Michael A. Statnick
Eli Lilly and Company
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Featured researches published by Michael A. Statnick.
International Journal of Experimental Diabetes Research | 2000
Michael A. Statnick; Lisa Selsam Beavers; Laura J. Conner; Helena Corominola; Dwayne Johnson; Craig Hammond; Ronit Rafaeloff-Phail; Thomas W. Seng; Todd M. Suter; James P. Sluka; Eric Ravussin; Robert Alan Gadski; Jose F. Caro
We have screened a subtracted cDNA library in order to identify differentially expressed genes in omental adipose tissue of human patients with Type 2 diabetes. One clone (#1738) showed a marked reduction in omental adipose tissue from patients with Type 2 diabetes. Sequencing and BLAST analysis revealed clone #1738 was the adipocyte-specific secreted protein gene apM1 (synonyms ACRP30, AdipoQ, GBP28). Consistent with the murine orthologue, apM1 mRNA was expressed in cultured human adipocytes and not in preadipocytes. Using RT-PCR we confirmed that apM1 mRNA levels were significantly reduced in omental adipose tissue of obese patients with Type 2 diabetes compared with lean and obese normoglycemic subjects. Although less pronounced, apM1 mRNA levels were reduced in subcutaneous adipose tissue of Type 2 diabetic patients. Whereas the biological function of apM1 is presently unknown, the tissue specific expression, structural similarities to TNFα and the dysregulated expression observed in obese Type 2 diabetic patients suggest that this factor may play a role in the pathogenesis of insulin resistance and Type 2 diabetes.
Endocrinology | 2002
Matthias H. Tschöp; Michael A. Statnick; Todd M. Suter; Mark L. Heiman
Ghrelin, an endogenous GH secretagogue, is capable of stimulating adiposity in rodents. Because such adiposity was thought to be mediated by hypothalamic NPY neurons, we investigated by which mechanism a synthetic ghrelin receptor agonist, GHRP-2, would generate a positive energy balance in NPY-deficient [Npy(−/−) mice] and wild-type controls. A dose-dependent increase in body weight and food intake was observed during daily sc injections with GHRP-2. Pre- and posttreatment analysis of body composition indicated increased fat mass and bone mass but not lean mass. Respiratory quotient was increased in GHRP-2-treated mice, indicating preservation of fat. Hypothalamic mRNA levels of agouti- related protein (AGRP), an orexigenic melanocortin receptor antagonist, increased after GHRP-2 treatment. Competitive blockade of AGRP action by melanocortin-receptor agonist MT-II prevented GHRP-induced weight gain in Npy(−/−) mice. In conclusion, chronic peripheral treatment with a ghrelin receptor agonist induced a pos...
Pharmacology & Therapeutics | 2014
Jeffrey M. Witkin; Michael A. Statnick; Linda Rorick-Kehn; John E. Pintar; Michael Ansonoff; Yanyun Chen; R. Craig Tucker; Roberto Ciccocioppo
Nociceptin/Orphanin FQ (N/OFQ) is a 17 amino acid peptide that was deorphanized in 1995. The generation of specific agonists, antagonists and receptor deficient mice and rats has enabled progress in elucidating the biological functions of N/OFQ. Additionally, radio-imaging technologies have been advanced for investigation of this system in animals and humans. Together with traditional neurobehavioral techniques, these tools have been utilized to identify the biological significance of the N/OFQ system and its interacting partners. The present review focuses on the role of N/OFQ in the regulation of feeding, body weight homeostasis, stress, the stress-related psychiatric disorders of depression and anxiety, and in drug and alcohol dependence. Critical evaluation of the current scientific preclinical literature suggests that small molecule modulators of nociceptin opioid peptide receptors (NOP) might be useful in the treatment of diseases related to these biological functions. In particular, the literature data suggest that antagonism of NOP receptors will produce anti-obesity and antidepressant activities in humans. However, there are also contradictory data discussed. The current literature on the role of N/OFQ in anxiety and addiction, on the other hand points primarily to a role of agonist modulation being potentially therapeutic. Some drug-like molecules that function either as agonists or antagonists of NOP receptors have been optimized for human clinical study to test some of these hypotheses. The discovery of PET ligands for NOP receptors, combined with the pharmacological tools and burgeoning preclinical data set discussed here bodes well for a rapid advancement of clinical understanding and potential therapeutic benefit.
