Serotonin 2C Receptor Agonists Improve Type 2 Diabetes via Melanocortin-4 Receptor Signaling Pathways

Zhou, Ligang; Sutton, Gregory M.; Rochford, Justin J.; Semple, Robert K.; Lam, Daniel D.; Oksanen, Laura; Thornton-Jones, Z.D.; Clifton, Peter G.; Yueh, Chen-Yu; Evans, Mark L.; McCrimmon, Rory J.; Elmquist, Joel K.; Butler, Andrew A.; Heisler, Lora K.

doi:10.1016/j.cmet.2007.10.008

Cited by 199 publications

(181 citation statements)

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“…Targeted mutation of insulin receptor production the brain led to obesity in mice, further suggesting a role of brain insulin in the control of feeding [294]. In microdialysis experiments, stimulation of 5-HT release caused activation of insulin in the PVN without affecting insulinemia or glycaemia [295], whereas serum insulin was reduced after administration of the sub-hypophagic doses of the 5-HT2C agonist mCPP [296]. This effect was mediated via downstream MC-4 receptors and suggests that pharmacological targeting of 5-HT2C receptors may enhance glucose tolerance independently of alterations in body weight [296].…”

Section: -Ht Interactions With Other Gastrointestinal Peptidesmentioning

confidence: 99%

Serotonin controlling feeding and satiety

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2015

Behavioural Brain Research

270

167

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Serotonin has been implicated in the control of satiety for almost four decades. Historically, the insight that the appetite suppressant effect of fenfluramine is linked to serotonin has stimulated interest in and research into the role of this neurotransmitter in satiety. Various rodent models, including transgenic models, have been developed to identify the involved 5-HT receptor subtypes. This approach also required the availability of receptor ligands of different selectivity, and behavioural techniques had to be developed simultaneously which allow differentiating between unspecific pharmacological effects of these ligands and 'true' 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 3 IntroductionWhat are the behavioural and physiological mechanisms that promote satiety? How is satiety defined? Satiety can be seen as a behavioural state which arises from food consumption and suppresses the initiation of eating for a particular period of time [1]. This description alone suggests a high degree of complexity as peripheral post-ingestive and post-absorptive signals need to be relayed to the brain where they are integrated with other signals to produce (or not) the behavioural state called satiety. The state of satiety is brought about a process called satiation, where sensory, cognitive and early post-ingestive mechanisms bring feeding to a halt and thus stopping a meal. Promoting satiation alone must not necessarily lead to reduced total food intake as the frequency of meals could be increased subsequently. Many peripheral and brain mechanisms have been identified that are involved in the expression satiety and it has been suggested that serotonin accelerates satiation and prolongs satiety [2]. In the following, we will review the role of serotonin in satiety in more detail 1 . The reader will see that, despite immense progress made during the last years, the field is still far from being resolved.As serotonin (5-Hydroxytryptamine; 5-HT) is a phylogenetically old neurotransmitter, various functions had time to evolve in different phyla, but maybe also in different species. 5-HT receptors exist in animal cells for millions of years and they are as old as adrenoreceptors ore some peptide receptors, possibly even older [5,6]. Even in invertebrates such as molluscs (Aplysia californica) and annelids (Hirudo medicinalis), 5-HT might functionally be related to food intake [7]. 5-HT is involved in feeding even in the honeybee where it has separate effects in the gut and in the insect brain [8]. In general, however, 5-HT seems rather to be involved in appetitive behaviours in invertebrates whereas it has more of a satiating effect in vertebrates [9]. In general, 5-HT neurons seem to be more extensively distributed throughout the body in lower animals than in higher animals including mammals where 5-HT neurones...

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Section: -Ht Interactions With Other Gastrointestinal Peptidesmentioning

confidence: 99%

Serotonin controlling feeding and satiety

Voigt

Fink

2015

Behavioural Brain Research

270

167

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“…MC4R has been associated with key components of nutrient absorption, lipid metabolism, energy expenditure, thermogenesis, adiposity, insulin secretion, food intake, and appetite (Adan et al 2006). Moreover, the MC pathway interacts with other key hormones or pathways such as leptin, 5-HT (Zhou et al 2007), NPY, AGRP, POMC (Biebermann et al 2012), and ANS (Rossi et al 2011;Sohn et al 2013) in the hypothalamus and brainstem (Loos 2011), GLP-1 pathway (Gautron et al 2010), CCK, and vagal afferent fibers (Guan et al 2012).…”

