Showing papers by "Jerrold M. Olefsky published in 2007"
TL;DR: These compounds bind to the SIRT1 enzyme–peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates and improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver.
Abstract: Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes. SIRT1, an NAD+-dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity. Resveratrol, a polyphenolic SIRT1 activator, mimics the anti-ageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival. Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bind to the SIRT1 enzyme-peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. In Zucker fa/fa rats, hyperinsulinaemic-euglycaemic clamp studies demonstrate that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes.
1,614 citations
TL;DR: The results show that FFAs can activate CD11c+ myeloid proinflammatory cells via TLR2/4 and JNK signaling pathways, thereby promoting inflammation and subsequent cellular insulin resistance.
948 citations
TL;DR: Deletion of Jnk1 in the nonhematopoietic compartment protects mice from high-fat diet (HFD)-induced insulin resistance, in part through decreased adiposity, and confers protection against HFD- induced insulin resistance by decreasing obesity-induced inflammation.
500 citations
TL;DR: Findings reveal an essential role of PPAR gamma in macrophages for the maintenance of whole-body insulin action and in mediating the antidiabetic actions of TZDs.
Abstract: PPAR gamma is required for fat cell development and is the molecular target of antidiabetic thiazolidinediones (TZDs), which exert insulin-sensitizing effects in adipose tissue, skeletal muscle, and liver. Unexpectedly, we found that inactivation of PPAR gamma in macrophages results in the development of significant glucose intolerance plus skeletal muscle and hepatic insulin resistance in lean mice fed a normal diet. This phenotype was associated with increased expression of inflammatory markers and impaired insulin signaling in adipose tissue, muscle, and liver. PPAR gamma-deficient macrophages secreted elevated levels of factors that impair insulin responsiveness in muscle cells in a manner that was enhanced by exposure to FFAs. Consistent with this, the relative degree of insulin resistance became more severe in mice lacking macrophage PPAR gamma following high-fat feeding, and these mice were only partially responsive to TZD treatment. These findings reveal an essential role of PPAR gamma in macrophages for the maintenance of whole-body insulin action and in mediating the antidiabetic actions of TZDs.
465 citations
TL;DR: Peroxisome proliferator-activated receptor-γ (PPAR-γ) plays a critical role in regulating insulin sensitivity and glucose homeostasis and is identified as a highly efficient small interferin target in animal studies.
Abstract: Peroxisome proliferator-activated receptor-γ (PPAR-γ) plays a critical role in regulating insulin sensitivity and glucose homeostasis. In this study, we identified highly efficient small interferin...
116 citations
TL;DR: It is shown that macrophages are an important cell type in the induction of insulin resistance and that Cap has a modulatory role in this function, and that the insulin-sensitive phenotype can be transferred to wild-type mice by transplantation of Sorbs1-null bone marrow.
Abstract: Bone marrow–specific Cap gene deletion protects against high-fat diet–induced insulin resistance
110 citations
TL;DR: The data indicate that myosin 5a is a newly identified direct substrate of Akt2 and, upon insulin stimulation, phosphorylated myos in 5a facilitates anterograde movement of GLUT4 vesicles along actin to the cell surface.
Abstract: Phosphatidylinositol 3-kinase activation of Akt signaling is critical to insulin-stimulated glucose transport and GLUT4 translocation. However, the downstream signaling events following Akt activation which mediate glucose transport stimulation remain relatively unknown. Here we identify an Akt consensus phosphorylation motif in the actin-based motor protein myosin 5a and show that insulin stimulation leads to phosphorylation of myosin 5a at serine 1650. This Akt-mediated phosphorylation event enhances the ability of myosin 5a to interact with the actin cytoskeleton. Small interfering RNA-induced inhibition of myosin 5a and expression of dominant-negative myosin 5a attenuate insulin-stimulated glucose transport and GLUT4 translocation. Furthermore, knockdown of Akt2 or expression of dominant-negative Akt (DN-Akt) abolished insulin-stimulated phosphorylation of myosin 5a, inhibited myosin 5a binding to actin, and blocked insulin-stimulated glucose transport. Taken together, these data indicate that myosin 5a is a newly identified direct substrate of Akt2 and, upon insulin stimulation, phosphorylated myosin 5a facilitates anterograde movement of GLUT4 vesicles along actin to the cell surface.