Neuropharmacology | 2014
Linda Rorick-Kehn; Michael A. Statnick; Elizabeth L. Eberle; Jamie H. McKinzie; Steven D. Kahl; Beth M. Forster; Conrad J. Wong; Xia Li; Robert S. Crile; David Shaw; Allison E. Sahr; Benjamin L. Adams; Steven J. Quimby; Nuria Diaz; Alma Jiménez; Concepcion Pedregal; Charles H. Mitch; Kelly L. Knopp; Wesley Anderson; Jeffrey W. Cramer; David L. McKinzie
Kappa opioid receptors and their endogenous neuropeptide ligand, dynorphin A, are densely localized in limbic and cortical areas comprising the brain reward system, and appear to play a key role in modulating stress and mood. Growing literature indicates that kappa receptor antagonists may be beneficial in the treatment of mood and addictive disorders. However, existing literature on kappa receptor antagonists has used extensively JDTic and nor-BNI which exhibit long-lasting pharmacokinetic properties that complicate experimental design and interpretation of results. Herein, we report for the first time the in vitro and in vivo pharmacological profile of a novel, potent kappa opioid receptor antagonist with excellent selectivity over other receptors and markedly improved drug-like properties over existing research tools. LY2456302 exhibits canonical pharmacokinetic properties that are favorable for clinical development, with rapid absorption (t(max): 1-2 h) and good oral bioavailability (F = 25%). Oral LY2456302 administration selectively and potently occupied central kappa opioid receptors in vivo (ED₅₀ = 0.33 mg/kg), without evidence of mu or delta receptor occupancy at doses up to 30 mg/kg. LY2456302 potently blocked kappa-agonist-mediated analgesia and disruption of prepulse inhibition, without affecting mu-agonist-mediated effects at doses >30-fold higher. Importantly, LY2456302 did not block kappa-agonist-induced analgesia one week after administration, indicating lack of long-lasting pharmacodynamic effects. In contrast to the nonselective opioid antagonist naltrexone, LY2456302 produced antidepressant-like effects in the mouse forced swim test and enhanced the effects of imipramine and citalopram. LY2456302 reduced ethanol self-administration in alcohol-preferring (P) rats and, unlike naltrexone, did not exhibit significant tolerance upon 4 days of repeated dosing. LY2456302 is a centrally-penetrant, potent, kappa-selective antagonist with pharmacokinetic properties favorable for clinical development and activity in animal models predictive of efficacy in mood and addictive disorders.
Brain Research | 1998
Michael A. Statnick; Douglas A. Schober; Susan L. Gackenheimer; Dwayne Johnson; Lisa Selsam Beavers; Nancy Gail Mayne; J. Paul Burnett; Robert Alan Gadski; Donald R. Gehlert
Neuropeptide Y (NPY) is a 36-amino-acid peptide that appears to play a central role in the control of feeding behavior. Recently, a cDNA encoding a novel NPY receptor subtype (Y5) was cloned from the rat and human hypothalamus, and shown to have a pharmacology consistent with NPY-induced feeding. We have subsequently cloned this cDNA from human hypothalamus and stably expressed it in CHO cells. Consistent with earlier reports, hY5 has a high affinity for NPY, [Leu31, Pro34]NPY, and NPY(3-36), but low affinity for larger C-terminal deletions of NPY and BIBP3226. High levels of hY5 mRNA were found in the human testis, brain, spleen and pancreas, with lower levels in several other tissues. In the human brain, hY5 mRNA levels were typically higher than hY2, but lower in comparison to hY1 receptor mRNA. To quantify the relative amounts of hY1, hY2 and hY5 mRNA in the human hypothalamus, we employed competitive RT-PCR. Interestingly, the relative amount of hY5 mRNA was substantially higher than either hY1 or hY2. However, pharmacological characterization of NPY binding sites in human hypothalamus membranes revealed predominantly the hY2 subtype. These data establish that while hY5 mRNA levels are very high in the human hypothalamus, conventional radioligand binding techniques do not detect hY5-like binding site. Whether hY5-like binding sites exist in the other human tissues that express hY5 mRNA (and what function hY5 has in those tissues) awaits future investigation.