Section: Introductionmentioning

confidence: 99%

Association of melanocortin 4 receptor gene variation with satiation and gastric emptying in overweight and obese adults

et al. 2014

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Melanocortin 4 receptor (MC4R) has a major role in energy homeostasis. The rs17782313 polymorphism, mapped 188 kb downstream from MC4R, has been associated with satiety, higher body mass index (BMI) and total calorie intake in adults. To assess the association of rs17782313 with gastric functions, satiation, or satiety, we studied 178 predominantly Caucasian overweight and obese people: 120 females, 58 males; mean BMI 33.4 ± 5.3 kg/m 2 (SD); age 37.7 ± 11.2 years. Quantitative traits assessed were gastric emptying (GE) of solids and liquids; fasting and postprandial gastric volume; satiation by maximum tolerated volume and 4 symptoms by 100-mm visual analog scales (VAS); and satiety by ad libitum buffet meal. Associations of genotype and quantitative traits were assessed by analysis of covariance (using gender and BMI as covariates), based on a dominant [TC (n = 72) -CC (n = 12) vs. TT (n = 94)] genetic model. rs17782313(C) was associated with postprandial satiation symptoms (median D total VAS 26.5 mm, p = 0.036), reduced proportion of solid GE at 2 h (median D 6.7 %, p = 0.008) and 4 h (median D 3.2 %, p = 0.006), and longer t (median D 6 min, p = 0.034). Associations of rs17782313 with obesity may be explained by reduced satiation and GE. The role of MC4R mechanisms in satiation and gastric function deserves further study.

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“…45 One mouse model suggests that 5-HT 2C signaling may also enhance glucose tolerance independently of its effect on body weight. 46 The 5-HT 2B receptor, by contrast, is expressed on cardiac cells and has been implicated as the cause of fenfluramine-associated valvulopathy and pulmonary hypertension. 47,48 The antiparkinsonian drugs pergolide and cabergoline activate the 5-HT 2B receptor and are associated with valvulopathy; but lisuride, which activates 5-HT 2A and 5-HT 2C but not 5-HT 2B , is not associated with valvular damage.…”

Section: Lorcaserinmentioning

confidence: 99%

Modern Obesity Pharmacotherapy: Weighing Cardiovascular Risk and Benefit

Cunningham

Wiviott

2014

Clinical Cardiology

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Obesity is a major correlate of cardiovascular disease. Weight loss improves cardiovascular risk factors and has the potential to improve outcomes. Two drugs, phentermine plus topiramate and lorcaserin, have recently been approved by the US Food and Drug Administration for the indication of obesity; a third, bupropion plus naltrexone, is under consideration for approval. In clinical trials, these drugs cause weight loss and improve glucose tolerance, lipid profile, and, with the exception of bupropion plus naltrexone, blood pressure. However, their effect on cardiovascular outcomes is unknown. In defining appropriate roles for these drugs in preventive cardiology, it is important to remember the checkered history of drugs for obesity. New weight-loss drugs share the serotonergic and sympathomimetic mechanisms that proved harmful in the cases of Fen-Phen and sibutramine, respectively, albeit with significant differences. Given these risks, randomized cardiovascular outcomes trials are needed to establish the safety, and potential benefit, of these drugs. This review will discuss the history of pharmacotherapy for obesity, existing efficacy and safety data for the novel weight-loss drugs, and issues in the design of postapproval clinical trials. IntroductionAdvances in prevention-smoking-cessation campaigns, statin therapy, and tight blood pressure (BP) control, among others-have contributed to decreases in the burden of coronary artery disease over the past several decades. However, the increasing prevalence of obesity and obesityassociated diseases like type 2 diabetes mellitus (T2DM) have tempered these gains. 1 Despite recent data suggesting a plateau, rates of obesity remain substantially higher than a few decades ago. 2 Intensive lifestyle interventions have produced clinically relevant weight loss, 3 but modest interventions that are feasible in the primary-care setting are less successful. 4 Many efforts to develop an effective and safe weight-loss pill have failed. In fact, the history of obesity pharmacotherapy has been notable for cardiovascular side effects, not benefits. In 2012, the US Food and Drug Administration (FDA) approved 2 medications for weight loss, the selective 5-HT 2C agonist lorcaserin and the combination pill phentermine plus topiramate; a third, bupropion plus naltrexone, is under consideration for approval at the time of this writing. 5 The mechanisms of

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Serotonin 2C Receptor Agonists Improve Type 2 Diabetes via Melanocortin-4 Receptor Signaling Pathways

Cited by 199 publications

References 22 publications

Serotonin controlling feeding and satiety

Serotonin controlling feeding and satiety

Association of melanocortin 4 receptor gene variation with satiation and gastric emptying in overweight and obese adults

Modern Obesity Pharmacotherapy: Weighing Cardiovascular Risk and Benefit

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