107 citations
TL;DR: The role of cross talk between RTKs and 7TMRs is described, focusing specifically on the role played in this process by β-arrestins and by G proteins.
Abstract: Receptor tyrosine kinases (RTKs) are a unique family of cell surface receptors, each containing a common intracellular domain that has tyrosine kinase activity. However, RTKs share many signaling molecules with another unique family of cell surface receptors, the seven-transmembrane receptors (7TMRs), and these receptor families can activate similar signaling cascades. In this review of RTK signaling, we describe the role of cross talk between RTKs and 7TMRs, focusing specifically on the role played in this process by β-arrestins and by G proteins.
85 citations
TL;DR: Selective modulation of PPARgamma by TZDs resulted in distinct expression profiles and transcription kinetics which may be due to differential promoter activation and chromatin remodeling of target genes.
76 citations
TL;DR: It is shown that young Atm-deficient mice show normal fasting glucose levels and normal insulin sensitivity, however, oral glucose tolerance testing revealed delayed insulin secretion and resulting transient hyperglycemia, indicating a role for ATM in metabolic function.
Abstract: Ataxia telangiectasia (A-T) is an autosomal recessive disease caused by mutations in the A-T mutated (ATM) gene. The gene encodes a serine/threonine kinase with important roles in the cellular response to DNA damage, including the activation of cell cycle checkpoints and induction of apoptosis. Although these functions might explain the cancer predisposition of A-T patients, the molecular mechanisms leading to glucose intolerance and diabetes mellitus (DM) are unknown. We have investigated the pathogenesis of DM in a mouse model of A-T. Here we show that young Atm-deficient mice show normal fasting glucose levels and normal insulin sensitivity. However, oral glucose tolerance testing revealed delayed insulin secretion and resulting transient hyperglycemia. Aged Atm-/- mice show a pronounced increase in blood glucose levels and a decrease in insulin and C-peptide levels. Our findings support a role for ATM in metabolic function and point toward impaired insulin secretion as the primary cause of DM in A-T.
65 citations
TL;DR: Results reveal novel elements of TNFα action; the trimeric G-protein component Gαq/11 and the adapter protein β-arrestin-1 can function as signaling molecules in the TNF α action cascade; β-Arrestin -1 can couple T NFα stimulation to ERK activation and lipolysis and mediate TNFβ-induced phosphatidylinositol 3-kinase activation and inflammatory gene expression.
TL;DR: Fellow AAP members, friends, and guests, it’s been a true pleasure serving the Association for the past 11 years, first as a Council member, then as an Officer, and this year as President.
Abstract: Fellow AAP members, friends, and guests, it’s been a true pleasure serving the Association for the past 11 years, first as a Council member, then as an Officer, and this year as President. The entire 11 years has been a real honor and privilege, and also a thoroughly enjoyable experience. I’m glad to report that the organization is strong, financially stable, and moving forward, and I think this year’s meeting has been an excellent one, at least to this point. And this of course, brings me to the annual ritual of the Presidential Address.
Patent•
22 Jan 2007TL;DR: In this paper, a method for treating insulin resistance or type II diabetes was proposed, which involves administering a CAP antagonist to a patient afflicted with insulin resistance in an amount sufficient to improve insulin action in target tissues.
Abstract: Provided are methods of treating insulin resistance or type II diabetes. Disrupting CAP in the macrophage can alter the inflammatory response associated with impaired insulin action and ultimately result in improved insulin action in target tissues. One aspect of the invention involves administering a CAP antagonist to a patient afflicted with insulin resistance or type II diabetes in an amount sufficient to improve insulin action in target tissues.