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Potentiation of Insulin Signaling in Tissues of Zucker Obese Rats After Potentiation of Insulin Signaling in Tissues of Zucker Obese Rats After Acute and Long-Term Treatment With PPAR␥ Agonists Guoqiang Jiang,1 Qing Dallas-Yang,1 Zhihua Li,1 Deborah Szalkowski,1 Franklin Liu,1 Xiaolan Shen,2 Margaret Wu,1 Gaochao Zhou,1 Thomas Doebber,1 Joel Berger,1 David E. Moller,1 and Bei B. Zhang1 Thiazolidinediones (TZDs), agonists of peroxisome pro- a member of a larger family of the ligand-activated nuclear liferator–activated receptor-␥ (PPAR␥), improve insu- receptor transcription factors (3). In in vitro systems, TZD lin sensitivity in vivo, and the mechanism remains and select non-TZD antidiabetic compounds of different largely unknown. In this study, we showed that, in structural classes bind to PPAR␥ with high affinity and Zucker obese (fa/fa) rats, acute (1-day) treatment with specificity, promote interaction of PPAR␥ with transcrip- both rosiglitazone (a TZD) and a non-TZD PPAR␥ ago- tional coactivators or corepressors, increase PPAR␥- nist (nTZD) reduced plasma free fatty acid and insulin mediated transcription regulation, and promote PPAR␥- levels and, concomitantly, potentiated insulin-stimu- lated Akt phosphorylation at threonine 308 (Akt- mediated cellular effects such as adipogenesis (3–5). pT308) in adipose and muscle tissues. A similar effect Furthermore, in vivo efficacy in rodents generally corre- on Akt was observed in liver after a 7-day treatment. lates with in vitro PPAR␥ activity, suggesting that PPAR␥ The increase in Akt-pT308 was correlated with an in- activation is the predominant mechanism for the antidia- crease in Akt phosphorylation at serine 473 (Akt- betic efficacy of the PPAR␥ agonists (3,6). pS473), tyrosine phosphorylation of insulin receptor ␤ The mechanism by which activation of PPAR␥ leads to subunit and insulin receptor substrate-1, and serine insulin sensitization is not fully understood. PPAR␥ and ␣ ␤ phosphorylation of glycogen synthase kinase-3 / . The TZDs regulate the expression of several dozens of genes agonists appeared to potentiate Akt1 phosphorylation in muscle and liver and both Akt1 and Akt2 in adipose. involved in a variety of cellular functions, including the Finally, potentiation of insulin signaling was also ob- metabolism of carbohydrates, fatty acids, triglycerides, served in isolated adipose tissue ex vivo and differenti- and cholesterol (3,7,8). It is not clear which, if any, of these ated 3T3 L1 adipocytes in vitro, but not in rat primary genes may be critical for insulin sensitization. It is also hepatocytes in vitro. These results suggest that 1) unknown which of the insulin-responsive tissues is the key PPAR␥ agonists acutely potentiate insulin signaling in target of TZDs, though adipose tissue is the leading adipose and muscle tissues and such regulation may be candidate. PPAR␥ is expressed at high levels in the physiologically relevant to insulin sensitization in vivo; adipose tissue but at much lower levels in muscle and liver 2) the agonists directly target adipose tissues; and 3) ␥ the metabolic and signaling effects of the agonists are tissues (9,10). PPAR agonists regulate adipocyte differ- mediated by structurally distinct PPAR␥ agonists. entiation and metabolism (7,11). However, the use of Diabetes 51:2412–2419, 2002 genetic manipulation to produce mice with adipose tissue ablation yielded contradictory results on whether adipose tissues are required for the antidiabetic effects of TZDs (12,13). Finally, it remains possible, though unlikely, that hiazolidinediones (TZDs) (e.g., troglitazone, pio- TZDs may exert their major effects independently of glitazone, and rosiglitazone) are a class of antidi- PPAR␥ (14). abetic drugs that act as insulin sensitizers by Activation of phosphatidylinositol 3-kinase (PI3K) is an Tdecreasing insulin resistance in human and ani- early and key event in insulin signaling. PI3K activation mal models (1,2). TZDs decrease circulating levels of results in rapid rise in phosphatidylinositol 3,4,5-trisphos- insulin, free fatty acids, and triglycerides and increase phate (PIP3) that subsequently activates PIP3-dependent insulin-stimulated glucose uptake and utilization (1,2). ␥ ␥ serine/threonine kinases, including Akt (15). Akt is known Peroxisome proliferator–activated receptor- (PPAR )is to undergo phosphorylation and activation upon insulin stimulation and is thought to play important roles in From the 1Department of Molecular Endocrinology–Diabetes, Merck Re- insulin-regulated metabolic effects (16). It was reported search Laboratories, Rahway, New Jersey; and the 2Department of Compara- recently that genetic deletion of Akt2 but not Akt1 in tive Medicine, Merck Research Laboratories, Rahway, New Jersey. Address correspondence and reprint requests to Guoqiang