scholarly journals Insulin Regulates Adipocyte Lipolysis via an Akt-Independent Signaling Pathway

2010 ◽  
Vol 30 (21) ◽  
pp. 5009-5020 ◽  
Author(s):  
Sarah M. Choi ◽  
David F. Tucker ◽  
Danielle N. Gross ◽  
Rachael M. Easton ◽  
Lisa M. DiPilato ◽  
...  
Keyword(s):  
Insulin Action ◽  
Hormone Sensitive Lipase ◽  
Dependent Manner ◽  
Impaired Insulin ◽  
Hormone Sensitive ◽  
Phosphoinositide 3 Kinase ◽  
Impaired Insulin Action ◽  
Differential Phosphorylation ◽  
Dependent Pathway ◽  
Kinase A

ABSTRACT After a meal, insulin suppresses lipolysis through the activation of its downstream kinase, Akt, resulting in the inhibition of protein kinase A (PKA), the main positive effector of lipolysis. During insulin resistance, this process is ineffective, leading to a characteristic dyslipidemia and the worsening of impaired insulin action and obesity. Here, we describe a noncanonical Akt-independent, phosphoinositide-3 kinase (PI3K)-dependent pathway that regulates adipocyte lipolysis using restricted subcellular signaling. This pathway selectively alters the PKA phosphorylation of its major lipid droplet-associated substrate, perilipin. In contrast, the phosphorylation of another PKA substrate, hormone-sensitive lipase (HSL), remains Akt dependent. Furthermore, insulin regulates total PKA activity in an Akt-dependent manner. These findings indicate that localized changes in insulin action are responsible for the differential phosphorylation of PKA substrates. Thus, we identify a pathway by which insulin regulates lipolysis through the spatially compartmentalized modulation of PKA.

Antecedent protein restriction exacerbates development of impaired insulin action after high-fat feeding

1999 ◽  
Vol 276 (1) ◽  
pp. E85-E93 ◽  
Author(s):  
Mark J. Holness ◽  
Mary C. Sugden
Keyword(s):  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Insulin Action ◽  
Protein Restriction ◽  
Protein Diet ◽  
Glucose Disposal ◽  
High Fat ◽  
Impaired Insulin ◽  
Impaired Insulin Action ◽  
Fat Feeding

The study investigated whether a persistent impairment of insulin secretion resulting from mild protein restriction predisposes to loss of glucoregulatory control and impaired insulin action after the subsequent imposition of the diabetogenic challenge of high-fat feeding. Offspring of dams provided with either control (20% protein) diet (C) or an isocaloric restricted (8%) protein diet (PR) were weaned onto the maintenance diet with which their mothers had been provided. At 20 wk of age, protein restriction enhanced glucose tolerance despite impaired insulin secretion and an augmented and sensitized lipolytic response to norepinephrine in adipocytes. C and PR rats were then transferred to a high-fat diet (HF, 19% protein, 22% lipid, 34% carbohydrate) and sampled after 8 wk. These groups are termed C-HF and PR-HF. Glucose tolerance was impaired in PR-HF, but not C-HF, rats. Insulin-stimulated glucose disposal rates were significantly lower (by 30%; P < 0.01) in the PR-HF group than in the C-HF group, and a specific impairment of antilipolytic response of insulin was unmasked in adipocytes from PR-HF, but not C-HF, rats. The study demonstrates that antecedent protein restriction accelerates and augments the development of impaired glucoregulation and insulin resistance after high-fat feeding.

Impaired Insulin Action in Rats with Non-insulin-dependent Diabetes

Diabetes ◽  
1984 ◽  
Vol 33 (9) ◽  
pp. 901-906 ◽  
Author(s):  
J. Levy ◽  
J. R. Gavin ◽  
A. Fausto ◽  
R. L. Gingerich ◽  
L. V. Avioli
Keyword(s):  
Insulin Action ◽  
Insulin Dependent Diabetes ◽  
Impaired Insulin ◽  
Insulin Dependent ◽  
Impaired Insulin Action

scholarly journals Current views on type 2 diabetes

2009 ◽  
Vol 204 (1) ◽  
pp. 1-11 ◽  
Author(s):  
Yi Lin ◽  
Zhongjie Sun
Keyword(s):  
Type 2 Diabetes ◽  
Animal Models ◽  
Insulin Action ◽  
Large Population ◽  
Specific Aspect ◽  
Multiple Organs ◽  
Impaired Insulin ◽  
Critical Components ◽  
Impaired Insulin Action

