biie-0246 and Body-Weight

Administration of dextran sodium sulfate (DSS) to rodents at varying concentrations and exposure times is commonly used to model human inflammatory bowel disease (IBD). Currently, the criteria used to assess IBD-like pathology seldom include surrogate measures of visceral pain. Thus, we sought to standardize the model and then identify surrogate measures to assess effects on visceral pain. We used various 4% DSS protocols and evaluated effects on weight loss, colon pathology, biochemistry, RNA signature, and open field behavior. We then tested the therapeutic potential of NPY Y1 and/or Y2 receptor inhibition for the treatment of IBD pathology using this expanded panel of outcome measures. DSS caused weight loss and colon shrinkage, increased colon NPY and inflammatory cytokine expression, altered behaviors in the open field and induced a distinct gene metasignature that significantly overlapped with that of human IBD patients. Inhibition of Y1 and/or Y2 receptors failed to improve gross colon pathology. Y1 antagonism significantly attenuated colon inflammatory cytokine expression without altering pain-associated behaviors while Y2 antagonism significantly inhibited pain-associated behaviors in spite of a limited effect on inflammatory markers. A protocol using 7 days of 4% DSS most closely modeled human IBD pathology. In this model, rearing behavior potentially represents a tool for evaluating visceral pain/discomfort that may be pharmacologically dissociable from other features of pathology. The finding that two different NPY receptor antagonists exhibited different efficacy profiles highlights the benefit of including a variety of outcome measures in IBD efficacy studies to most fully evaluate the therapeutic potential of experimental treatments.

Topics: Animals; Arginine; Benzazepines; Body Weight; Colitis; Dextran Sulfate; Disease Models, Animal; Female; Humans; Inflammatory Bowel Diseases; Male; Mice; Mice, Inbred C57BL; Receptors, Neuropeptide Y

Exaggerated GLP-1 and PYY secretion is thought to be a major mechanism in the reduced food intake and body weight after Roux-en-Y gastric bypass surgery. Here, we use complementary pharmacological and genetic loss-of-function approaches to test the role of increased signaling by these gut hormones in high-fat diet-induced obese rodents. Chronic brain infusion of a supramaximal dose of the selective GLP-1 receptor antagonist exendin-9-39 into the lateral cerebral ventricle significantly increased food intake and body weight in both RYGB and sham-operated rats, suggesting that, while contributing to the physiological control of food intake and body weight, central GLP-1 receptor signaling tone is not the critical mechanism uniquely responsible for the body weight-lowering effects of RYGB. Central infusion of the selective Y2R-antagonist BIIE0246 had no effect in either group, suggesting that it is not critical for the effects of RYGB on body weight under the conditions tested. In a recently established mouse model of RYGB that closely mimics surgery and weight loss dynamics in humans, obese GLP-1R-deficient mice lost the same amount of body weight and fat mass and maintained similarly lower body weight compared with wild-type mice. Together, the results surprisingly provide no support for important individual roles of either gut hormone in the specific mechanisms by which RYGB rats settle at a lower body weight. It is likely that the beneficial effects of bariatric surgeries are expressed through complex mechanisms that require combination approaches for their identification.

Topics: Animals; Arginine; Benzazepines; Body Composition; Body Weight; Dietary Fats; Eating; Energy Metabolism; Gastric Bypass; Glucagon-Like Peptide-1 Receptor; Male; Mice; Mice, Knockout; Motor Activity; Obesity; Oxygen Consumption; Peptide Fragments; Rats; Rats, Sprague-Dawley; Receptors, Glucagon; Weight Loss

Selective activation of the neuropeptide Y (NPY)2 receptor to suppress appetite provides a promising approach to obesity management. A selective NPY2 polyethylene glycol-conjugated (PEGylated) peptide agonist is described that consists of a peptide core corresponding to residues 13 to 36 of human peptide YY (PYY) and a nonpeptidic moiety (2-mercaptonicotinic acid) at the peptide N terminus that is derivatized with 20-kDa monomethoxypolyethylene glycol. The PEGylated peptide elicits a dose-dependent reduction in food intake in lean C57BL/6 mice and Wistar rats that persists for 72 and 48 h, respectively. The effect on food intake in lean C57BL/6 mice is blocked by the selective NPY2 antagonist BIIE0246 (N-[(1S)-4-[(aminoiminomethyl)amino]-1-[[[2-(3,5-dioxo-1,2-diphenyl-1,2,4-triazolidin-4-yl)ethyl]amino]carbonyl]butyl]-1-[2-[4-(6,11-dihydro-6-oxo-5H-dibenz[b,e]azepin-11-yl)-1-piperazinyl]-2-oxoethyl]-cyclopentaneacetamide formate). A dose-dependent reduction in body weight in diet-induced obese (DIO) mice is seen following daily dosing for 14 days. The reduction in body weight is sustained following dosing for 40 days, and it is accompanied by an increase in plasma adiponectin. Improvements in glucose disposal and in plasma insulin and glucose levels that are risk factors for type II diabetes are observed following once-daily subcutaneous dosing in DIO mice. The results provide evidence from two animal species that the long-acting selective NPY2 peptide agonist has potential for obesity management.

Topics: Adiponectin; Animals; Appetite Depressants; Arginine; Benzazepines; Body Weight; Dose-Response Relationship, Drug; Eating; Glucose; Humans; Male; Mice; Mice, Inbred C57BL; Peptide Fragments; Peptide YY; Polyethylene Glycols; Rats; Rats, Wistar; Receptors, Neuropeptide Y; Structure-Activity Relationship