Jiang, Molecular mouse model is associated with insulin resistance and Endocrinology–Diabetes, RY80N-C31, Merck Research Laboratories, P.O. Box diabetes (17,18). Insulin-stimulated PI3K and Akt activa- 2000, Rahway, NJ 07065. E-mail: [email protected]. Received for publication 22 January 2002 and accepted in revised form 20 tion have been found to be blunted in the diabetic and May 2002/ insulin-resistant states in both animals and humans (19– GSK, glycogen synthase kinase; IRS-1, insulin receptor substrate-1; PI3K, 28). It has been reported that TZDs exert their insulin- phosphatidylinositol 3-kinase; PIP3, phosphatidylinositol 3,4,5-trisphosphate; PPAR␥, peroxisome proliferator–activated receptor-␥; nTZD, non-TZD PPAR␥ sensitizing effects at least partially by potentiating insulin- agonist; TZD, thiazolidinedione. stimulated PI3K and Akt activation (27,29–34). However, it 2412 DIABETES, VOL. 51, AUGUST 2002 G. JIANG AND ASSOCIATES is not clear whether TZD-mediated effects on PI3K and Akt medium by centrifugation, and then lyzed as described above for frozen activation are an early event that contributes to insulin tissues. Immunoprecipitation and Western blot analysis. For immunoprecipita- sensitization or a late event consequential to improved tion, lysates were mixed with antisera for 2–4 h and then protein-A or insulin sensitivity in vivo. protein-G agarose beads for another 1–4hat4°C with gentle shaking. The The current study used both cellular and animal models beads were washed with lysis buffers for three times. Cell and tissue lysates to investigate the effects of PPAR␥ agonists on multiple or immunoprecipitations were resuspended in SDS-loading buffer (Invitrogen, Carlsbad, CA) and separated in precast 4–20% gradient NuPAGE SDS-PAGE components of the insulin signaling pathway. The results gels (Invitrogen, Carlsbad, CA). The proteins were then transferred to a showed that PPAR␥ agonists potentiated insulin signaling polyvinylidine fluoride (PVDF) membrane and probed with primary antibody. in vivo in a tissue- and time-dependent fashion, and that Detection was performed with Phototope-HRP Western blot Detection Kit by such potentiation may play a role in PPAR␥ agonist– film exposure (New England BioLabs, Beverly, MA) or ECF Western Blotting Kit (Amersham Pharmacia Biotech, Piscataway, NJ) by scanning with a Storm mediated insulin sensitization in vivo. gel and blot imaging system (Molecular Dynamics), per the manufacturer’s recommendation. Akt1 and Akt2 were isolated from tissue lysates with equivalent amounts of RESEARCH DESIGN AND METHODS total proteins by immunoprecipitation with Akt1- and Akt2-specific sheep polyclonal antibody, respectively. The levels of total or phosphorylated Akt1 Materials. Insulin was purchased from Sigma. Rabbit polyclonal antibodies and Akt2 in the immunoprecipitates were determined by Western blot using ␤ against insulin receptor -subunit and insulin receptor substrate-1 (IRS-1), the antibody against all isoforms of total Akt or Akt-p308, respectively. The sheep polyclonal antibodies against Akt1 and Akt2, and mouse monoclonal specificity of the isoform-specific antibodies was confirmed by experiments antibody 4G10 specifically against tyrosine phosphorylated proteins were showing, for example, that Akt2 antibody but not Akt1 antibodies detected a purchased from Upstate Biotechnology (Lake Placid, NY). Rabbit polyclonal 60-kDa band in the immunoprecipitation of Akt2 antibody from adipose tissue antibodies against Akt isoforms phosphorylated at a position equivalent to lysate (data not shown). An excessive amount (20 ␮g) of Akt1 and Akt2 threonine 308 (Akt-pT308) and serine 473 (Akt-pS473) in Akt1, mouse mono- antibodies was used in each of the immunoprecipitates. That Akt1 and Akt2 ␣ ␤ clonal antibody against glycogen synthase kinase-3 / (GSK3␣/␤), and poly- proteins were completely immunoprecipitated from the tissue lysates was clonal antibody against both GSK3␣ phosphorylated at serine 21 and GSK3␤ confirmed by experiments showing that Akt1 and Akt2 antibodies clearly phosphorylated at serine 9 (GSK3␣/␤-pS21/9) were purchased from Cell detected an ϳ60-kDa band in the lysate before but not after the corresponding Signaling (Beverly, MA). The TZD rosiglitazone [(ϩ/Ϫ)-5-(4-(2-(methyl-2- immunoprecipitates (data not shown). pyridinylamino)ethoxy)phenyl)methyl)-2,4-thiazolidinedione] was used in For determination of tyrosine phosphorylation of IRS-1 and insulin recep- these studies. In addition, a novel indole-acetic acid PPAR␥ agonist, nTZD tor, IRS-1 and insulin receptor ␤ subunit were isolated from adipose and [2-(2-(4-phenoxy-2-propylphenoxy)ethyl)indole-5-acetic acid] was kindly pro- muscle tissue lysates with equivalent amounts of total proteins (1 mg) by vided by Drs. Derek Von Langen and Michael Kress
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