Type 2 diabetes mellitus (T2DM) affects a large population worldwide. T2DM is a complex heterogeneous group of metabolic disorders including hyperglycemia and impaired insulin action and/or insulin secretion. T2DM causes dysfunctions in multiple organs or tissues. Current theories of T2DM include a defect in insulin-mediated glucose uptake in muscle, a dysfunction of the pancreatic β-cells, a disruption of secretory function of adipocytes, and an impaired insulin action in liver. The etiology of human T2DM is multifactorial, with genetic background and physical inactivity as two critical components. The pathogenesis of T2DM is not fully understood. Animal models of T2DM have been proved to be useful to study the pathogenesis of, and to find a new therapy for, the disease. Although different animal models share similar characteristics, each mimics a specific aspect of genetic, endocrine, metabolic, and morphologic changes that occur in human T2DM. The purpose of this review is to provide the recent progress and current theories in T2DM and to summarize animal models for studying the pathogenesis of the disease.

059. POOR GROWTH BEFORE BIRTH IMPAIRS INSULIN SECRETION - WHAT WE HAVE LEARNT ABOUT THE MECHANISMS FROM THE PLACENTALLY-RESTRICTED SHEEP

2009 ◽  
Vol 21 (9) ◽  
pp. 14
Author(s):  
K. L. Gatford
Keyword(s):  
Insulin Resistance ◽  
Insulin Secretion ◽  
Beta Cell ◽  
Insulin Action ◽  
Cell Function ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Poor Growth ◽  
Impaired Insulin ◽  
Impaired Insulin Action

Diabetes occurs when insulin secretion fails to increase sufficiently to compensate for developing insulin resistance. This implies that the increased risk of diabetes in adults who were small at birth reflects impaired insulin secretion as well as their well-known insulin resistance. More recently, direct evidence has been obtained that adults and children who were growth-restricted before birth secrete less insulin than they should, given their level of insulin resistance. Our research group is using the placentally-restricted (PR) sheep to investigate the mechanisms underlying impaired insulin action (sensitivity and secretion) induced by poor growth before birth. Like the intra-uterine growth-restricted (IUGR) human, the PR sheep develops impaired insulin action by adulthood, but has enhanced insulin sensitivity in infancy, associated with neonatal catch-up growth1, 2. Impaired insulin action begins to develop in early postnatal life, where although basal insulin action is high due to enhanced insulin sensitivity, maximal glucose-stimulated insulin action is already impaired in males3. Our cellular and molecular studies have identified impaired beta-cell function rather than mass as the likely cause of impaired insulin secretion, and we have reported a novel molecular defect in the calcium channels involved in the insulin secretion pathway in the pancreas of these lambs3. Upregulation of IGF-II and insulin receptor are implicated as key molecular regulators of beta-cell mass in the PR lamb3. By adulthood, both basal and maximal insulin action are profoundly impaired in the male lamb who was growth-restricted at birth2. These studies suggest therapies to prevent diabetes in the individual who grew poorly before birth should target beta-cell function, possibly in addition to further increasing beta-cell mass, to improve insulin secretion capacity, and its ability to increase in response to development of insulin resistance. We are now using the PR sheep to test potential therapies, since the timing of pancreatic development and hence exposure to a growth-restricting environment, is similar to that of the human.

Impaired insulin action but normal insulin receptor activity in diabetic rat liver: effect of vanadate

1990 ◽  
Vol 258 (3) ◽  
pp. E459-E467 ◽  
Author(s):  
O. Blondel ◽  
J. Simon ◽  
B. Chevalier ◽  
B. Portha
Keyword(s):  
Insulin Receptor ◽  
Insulin Action ◽  
Diabetic Rats ◽  
Receptor Kinase ◽  
Peripheral Tissues ◽  
Impaired Insulin ◽  
Insulin Dependent ◽  
Insulin Receptor Kinase ◽  
Impaired Insulin Action

In vivo insulin resistance is a characteristic of the liver and peripheral tissues in 10-wk-old female rats with non-insulin-dependent diabetes induced by streptozotocin given on day 5 after birth. Oral administration of vanadate (0.2 mg/ml) for 20 days in the diabetic rats lowered their plasma glucose levels to normal values without affecting their basal plasma insulin levels. In the basal state as well as after submaximal or maximal hyperinsulinemia (euglycemic clamp studies), peripheral glucose utilization and hepatic glucose production in vivo were normalized in the diabetic rats after the vanadate treatment. In wheat germ agglutinin purified receptors, 125I-labeled porcine insulin binding, basal and insulin-stimulated insulin receptor kinase activities for both the autophosphorylation of the beta-subunit and the phosphorylation of the artificial substrate poly (Glu-Tyr) 4:1, were found identical in diabetic and control rats, treated or not with vanadate. Liver phosphoenolpyruvate carboxykinase activity was significantly enhanced in untreated diabetic rats (P less than 0.01) as compared with control rats and returned to normal values after the 20-day vanadate treatment. Thus, in that model of non-insulin-dependent diabetes, 1) oral vanadate exerts a corrective insulin-like effect on impaired insulin action both at the level of liver and peripheral tissues, 2) impaired insulin action with no alteration of the insulin receptor tyrosine kinase is observed in the liver of untreated rats, and 3) corrective effect of vanadate on liver glucose metabolism is probably distal to the insulin receptor kinase activity.