Cell Metabolism | 2014
Garron T. Dodd; Amy Worth; Nicolas Nunn; Aaron K. Korpal; David A. Bechtold; Margaret B. Allison; Martin G. Myers; Michael A. Statnick; Simon M. Luckman
Summary Leptin is a critical regulator of metabolism, which acts on brain receptors (Lepr) to reduce energy intake and increase energy expenditure. Some of the cellular pathways mediating leptin’s anorectic actions are identified, but those mediating the thermogenic effects have proven more difficult to decipher. We define a population of neurons in the dorsomedial hypothalamic nucleus (DMH) containing the RFamide PrRP, which is activated by leptin. Disruption of Lepr selectively in these cells blocks thermogenic responses to leptin and causes obesity. A separate population of leptin-insensitive PrRP neurons in the brainstem is required, instead, for the satiating actions of the gut-derived hormone cholecystokinin (CCK). Global deletion of PrRP (in a loxSTOPlox-PrRP mouse) results in obesity and attenuated responses to leptin and CCK. Cre-recombinase-mediated reactivation of PrRP in brainstem rescues the anorectic actions of CCK, but reactivation in the hypothalamus is required to re-establish the thermogenic effect of leptin.
American Journal of Physiology-regulatory Integrative and Comparative Physiology | 2008
Allison E. Sahr; Dana Sindelar; Jesline Alexander-Chacko; Brian Eastwood; Charles H. Mitch; Michael A. Statnick
An analog of the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine series (LY255582) exhibits high in vitro binding affinity and antagonist potency for the mu-, delta-, and kappa-opioid receptors. In vivo, LY255582 exhibits potent effects in reducing food intake and body weight in several rodent models of obesity. In the present study, we evaluated the effects of LY255582 to prevent the consumption of a highly palatable (HP) diet (a high-fat/high-carbohydrate diet) both when the food was novel and following daily limited access to the HP diet. Additionally, we examined the effects of consumption of the HP diet and of LY255582 treatment on mesolimbic dopamine (DA) signaling by in vivo microdialysis. Consumption of the HP diet increased extracellular DA levels within the nucleus accumbens (NAc) shell. Increased DA in the NAc shell was not related to the quantity of the HP diet consumed, and the DA response did not habituate following daily scheduled access to the HP diet. Interestingly, treatment with LY255582 inhibited consumption of the HP diet and the HP diet-associated increase in NAc shell DA levels. Moreover, the increased HP diet consumption observed following daily limited access to the HP diet was completely prevented by LY255582 treatment. LY255582 may be a useful tool in understanding the neural mechanisms involved in the reinforcement mechanisms regulating food intake.
Obesity | 2010
Traci A. Czyzyk; Allison E. Sahr; Michael A. Statnick
Binge eating disorder (BED) is characterized by excessive food intake during a short period of time and is often associated with obesity. Mouse models of binge‐like eating behavior are lacking making it difficult to employ genetic models in the identification of mechanisms regulating excessive eating. We report a rapid and simple model to induce binge‐like eating behavior in mice that does not require food deprivation or exogenous stressors. Weekly 24 h access to a nutritionally complete high energy diet (HED), along with continuous access to standard chow, resulted in a significant increase in HED intake following its presentation compared to mice that had continuous access to both diets. Mice exhibiting binge‐like eating consumed one‐third of their normal total daily caloric intake within 2.5 h of HED presentation. Moreover, total 24‐h caloric intakes were increased by 50% in mice exhibiting binge‐like eating. Following repeated cycles, binge‐like eating of the HED was maintained over several weeks with no evidence of habituation or significant alterations in body weight and adiposity. Pharmacological evaluation of binge‐like eating behavior was performed using clinically employed compounds. Interestingly, binge‐like eating was dose‐dependently decreased by fluoxetine, but not baclofen or topiramate. These data support clinical validation of this mouse model of binge‐like eating behavior, as fluoxetine has been shown to reduce binge frequency in human subjects with BED. The availability of transgenic and knockout mice will allow for the determination of genes that are involved in the initiation and maintenance of binge‐like eating behavior.
