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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A series of trans-4-phenylpyrrolidine-3-carboxamides were synthesized and characterized as potent ligands of the human melanocortin-4 receptor. Interestingly, a pair of diastereoisomers 13b displayed potent functional agonist and antagonist activity, respectively. Thus, the 3S,4R-pyrrolidine 13b-1 possessed a Ki of 1.0 nM and an EC50 of 3.8 nM, while its 3R,4S-isomer 13b-2 exhibited a Ki of 4.7 and an IC50 of 64 nM. Both compounds were highly selective over other melanocortin receptor subtypes. The MC4R agonist 13b-1 also demonstrated efficacy in a diet-induced obesity model in rats.
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PMID:Identification and characterization of pyrrolidine diastereoisomers as potent functional agonists and antagonists of the human melanocortin-4 receptor. 1803 40

The melanocortin system consists of five seven-transmembrane spanning G-protein coupled receptors (MC1-5) that are stimulated by endogenous agonists and antagonized by the only two known endogenous antagonists of GPCRs, agouti and agouti-related protein (AGRP). These receptors have been associated with many physiological functions, including the involvement of the MC4R in feeding behavior and energy homeostasis, making this system an attractive target for the treatment of obesity. Small-molecule mimetics of endogenous ligands may result in the development of compounds with properties more suitable for use as therapeutic agents. The research presented herein involves the synthesis and analysis of 12 melanocortin receptor agonists using the 1,4-benzodiazepine-2,5-dione template and is the first report of these derivatives as melanocortin receptor agonists. Structure-activity relationship studies using this privileged structure template has resulted in molecules with molecular weights around 400 that possess nanomolar agonist potency at the melanocortin receptors examined in this study.
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PMID:The 1,4-benzodiazepine-2,5-dione small molecule template results in melanocortin receptor agonists with nanomolar potencies. 1827 18

Animal obesity models differ widely in type and extent of obesity. They are either based on environmental factors (e.g., high-fat diet-induced obesity), spontaneous mutants (i.e., ob/ob mice), genetically engineered animals (e.g., mice with melanocortin receptor subtype-4 gene disruption (knock-out), or mechanical intervention (e.g., chemical lesion of the ventromedial hypothalamus). This unit reviews available rodent models to study obesity and attempts to highlight the greatest utility for each model.
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PMID:Overview of rodent models for obesity research. 1842 69

The nose provides an effective way for delivering neuropeptides to the central nervous system, bypassing the blood-brain barrier and avoiding systemic side effects. Thereby intranasal neuropeptide administration enables the modulation of central nervous signaling pathways of body weight regulation and cognitive functions. Central nervous control of energy homeostasis is assumed to rely on hypothalamic neuropeptidergic pathways that are triggered by the peripheral adiposity signals insulin and leptin conveying the amount of body fat to the brain. Melanocortins, including alpha-melanocyte stimulating hormone (alpha-MSH), are essential for inducing anorexigenic/catabolic effects, i.e. for inhibiting caloric intake and increasing energy expenditure. Insulin, in addition to its function as an adiposity signal, also influences memory formation. Here we present a series of studies on the intranasal administration of MSH/ACTH4-10, a melanocortin receptor agonist, and of insulin. Prolonged administration of MSH/ACTH4-10 induced weight loss in normal-weight, but not in overweight humans. Intranasal insulin reduced body fat and improved memory functions in the absence of adverse peripheral side effects. Our results may contribute to the future development of therapeutic strategies in disorders like obesity and cognitive impairments that derive from dysfunctions of central nervous neuropeptidergic pathways.
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PMID:Towards the therapeutic use of intranasal neuropeptide administration in metabolic and cognitive disorders. 1844 62