scholarly journals Perilipin A is essential for the translocation of hormone-sensitive lipase during lipolytic activation

2003 ◽  
Vol 161 (6) ◽  
pp. 1093-1103 ◽  
Author(s):  
Carole Sztalryd ◽  
Guoheng Xu ◽  
Heidi Dorward ◽  
John T. Tansey ◽  
Juan A. Contreras ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Chinese Hamster Ovary ◽  
Lipid Droplets ◽  
Chinese Hamster ◽  
Hormone Sensitive Lipase ◽  
Ovary Cell ◽  
Perilipin A ◽  
Hormone Sensitive ◽  
Kinase A

Akey step in lipolytic activation of adipocytes is the translocation of hormone-sensitive lipase (HSL) from the cytosol to the surface of the lipid storage droplet. Adipocytes from perilipin-null animals have an elevated basal rate of lipolysis compared with adipocytes from wild-type mice, but fail to respond maximally to lipolytic stimuli. This defect is downstream of the β-adrenergic receptor–adenylyl cyclase complex. Now, we show that HSL is basally associated with lipid droplet surfaces at a low level in perilipin nulls, but that stimulated translocation from the cytosol to lipid droplets is absent in adipocytes derived from embryonic fibroblasts of perilipin-null mice. We have also reconstructed the HSL translocation reaction in the nonadipocyte Chinese hamster ovary cell line by introduction of GFP-tagged HSL with and without perilipin A. On activation of protein kinase A, HSL-GFP translocates to lipid droplets only in cells that express fully phosphorylatable perilipin A, confirming that perilipin is required to elicit the HSL translocation reaction. Moreover, in Chinese hamster ovary cells that express both HSL and perilipin A, these two proteins cooperate to produce a more rapidly accelerated lipolysis than do cells that express either of these proteins alone, indicating that lipolysis is a concerted reaction mediated by both protein kinase A–phosphorylated HSL and perilipin A.

scholarly journals Effect of Gambisan on the Inhibition of Adipogenesis in 3T3-L1 Adipocytes

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Jung Won Kang ◽  
Dongwoo Nam ◽  
Kun Hyung Kim ◽  
Jeong-Eun Huh ◽  
Jae-Dong Lee
Keyword(s):  
Dna Content ◽  
Hormone Sensitive Lipase ◽  
Dependent Manner ◽  
Rt Pcr ◽  
Hormone Sensitive ◽  
Ldh Assay ◽  
Dose Dependent ◽  
Oil Red O Staining ◽  
Oil Red O

This study was conducted to explore the antiadipogenic effect and possible mechanism of Gambisan on 3T3-L1 cells. For quality control, Gambisan was standardized by HPLC and the standard compounds ephedrine, epigallocatechin-3-gallate, and caffeine were screened. Cultured 3T3-L1 cells that had been induced to differentiate were treated with various concentrations of Gambisan or its major component extracts (Ephedra intermediaSchrenk,Atractylodes lanceaDC., andThea sinensisL.) for 72 hours for MTT assay to determine cell viability or 10 days for LDH assay, triglyceride assay, DNA content measurement, Oil red O staining, RT-PCR, and western blot. Gambisan significantly inhibited adipogenesis in 3T3-L1 cells by reducing triglyceride contents and lipid accumulation in a dose-dependent manner without obvious cytotoxicity. Viability and DNA content in 3T3-L1 cells treated with Gambisan were significantly higher than cells treated with the major component extracts at every concentration. The anti-adipogenic effects of Gambisan appeared to be mediated by a significant downregulation of the expression of lipoprotein lipase mRNA and PPARγ, C/EBPα, and SREBP-1 protein apart from the expression of hormone-sensitive lipase. Gambisan could act as a possible therapeutic agent for obesity. However, further studies includingin vivoassays and clinical trials are needed to confirm the efficacy, safety and mechanisms of the antiobesity effects of Gambisan.

