A5026935251- Regulation of Appetite and Obesity
- Biochemical Analysis and Sensing Techniques
- Diabetes Treatment and Management
- melanin and skin pigmentation
- Receptor Mechanisms and Signaling
- Diabetes Management and Research
- Pancreatic function and diabetes
- Neuropeptides and Animal Physiology
- Mast cells and histamine
- Metabolism, Diabetes, and Cancer
- Pharmacology and Obesity Treatment
- Diet and metabolism studies
- Peptidase Inhibition and Analysis
- Adipose Tissue and Metabolism
- Eating Disorders and Behaviors
- Chemical Synthesis and Analysis
- Biochemical effects in animals
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Helicobacter pylori-related gastroenterology studies
- Sleep and Wakefulness Research
- Neurobiology and Insect Physiology Research
- Cannabis and Cannabinoid Research
- Medication Adherence and Compliance
- Apelin-related biomedical research
- Antimicrobial Peptides and Activities
Merck & Co., Inc., Rahway, NJ, USA (United States)
2010-2025
University of Michigan–Ann Arbor
1996-2005
Ann Arbor VA Medical Center
1999-2003
Pediatrics and Genetics
1997-2002
Howard Hughes Medical Institute
1997-2002
Stanford Medicine
2002
University of California, Santa Cruz
2002
Michigan United
1999
United States Department of Veterans Affairs
1999
Gryphon Scientific (United States)
1998
Expression of Agouti protein is normally limited to the skin where it affects pigmentation, but ubiquitous expression causes obesity. An expressed sequence tag was identified that encodes Agouti-related protein, whose RNA in hypothalamus and levels were increased eightfold ob/ob mice. Recombinant a potent, selective antagonist Mc3r Mc4r, melanocortin receptor subtypes implicated weight regulation. Ubiquitous human AGRP complementary DNA transgenic mice caused obesity without altering...
The recent cloning of three melanocortin receptors suggests an unexpected diversity in this family seven transmembrane G-protein linked receptors. Herein, we report the cloning, expression, and gene localization a fourth human receptor, melanocortin-4 receptor. By Northern blot analysis situ hybridization, receptor is expressed primarily brain, but its expression notably absent adrenal cortex, melanocytes, placenta. Agonist stimulation COS-1 cells transiently transfected L-cells permanently...
Using the technique of polymerase chain reaction primed with oligonucleotides based on homologous transmembrane regions seven G protein-linked receptors, we isolated three full-length human genes that encode a novel subgroup this receptor family. Recently, two these receptors were identified as specific for alpha-melanocyte-stimulating hormone (alpha-MSH) and adrenocorticotropic hormone. We report molecular cloning pharmacologic characterization third member subgroup. The gene encodes...
Agouti-related protein (AGRP) is a recently discovered orexigenic neuropeptide that inhibits the binding and action of ␣-melanocyte-stimulating hormone derived from proopiomelanocortin (POMC) at melanocortin 3 receptor (MC3R) 4 (MC4R) has been proposed to function primarily as an endogenous antagonist.To better understand interplay between AGRP signaling systems, we compared their nerve fiber distributions with each other by immunohistochemistry perikarya distribution MC3R MC4R double in...
Agouti-related protein (AGRP) is an orexigenic neuropeptide that acts via central melanocortin receptors, and whose messenger RNA (mRNA) levels are elevated in leptin-deficient mice. Fasting associated with a decline circulating leptin normally causes 15-fold elevation of hypothalamic Agrp mRNA but has no effect Chronic hyperleptinemia the tubby Cpefat mutations on levels, short term administration 17% reduction nonmutant mice 700% In young nonobese animals, receptor blockade Ay mutation...
The gastrointestinal peptide hormone, YY(3-36) (PYY(3-36)), is implicated to be a postprandial satiety factor.The aim of this study assess the safety, tolerability, and efficacy intranasal PYY(3-36) induce weight loss in obese patients.The was designed as randomized, 2-wk, single-blind placebo run-in followed by 12-wk double-blind, placebo-controlled treatment period.The set within private institutional practice.A total 133 patients (body mass index, 30-43 kg/m(2); age, 18-65 yr)...
Abstract Background Omarigliptin is a once-weekly (q.w.) oral DPP-4 inhibitor that approved for the treatment of patients with type 2 diabetes mellitus (T2DM) in Japan. To support approval omarigliptin United States, clinical development program included cardiovascular (CV) safety study. Subsequently, business decision was made not to submit marketing application and CV study terminated. Herein we report an analysis data from early-terminated Methods In this randomized, double-blind study,...