Newborn rat pups artificially raised on a high-carbohydrate (HC) milk formula are chronically hyperinsulinemic and develop adult-onset obesity. As HC rats display aberrations in body weight regulation, hypothalamic adaptations predisposing to obesity have been investigated in this study. The artificial rearing of neonatal rat pups on the HC milk formula resulted in significant increases in the mRNA levels of neuropeptide Y, agouti-related polypeptide, and galanin in the hypothalamus of 12-day-old HC rats. Simultaneously, decreases in the mRNA levels of POMC, melanocortin receptor-4, cocaine- and amphetamine-regulated transcript, and corticotrophin-releasing factor were observed in the hypothalamus of these rats. These changes persisted in 100-day-old HC rats despite weaning onto a rodent diet on postnatal day 24. Marked hyperphagia and increased body weight gain were observed in the post-weaning period. The mRNA levels and protein content of insulin receptor beta (IR-beta) and leptin receptor (long form) showed significant decreases in the hypothalamus of both 12- and 100-day-old HC rats. Further investigation of insulin signaling in the hypothalamus of HC rats indicated significant decreases in the proximal signaling components (insulin receptor substrate proteins 1 and 2 and phosphotidylinositol 3-kinase) in 100-day-old HC rats. These results suggest that hypothalamic neuropeptides respond to the increased carbohydrate availability with associated hormonal alterations during the period of dietary modulation and that these adaptations by persisting in the post-weaning period predispose the HC rats for adult-onset obesity.
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PMID:A high-carbohydrate diet in the immediate postnatal life of rats induces adaptations predisposing to adult-onset obesity. 1849 20

Obesity is an excess of fat mass. Fat mass is an energy depot but also an endocrine organ. A deregulation of the sympathetic nervous system (SNS) might produce obesity. Stress exaggerates diet-induced obesity. After stress, SNS fibers release neuropeptide Y (NPY) which directly increases visceral fat mass producing a metabolic syndrome (MbS)-like phenotype. Adrenergic receptors are the main regulators of lipolysis. In severe obesity, we demonstrated that the adrenergic receptor subtypes are differentially expressed in different fat depots. Liver and visceral fat share a common sympathetic pathway, which might explain the low-grade inflammation which simultaneously occurs in liver and fat of the obese with MbS. The neuroendocrine melanocortinergic system and gastric ghrelin are also greatly deregulated in obesity. A specific mutation in the type 4 melanocortin receptor induces early obesity onset, hyperphagia and insulin-resistance. Nonetheless, it was recently discovered that a mutation in the prohormone convertase 1/3 simultaneously produces severe gastrointestinal dysfunctions and obesity.
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PMID:Neuroendocrine deregulation of food intake, adipose tissue and the gastrointestinal system in obesity and metabolic syndrome. 1856 42

The offspring of high fat (HF) diet-fed rats display increased body weight during adulthood. However, it is not known whether the changes in appetite regulation in these animals occur in utero or postnatally. We investigated the effects of maternal obesity induced by a HF diet prior to and during pregnancy on leptin and insulin signaling and the expression of orexigenic and anorexigenic peptides in term fetal hypothalami. The consumption of a HF diet prior to and during pregnancy resulted in obesity in HF female rats; additionally, HF female rats exhibited hyperinsulinemia and hyperleptinemia which were exaggerated in late gestation compared with control female rats that were fed a standard rodent laboratory chow (LC). Term fetuses of HF female rats (FHF) also had significantly higher serum leptin and insulin levels compared with control fetuses (FLC) while there was no difference in average fetal weight between the two groups. FHF hypothalami showed elevated levels of mRNA and proteins for leptin long receptor and insulin receptor beta-subunit. However, the protein levels of signal transducers and activators of transcription-3 and insulin receptor substrate-2, the downstream signaling components of leptin and insulin signaling respectively were decreased. Also, FHF hypothalami had increased mRNA levels of neuropeptide Y and agouti-related polypeptide indicating that orexigenic neuropeptides in HF progeny are already upregulated by term fetal stage. Additionally, the mRNA levels of pro-opiatemelanocortin and melanocortin receptor-4 were also increased in the HF fetal hypothalami. These findings indicate potential programming effects of an altered intrauterine environment induced by HF diet consumption on appetite-regulating neuropeptides and leptin and insulin signaling in the late fetal period.
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PMID:Hypothalamic alterations in fetuses of high fat diet-fed obese female rats. 1907 72