Prostaglandin E2 activates outwardly rectifying Cl− channels via a cAMP-dependent pathway and reduces cell motility in rat osteoclasts

2004 ◽  
Vol 287 (1) ◽  
pp. C114-C124 ◽  
Author(s):  
Fujio Okamoto ◽  
Hiroshi Kajiya ◽  
Hidefumi Fukushima ◽  
Eijiro Jimi ◽  
Koji Okabe
Keyword(s):  
Protein Kinase ◽  
Bone Resorption ◽  
Morphological Properties ◽  
Disulfonic Acid ◽  
Dependent Manner ◽  
Extracellular Solution ◽  
Concentration Dependent Manner ◽  
Cl Channels ◽  
Dependent Pathway ◽  
Kinase A

We examined changes in electrical and morphological properties of rat osteoclasts in response to prostaglandin (PG)E2. PGE2 (>10 nM) stimulated an outwardly rectifying Cl− current in a concentration-dependent manner and caused a long-lasting depolarization of cell membrane. This PGE2-induced Cl− current was reversibly inhibited by 4,4′-diisothiocyanostilbene-2,2′-disulfonic acid (DIDS), 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB), and tamoxifen. The anion permeability sequence of this current was I− > Br− ≈ Cl− > gluconate−. When outwardly rectifying Cl− current was induced by hyposmotic extracellular solution, no further stimulatory effect of PGE2 was seen. Forskolin and dibutyryl adenosine 3′,5′-cyclic monophosphate (DBcAMP) mimicked the effect of PGE2. The PGE2-induced Cl− current was inhibited by pretreatment with guanosine 5′- O-2-(thiodiphosphate) (GDPβS), Rp-adenosine 3′,5′-cyclic monophosphorothioate (Rp-cAMPS), N-(2-[ p-bromocinnamylamino]ethyl)-5-isoquinolinesulfonamide dihydrochloride (H-89), and protein kinase A inhibitors. Even in the absence of nonosteoclastic cells, PGE2 (1 μM) reduced cell surface area and suppressed motility of osteoclasts, and these effects were abolished by Rp-cAMPS or H-89. PGE2 is known to exert its effects through four subtypes of PGE receptors (EP1–EP4). EP2 and EP4 agonists (ONO-AE1-259 and ONO-AE1-329, respectively), but not EP1 and EP3 agonists (ONO-DI-004 and ONO-AE-248, respectively), mimicked the electrical and morphological actions of PGE2 on osteoclasts. Our results show that PGE2 stimulates rat osteoclast Cl− current by activation of a cAMP-dependent pathway through EP2 and, to a lesser degree, EP4 receptors and reduces osteoclast motility. This effect is likely to reduce bone resorption.

scholarly journals Hormonal activation of type-L hormone-sensitive lipase measured in defatted heart powders

1983 ◽  
Vol 212 (2) ◽  
pp. 379-383 ◽  
Author(s):  
W K Palmer ◽  
T A Kane
Keyword(s):  
Cyclic Amp ◽  
Diethyl Ether ◽  
Rat Heart ◽  
Hormone Sensitive Lipase ◽  
Dependent Manner ◽  
Ph Optimum ◽  
Protamine Sulphate ◽  
Hormone Sensitive ◽  
The Stability ◽  
Ether Treatment

Adrenaline, 3-isobutyl-1-methylxanthine (MIX) and dibutyryl cyclic AMP (Bt2 cyclic AMP) stimulated type-L hormone-sensitive lipase (HSL) activity when measurements were made on defatted rat heart powders. These lipolytic agents stimulated the activity of this enzyme in a time- and dose-dependent manner. This activation was reversible, because removal of adrenaline from the perfusate was accompanied by the return of type-L HSL activity to control levels. We have reported [Palmer, Caruso & Oscai (1981) Biochem. J. 198, 159-166] that perfusion with low levels of adrenaline, MIX or Bt2 cyclic AMP reduced type-L HSL activity below control levels when measurements were made in aqueous homogenates. However, in the present study, when activities were measured in acetone/diethyl ether heart powders, all concentrations of these agents studied stimulated enzyme activity, and at no concentration was there enzyme inhibition. These data suggest that acetone/diethyl ether treatment may remove a factor that plays a role in type-L HSL regulation. Type-L HSL activity measured in acetone/diethyl ether powders of control and stimulated rat heart exhibited properties that include alkaline pH optimum, serum requirement, activation by heparin and inhibition by high salt and protamine sulphate. These characteristics, in addition to the stability of the enzyme to treatment with organic solvents, fulfil the requirements for the type-L HSL classification.

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