Lynnetta Watts
Isis Pharmaceuticals
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Publication
Featured researches published by Lynnetta Watts.
Journal of Biological Chemistry | 2007
Sanjay K. Pandey; Xing Xian Yu; Lynnetta Watts; M. Dodson Michael; Kyle W. Sloop; Amber R. Rivard; Thomas A. Leedom; Vara Prasad Manchem; Laura Samadzadeh; Robert Mckay; Brett P. Monia; Sanjay Bhanot
To investigate the role of low molecular weight protein-tyrosine phosphatase (LMW-PTP) in glucose metabolism and insulin action, a specific antisense oligonucleotide (ASO) was used to reduce its expression both in vitro and in vivo. Reduction of LMW-PTP expression with the ASO in cultured mouse hepatocytes and in liver and fat tissues of diet-induced obese (DIO) mice and ob/ob mice led to increased phosphorylation and activity of key insulin signaling intermediates, including insulin receptor-β subunit, phosphatidylinositol 3-kinase, and Akt in response to insulin stimulation. The ASO-treated DIO and ob/ob animals showed improved insulin sensitivity, which was reflected by a lowering of both plasma insulin and glucose levels and improved glucose and insulin tolerance in DIO mice. The treatment did not decrease body weight or increase metabolic rate. These data demonstrate that LMW-PTP is a key negative regulator of insulin action and a potential novel target for the treatment of insulin resistance and type 2 diabetes.
Endocrinology | 2009
Michael M. Swarbrick; Peter J. Havel; Arthur A. Levin; Andrew A. Bremer; Kimber L. Stanhope; Madeline M. Butler; Sheri L. Booten; James L. Graham; Robert Mckay; Susan F. Murray; Lynnetta Watts; Brett P. Monia; Sanjay Bhanot
Protein tyrosine phosphatase (PTP)-1B antagonizes insulin signaling and is a potential therapeutic target for insulin resistance associated with obesity and type 2 diabetes. To date, studies of PTP-1B have been limited by the availability of specific antagonists; however, treatment of rodents with antisense oligonucleotides (ASOs) directed against PTP-1B improves insulin sensitivity, inhibits lipogenic gene expression, and reduces triglyceride accumulation in liver and adipose tissue. Here we investigated ASO-mediated PTP-1B inhibition in primates. First, PTP-1B ASO (ISIS 113715) dose-dependently inhibited PTP-1B mRNA and protein expression in cultured monkey hepatocytes. Subcutaneous administration of ISIS 113715 reduced PTP-1B mRNA expression in liver and adipose tissue of normal-weight monkeys by 40-50% and improved insulin sensitivity during an iv glucose tolerance test (IVGTT). In obese, insulin-resistant rhesus monkeys, treatment with 20 mg/kg ISIS 113715 for 4 wk reduced fasting concentrations of insulin and glucose and reduced insulin responses during an IVGTT. In these animals, adiponectin concentrations were also increased by 70%, most of which was an increase of high-molecular-weight oligomers. These effects were not observed in monkeys on a lower, dose-escalation regimen (1-10 mg/kg over 9 wk). Overall, the increase of adiponectin concentrations during ISIS 113715 treatment was correlated with the lowering of insulin responses during IVGTT (r = -0.47, P = 0.042). These results indicate that inhibition of PTP-1B with ASOs such as ISIS 113715 may be a viable approach for the treatment and prevention of obesity-associated insulin resistance and type 2 diabetes because they potently increase adiponectin concentrations in addition to improving insulin sensitivity.
American Journal of Physiology-endocrinology and Metabolism | 2008
Xing Xian Yu; Susan F. Murray; Lynnetta Watts; Sheri L. Booten; Justin Tokorcheck; Brett P. Monia; Sanjay Bhanot
To investigate the role of JNK1 in metabolism, male ob/ob and diet-induced obese mice were treated with a JNK1-specific antisense oligonucleotide (ASO) or control ASO at 25 mg/kg or saline twice/wk for 6 and 7 wk, respectively. JNK1 ASO reduced JNK1 mRNA and activity by 65-95% in liver and fat tissues in both models. Compared with controls, treatment with JNK1 ASO did not change food intake but lowered body weight, fat pad weight, and whole body fat content. The treatment increased metabolic rate. In addition, the treatment markedly reduced plasma cholesterol levels and improved liver steatosis and insulin sensitivity. These positive observations were accompanied by the following changes: 1) increased mRNA levels of AR-beta(3) and UCP1 by >60% in BAT, 2) reduced mRNA levels of ACC1, ACC2, FAS, SCD1, DGAT1, DGAT2, and RBP4 by 30-60% in WAT, and 3) reduced mRNA levels of ACC1, FAS, G-6-Pase, and PKCepsilon by 40-70% and increased levels of UCP2 and PPARalpha by more than twofold in liver. JNK1 ASO-treated mice demonstrated reduced levels of pIRS-1 Ser(302) and pIRS-1 Ser(307) and increased levels of pAkt Ser(473) in liver and fat in response to insulin. JNK1 ASO-transfected mouse hepatocytes showed decreased rates of de novo sterol and fatty acid synthesis and an increased rate of fatty acid oxidation. These results indicate that inhibition of JNK1 expression in major peripheral tissues can improve adiposity via increasing fuel combustion and decreasing lipogenesis and could therefore provide clinical benefit for the treatment of obesity and related metabolic abnormalities.
