neuropeptide-y and dorsomorphin

Drug discovery and development is commonly schematized as a "pipeline," and, although appreciated by drug developers to be a useful oversimplification, this cartology may perpetuate inaccurate notions of straightforwardness and is of minimal utility for process engineering to improve efficiency. To create a more granular schema, a group of drug developers, researchers, patient advocates, and regulators developed a crowdsourced atlas of the steps involved in translating basic discoveries into health interventions, annotated with the steps that are particularly prone to difficulty or failure. This Drug Discovery, Development, and Deployment Map (4DM), provides a network view of the process, which will be useful for communication and education to those new to the field, orientation and navigation of individual projects, and prioritization of technology development and re-engineering endeavors to improve efficiency and effectiveness. The 4DM is freely available for utilization, modification, and further development by stakeholders across the translational ecosystem.

Topics: Biomedical Technology; Clinical Trials as Topic; Communication; Drug Development; Drug Discovery; Humans; Intersectoral Collaboration; Learning; Myositis Ossificans; National Academies of Science, Engineering, and Medicine, U.S., Health and Medicine Division; Neuropeptide Y; Obesity; Polycystic Kidney, Autosomal Dominant; Pyrazoles; Pyrimidines; Research Design; Translational Research, Biomedical; United States; United States Food and Drug Administration

Thyroid hormone regulates food intake. We previously reported that rats with triiodothyronine (T3)-induced thyrotoxicosis display hyperphagia associated with suppressed circulating leptin levels, increased hypothalamic neuropeptide Y (NPY) mRNA and decreased hypothalamic pro-opiomelanocortin (POMC) mRNA. AMP-activated kinase (AMPK) is a serine/threonine protein kinase that is activated when cellular energy is depleted. We hypothesized that T3 causes an increase in hypothalamic AMPK activity, which in turn contributes to the development of T3-induced hyperphagia. Rats that were given s.c. injections of T3 (4.5 nmol/kg) had increased food intake 2 h later without alterations in NPY and POMC mRNA levels, but with increased hypothalamic phosphorylated AMPK (169%) and phosphorylated acetyl-CoA carboxylase (194%). To determine the more chronic effects of T3, rats were given 6 daily s.c. injection of T3 or the vehicle. Food intake was significantly increased. Multiple T3 injections increased hypothalamic phosphorylated AMPK (278%) and phosphorylated acetyl-CoA carboxylase (335%) compared to the controls. Intracerebroventricular administration of compound C, an AMPK inhibitor, blocked the food intake induced by a single or multiple injections of T3. Taken together, these results suggest that enhanced hypothalamic AMPK phosphorylation contributes to T3-induced hyperphagia. Hypothalamic AMPK plays an important role in the regulation of food intake and body weight.

Topics: Acetyl-CoA Carboxylase; Adiposity; AMP-Activated Protein Kinases; Animals; Body Weight; Eating; Hypothalamus; Male; Neuropeptide Y; Phosphorylation; Pro-Opiomelanocortin; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Rats; Rats, Sprague-Dawley; RNA, Messenger; Triiodothyronine

Changes in the activity of glucose-excited and glucose-inhibited neurons within the basomedial hypothalamus are key to the central regulation of satiety. However, the molecular mechanisms through which these cells respond to extracellular stimuli remain poorly understood. Here, we investigate the role of 5'-AMP-activated protein kinase (AMPK), a trimeric complex encoded by seven distinct genes of the PRKA family, in the responses to glucose and leptin of each cell type.. The activity of isolated rat basomedial hypothalamic neurons was assessed by: (1) recording cellular voltage responses under current clamp; (2) measuring intracellular free Ca(2+) with fluo-3 or fura-2; and (3) developing a neuropeptide Y (NPY) promoter-driven adenovirally produced ratiometric 'pericam' (a green fluorescent protein-based Ca(2+) sensor) to monitor [Ca(2+)] changes selectively in NPY-positive neurons.. The stimulatory effects of decreased (0 or 1.0 vs 15 mmol/l) glucose on glucose-inhibited neurons were mimicked by the AMPK activator, 5-amino-imidazole-4-carboxamide riboside (AICAR) and blocked by the inhibitor Compound C. Similarly, AICAR reversed the inhibitory effects of leptin in the majority of glucose-inhibited neurons. The responses to glucose of Npy-expressing cells, which represented approximately 40 % of all glucose-inhibited neurons, were also sensitive to Compound C or AICAR. Forced changes in AMPK activity had no effect on glucose-excited and non-glucose-responsive neurons.. Changes in AMPK activity are involved in the responses of glucose-inhibited neurons to large fluctuations in glucose concentration, and possibly also to leptin. This mechanism may contribute to the acute reduction of electrical activity and Ca(2+) oscillation frequency in these, but not other neurons, in the basomedial hypothalamus.

Topics: Aminoimidazole Carboxamide; AMP-Activated Protein Kinases; Animals; Calcium; Cells, Cultured; Dose-Response Relationship, Drug; Glucose; Hypoglycemic Agents; Hypothalamus; Leptin; Membrane Potentials; Multienzyme Complexes; Neurons; Neuropeptide Y; Patch-Clamp Techniques; Protein Serine-Threonine Kinases; Pyrazoles; Pyrimidines; Rats; Rats, Wistar; Ribonucleotides