Neuropsychopharmacology | 2016
Anke Post; Trevor S. Smart; Judith Krikke-Workel; Gerard R. Dawson; Catherine J. Harmer; Michael Browning; Kimberley Jackson; Rishi Kakar; Richard C. Mohs; Michael A. Statnick; Keith A. Wafford; Andrew McCarthy; Vanessa N. Barth; Jeffrey M. Witkin
Nociceptin/Orphanin FQ (N/OFQ) is an endogenous ligand of the N/OFQ peptide (NOP) receptor, which is a G protein-coupled receptor in brain regions associated with mood disorders. We used a novel, potent, and selective orally bioavailable antagonist, LY2940094, to test the hypothesis that blockade of NOP receptors would induce antidepressant effects. In this study we demonstrate that targeting NOP receptors with LY2940094 translates to antidepressant-like effects in rodent models and, importantly, to antidepressant efficacy in patients with major depressive disorder (MDD). The proof-of-concept study (POC) was an 8-week, double-blind, placebo-controlled trial that evaluated LY2940094 as a novel oral medication for the treatment of patients with MDD. Once daily oral dosing of LY2940094 at 40 mg for 8 weeks vs placebo provided some evidence for an antidepressant effect based on the change from baseline to week 8 in the GRID-Hamilton Depression Rating Scale-17 item total score, although the predefined POC efficacy criterion (probability of LY2940094 being better than placebo⩾88%) was not met (82.9%). LY2940094 also had an early effect on the processing of emotional stimuli at Week 1 as shown by an increased recognition of positive relative to negative facial expressions in an emotional test battery. LY2940094 was safe and well tolerated. Overall, these are the first human data providing evidence that the blockade of NOP receptor signaling represents a promising strategy for the treatment of MDD.
The FASEB Journal | 2010
Traci A. Czyzyk; Ruben Nogueiras; John F. Lockwood; Jamie H. McKinzie; Tamer Coskun; John E. Pintar; Craig Hammond; Matthias H. Tschöp; Michael A. Statnick
General opioid receptor antagonists reduce food intake and body weight in rodents, but the contributions of specific receptor subtypes are unknown. We examined whether genetic deletion of the K‐opioid receptor (KOR) in mice alters metabolic physiology. KOR‐knockout (KO) and wild‐type (WT) mice were fed a high‐energy diet (HED) for 16 wk. KO mice had 28% lower body weight and 45% lower fat mass when compared to WT mice fed an HED. No differences in caloric intake were found. An HED reduced energy expenditure in WT mice, but not in KO mice. KOR deficiency led to an attenuation of triglyceride synthesis in the liver. Malonyl CoA levels were also reduced in response to an HED, thereby promoting hepatic β‐oxidation. Glycemic control was also found to be improved in KO mice. These data suggest a key role for KORs in the central nervous system regulation of the metabolic adaptation to an HED, as we were unable to detect expression of KOR in liver, white adipose tissue, or skeletal muscle in WT mice. This study provides the first evidence that KORs play an essential physiological role in the control of hepatic lipid metabolism, and KOR activation is a permissive signal toward fat storage.—Czyzyk, T. A., Nogueiras, R., Lockwood, J. F., McKinzie, J. H., Coskun, T., Pintar, J. E., Hammond, C., Tschop, M. H., Statnick, M. A. κ‐Opioid receptors control the metabolic response to a high‐energy diet in mice. FASEB J. 24, 1151–1159 (2010). www.fasebj.org