Agouti-related protein (AGRP) is a naturally occurring antagonist of melanocortin action that thought to play an important role in the hypothalamic control feeding behavior. The exact mechanism AGRP and Agouti has been difficult examine, part because difficulties producing homogeneous forms these molecules can be used for direct binding assays. In this report we describe application chemical synthesis construction two novel variants. Examination biological activity variants demonstrates...
To elucidate the molecular basis for interaction of ligands with human melanocortin-4 receptor (hMC4R), agonist structure−activity studies and point mutagenesis were performed. Structure−activity [Nle4,d-Phe7]-α-melanocyte stimulating hormone (NDP-MSH) identified d-Phe7-Arg8-Trp9 as minimal NDP-MSH fragment that possesses full efficacy at hMC4R. In an effort to identify residues might interact amino acids in this tripeptide sequence 24 hMC4R transmembrane (TM) mutated (the rationale choosing...
We undertook these studies to explore the intracellular signaling mechanisms activated by a newly described human brain melanocortin receptor (hMC3R). Hepa cells transfected with hMC3R gene responded stimulation alpha-melanocyte hormone (alpha-MSH) and adrenocorticotropic (ACTH) dose-dependent increases in cellular content of cyclic 3',5'-adenosine monophosphate (cAMP) reaching maximum over 1500% control at 10(-8) M dose (EC50 = 10(-11) M). In contrast, production [3H]inositol phosphates...
We undertook these studies to characterize the molecular basis of interaction histamine with H2 receptor. Key areas homology in structures and beta 2 adrenergic receptor suggested specific transmembrane amino acids that might be important for binding histamine. A third aspartic acid (Asp98), thought serve as a counter anion interacts cationic amine moiety histamine, was mutated Asn98, expressed Hepa cells. Removal negatively charged abolished both antagonist [methyl-3H]tiotidine stimulated...
The melanocortin-1 receptor (MC1R) is a seven-transmembrane (TM) G-protein-coupled whose natural ligands are the melanocortin peptides, adrenocorticotropic hormone, and α-, β-, γ- melanocyte stimulating hormone (MSH). To test previously constructed three-dimensional model of molecular interaction between long-acting, superpotent α-MSH analog [Nle<sup>4</sup>,d-Phe<sup>7</sup>]MSH (NDP-MSH) human MC1R we examined effects site-directed mutagenesis on binding affinity potency NDP-MSH. In...
Mouse agouti protein is a paracrine signaling molecule that has previously been demonstrated to be an antagonist of melanocortin action at several cloned rodent and human receptors. In this study we report the effects agouti-signaling (ASIP), homolog mouse agouti, on ofα -MSH or ACTH five known receptor subtypes (hMCR 1–5). When stably expressed in L cells (hMC1R, hMC3R, hMC4R, hMC5R) adrenocortical cell line OS3 hMC2R, hMC4R), purified recombinant ASIP inhibits generation cAMP stimulated...
The hypothesis that macrophages contain an autocrine circuit based on melanocortin [ACTH and α-melanocyte-stimulating hormone (α-MSH)] peptides has major implications for neuroimmunomodulation research inflammation therapy. To test this hypothesis, cells of the THP-1 human monocyte/macrophage line were stimulated with lipopolysaccharide (LPS) in presence absence α-MSH. inflammatory cytokine tumor necrosis factor (TNF)-α was inhibited relation to α-MSH concentration. Similar inhibitory...
Gastrin and its carboxyl-terminal homolog cholecystokinin (CCK) exert a variety of biological actions in the brain gastrointestinal tract that are mediated part through one or more G protein-coupled receptors which exhibit similar affinity for both peptides. Genomic clones encoding human gastrin/CCKB receptor were isolated by screening EMBL phage library with partial-length DNA fragment was based on nucleotide sequence canine gastrin receptor. The gene contained 1356-bp open reading frame...
Ghrelin, a novel gastric hormone, regulates food intake and energy metabolism via central mechanisms. The peripheral effect of ghrelin on adiposity is poorly understood. We established stable 3T3-L1 cell line expressing to study the direct adipogenesis. Cells overexpressing demonstrate significantly attenuated differentiation preadipocytes into adipocytes. Expression peroxisome proliferator-activator receptor-gamma inhibited as demonstrated by decrease mRNA protein. Both overexpression...