Obesity is a major public health problem in most developed countries and a major risk factor for diabetes and cardiovascular disease. Emerging evidence indicates that ciliary dysfunction can contribute to human obesity but the underlying molecular and cellular mechanisms are unknown. Bardet-Biedl syndrome (BBS) is a genetically heterogeneous human obesity syndrome associated with ciliary dysfunction. BBS proteins are thought to play a role in cilia function and intracellular protein/vesicle trafficking. Here, we show that BBS proteins are required for leptin receptor (LepR) signaling in the hypothalamus. We found that Bbs2(-/-), Bbs4(-/-) and Bbs6(-/-) mice are resistant to the action of leptin to reduce body weight and food intake regardless of serum leptin levels and obesity. In addition, activation of hypothalamic STAT3 by leptin is significantly decreased in Bbs2(-/-), Bbs4(-/-) and Bbs6(-/-) mice. In contrast, downstream melanocortin receptor signaling is unaffected, indicating that LepR signaling is specifically impaired in Bbs2(-/-), Bbs4(-/-) and Bbs6(-/-) mice. Impaired LepR signaling in BBS mice was associated with decreased Pomc gene expression. Furthermore, we found that BBS1 protein physically interacts with the LepR and that loss of BBS proteins perturbs LepR trafficking. Our data indicate that BBS proteins mediate LepR trafficking and that impaired LepR signaling underlies energy imbalance in BBS. These findings represent a novel mechanism for leptin resistance and obesity.
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PMID:Requirement of Bardet-Biedl syndrome proteins for leptin receptor signaling. 1915 Sep 89

A variety of metabolic/molecular changes in obese adipose tissue considerably contribute to the pathophysiology of life style-related diseases. Fat cell-derived hormone leptin controls appetite and energy homeostasis, thereby enhancing whole body insulin sensitivity. However, clinical application of leptin for the treatment of obesity/metabolic syndrome has been hampered by the fact that leptin does not fully exert its beneficial metabolic impact on prevalent forms of obesity. In an attempt to elucidate underlying mechanism of leptin resistance in obesity, we found that the activity of skeletal muscle AMP-activated protein kinase (AMPK) tightly parallels hypothalamic leptin sensitivity and metabolic phenotype in transgenic mice overexpressing leptin. Actually, intracerebroventricular administration of melanocortin agonist MT-II robustly overcomes high fat diet-induced leptin resistance and ameliorates fuel dyshomeostasis and hyperphagia in mice, with a concomitant recovery of AMPK activity in skeletal muscle, thereby highlighting the system as a therapeutic target for leptin resistance. In this context, type 4 melanocortin receptor is a promising drug target for the treatment of obesity/metabolic syndrome.
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PMID:[Energy homeostasis regulated by an adipocyte-derived hormone--mechanism of leptin resistance and role of hypothalamic melanocortin signaling]. 1920 1

The melanocortin receptor (MCR) family consists of 5 G protein-coupled receptors (MC1R-MC5R) with diverse physiologic roles. MC2R is a critical component of the hypothalamic-pituitary-adrenal axis, whereas MC3R and MC4R have an essential role in energy homeostasis. Mutations in MC4R are the single most common cause of monogenic obesity. Investigating the way in which these receptors signal and traffic to the cell membrane is vital in understanding disease processes related to MCR dysfunction. MRAP is an MC2R accessory protein, responsible for adrenal MC2R trafficking and function. Here we identify MRAP2 as a unique homologue of MRAP, expressed in brain and the adrenal gland. We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). Collectively, our data identify MRAP and MRAP2 as unique bidirectional regulators of the MCR family.
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PMID:MRAP and MRAP2 are bidirectional regulators of the melanocortin receptor family. 1932 86


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