which possess ATPase and DNA helicase activities, that promote histone acetylation in nucleosomes (12). It associates with transcriptional activators, such as HIV-1 Tat, type I nuclear hormone receptors, and APP (-Amyloid Precursor Protein), to activate gene expression (7,13,14). Tip60 has also been implicated in the negative regulation of gene expression through binding to CREB or the transcriptional repressor ZEB (Zinc Finger E Box-binding Protein) (15,16). Interestingly, Tip60 interacts with membrane receptors for IL-9 and endothelin (10, 11), suggesting its involvement in signal transduction in response to extracellular stimuli. Cytosolic phospholipase A2-interacting protein, a differentially spliced form of Tip60, interacts with cytosolic phospholipase A2 to enhance cytosolic phospholipase A2-mediated cell death and prostaglandin E2 production (9).Eucaryotic genomic DNA is packaged with histones into nucleosomes, which are the primary structural units of chromatin. The packaging of DNA into chromatin inhibits transcription in part by hindering the binding of transcription factors and basal transcriptional m...
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