PLOS ONE | 2013
Xing Xian Yu; Lynnetta Watts; Vara Prasad Manchem; Kaushik Chakravarty; Brett P. Monia; Michael L. McCaleb; Sanjay Bhanot
Obesity is a primary risk factor for multiple metabolic disorders. Many drugs for the treatment of obesity, which mainly act through CNS as appetite suppressants, have failed during development or been removed from the market due to unacceptable adverse effects. Thus, there are very few efficacious drugs available and remains a great unmet medical need for anti-obesity drugs that increase energy expenditure by acting on peripheral tissues without severe side effects. Here, we report a novel approach involving antisense inhibition of fibroblast growth factor receptor 4 (FGFR4) in peripheral tissues. Treatment of diet-induce obese (DIO) mice with FGFR4 antisense oligonucleotides (ASO) specifically reduced liver FGFR4 expression that not only resulted in decrease in body weight (BW) and adiposity in free-feeding conditions, but also lowered BW and adiposity under caloric restriction. In addition, combination treatment with FGFR4 ASO and rimonabant showed additive reduction in BW and adiposity. FGFR4 ASO treatment increased basal metabolic rate during free-feeding conditions and, more importantly, prevented adaptive decreases of metabolic rate induced by caloric restriction. The treatment increased fatty acid oxidation while decreased lipogenesis in both liver and fat. Mechanistic studies indicated that anti-obesity effect of FGFR4 ASO was mediated at least in part through an induction of plasma FGF15 level resulted from reduction of hepatic FGFR4 expression. The anti-obesity effect was accompanied by improvement in plasma glycemia, whole body insulin sensitivity, plasma lipid levels and liver steatosis. Therefore, FGFR4 could be a potential novel target and antisense reduction of hepatic FGFR4 expression could be an efficacious therapy as an adjunct to diet restriction or to an appetite suppressant for the treatment of obesity and related metabolic disorders.
Diabetes Care | 2018
Andres DiGenio; Nguyen C. Pham; Lynnetta Watts; Erin S. Morgan; Shiangtung W. Jung; Brenda F. Baker; Richard S. Geary; Sanjay Bhanot
OBJECTIVE To evaluate safety and efficacy of IONIS-PTP-1BRx, a second-generation 2′-O-methoxyethyl antisense inhibitor of protein tyrosine phosphatase 1B, as add-on therapy in overweight patients with type 2 diabetes inadequately controlled with metformin with or without sulfonylurea therapy. RESEARCH DESIGN AND METHODS In this phase II, double-blind, randomized, placebo-controlled, multicenter trial, overweight and obese patients (BMI ≥27 kg/m2) with type 2 diabetes (HbA1c ≥7.5% [58 mmol/mol] and ≤10.5% [91 mmol/mol]) on a stable dose of metformin alone or with sulfonylurea were randomized 2:1 to IONIS-PTP-1BRx 200 mg (n = 62) or placebo (n = 30) once weekly for 26 weeks. RESULTS Mean baseline HbA1c was 8.6% (70 mmol/mol) and 8.7% (72 mmol/mol) in placebo and active treatment, respectively. At week 27, IONIS-PTP-1BRx reduced mean HbA1c levels by −0.44% (−4.8 mmol/mol; P = 0.074) from baseline and improved leptin (−4.4 ng/mL; P = 0.007) and adiponectin (0.99 μg/mL; P = 0.026) levels compared with placebo. By week 36, mean HbA1c was significantly reduced (−0.69% [−7.5 mmol/mol]; P = 0.034) and accompanied by reductions in fructosamine (−33.2 μmol/L; P = 0.005) and glycated albumin (−1.6%; P = 0.031) versus placebo. Despite both treatment groups receiving similar lifestyle counseling, mean body weight significantly decreased from baseline to week 27 with IONIS-PTP-1BRx versus placebo (−2.6 kg; P = 0.002) independent of HbA1c reduction (R2 = 0.0020). No safety concerns were identified in the study. CONCLUSIONS Compared with placebo, IONIS-PTP-1BRx treatment for 26 weeks produced prolonged reductions in HbA1c, improved medium-term glycemic parameters, reduced leptin and increased adiponectin levels, and resulted in a distinct body weight–reducing effect.
Cell Metabolism | 2006
Christine Esau; Scott Davis; Susan F. Murray; Xing Xian Yu; Sanjay K. Pandey; Michael Pear; Lynnetta Watts; Sheri L. Booten; Mark J. Graham; Robert Mckay; Amuthakannan Subramaniam; Stephanie Propp; Bridget Lollo; Susan M. Freier; C. Frank Bennett; Sanjay Bhanot; Brett P. Monia
Journal of Clinical Investigation | 2004
Kyle W. Sloop; Julia Xiao-Chun Cao; Angela M. Siesky; Hong Yan Zhang; Diane M. Bodenmiller; Amy L. Cox; Steven J. Jacobs; Julie S. Moyers; Rebecca A. Owens; Aaron D. Showalter; Martin B. Brenner; Achim Raap; Jesper Gromada; Brian R. Berridge; David Monteith; Niels Porksen; Robert Mckay; Brett P. Monia; Sanjay Bhanot; Lynnetta Watts; M. Dodson Michael
Diabetes | 2005
Lynnetta Watts; Vara Prasad Manchem; Thomas A. Leedom; Amber L. Rivard; Robert Mckay; Dingjiu Bao; Teri Neroladakis; Brett P. Monia; Diane M. Bodenmiller; Julia Xiao-Chun Cao; Hong Yan Zhang; Amy L. Cox; Steven Jacobs; M. Dodson Michael; Kyle W. Sloop; Sanjay Bhanot
Archive | 2004
Andrew M. Siwkowski; Edward Wancewicz; Thomas A. Leedom; Lynnetta Watts; Mausumee Guha; Brett P. Monia
Metabolism-clinical and Experimental | 2005
Yin Liang; Melville C. Osborne; Brett P. Monia; Sanjay Bhanot; Lynnetta Watts; Pengxiang She; Stephanie O. DeCarlo; Xiaoli Chen; Keith T. Demarest