Increased alternate splicing of Htr2c in a mouse model for Prader-Willi syndrome leads disruption of 5HT(2C) receptor mediated appetite

Alternate splicing of serotonin (5-hydroxytryptamine; 5-HT) 2C receptor (5-HT2CR) pre-RNA is negatively regulated by the small nucleolar RNA, Snord115, loss of which is observed in nearly all individuals with Prader-Willi Syndrome (PWS), a multigenic disorder characterised by hyperphagia and obesity. Given the role of the 5-HT2CR in the regulation of ingestive behaviour we investigated the pathophysiological implications of Snord115 deficiency on 5-HT2CR regulated appetite in a genotypically relevant PWS mouse model (PWS-IC). Specifically, we demonstrate that loss of Snord115 expression is associated with increased levels of hypothalamic truncated 5-HT2CR pre-mRNA. The 5-HT2CR promotes appetite suppression via engagement of the central melanocortin system. Pro-opiomelancortin (Pomc) mRNA levels within the arcuate nucleus of the hypothalamus (ARC) were reduced in PWS-IC mice. We then went on to assess the functional consequences of these molecular changes, demonstrating that PWS-IC mice are unresponsive to an anorectic doses of a 5-HT2CR agonist and that this is associated with attenuated activation of POMC neurons within the ARC. These data provide new insight into the significance of Htr2c pre-mRNA processing to the physiological regulation of appetite and potentially the pathological manifestation of hyperphagia in PWS. Furthermore, these findings have translational relevance for individuals with PWS who may seek to control appetite with another 5-HT2CR agonist, the new obesity treatment lorcaserin

Intracerebroventricular Catalase Reduces Hepatic Insulin Sensitivity and Increases Responses to Hypoglycemia in Rats

Specialized metabolic-sensors in the hypothalamus regulate blood glucose levels by influencing hepatic glucose output and hypoglycemic counter regulatory responses. Hypothalamic reactive oxygen species (ROS) may act as a metabolic signal mediating responses to changes in glucose, other substrates and hormones. The role of ROS in the brain's control of glucose homeostasis remains unclear. We hypothesized that hydrogen peroxide (H$_2$O$_2$), a relatively stable form of ROS, acts as a sensor of neuronal glucose consumption and availability and that lowering brain H$_2$O$_2$ with the enzyme catalase would lead to systemic responses increasing blood glucose. During hyperinsulinemic euglycemic clamps in rats, ICV catalase infusion resulted in increased hepatic glucose output, which was associated with reduced neuronal activity in the arcuate nucleus of the hypothalamus (ARC). Electrophysiological recordings revealed a subset of ARC neurons expressing pro-opiomelanocortin (POMC) that were inhibited by catalase and excited by H$_2$O$_2$. During hypoglycemic clamps, ICV catalase increased glucagon and epinephrine responses to hypoglycemia, consistent with perceived lower glucose levels. Our data suggest that H$_2$O$_2$ represents an important metabolic cue which, through tuning the electrical activity of key neuronal populations such as POMC neurons, may have a role in the brain's influence of glucose homeostasis and energy balance.This work was supported by the Juvenile Diabetes Research Foundation Grant 1-2006-29 and the Diabetes UK Grant RD05/ 003059 (to M.L.E.), the Wellcome Trust Grant WT098012 (to L.K.H.), and Cambridge Medical Research Council Centre for Study of Obesity and Related Disorders. In addition, PhD studentships/fellowships were supported for S.P.M. (Elmore Fund), P.H. (Sir Jules Thorn Trust), and C.-Y.Y. (Chang Gung University College of Medicine Grant numbers CMRPG6B0291 and CMRPG6B0292)

Activation of Ventral Tegmental Area 5-HT2C Receptors Reduces Incentive Motivation

FUNDING AND DISCLOSURE The research was funded by Wellcome Trust (WT098012) to LKH; and National Institute of Health (DK056731) and the Marilyn H. Vincent Foundation to MGM. The University of Michigan Transgenic Core facility is partially supported by the NIH-funded University of Michigan Center for Gastrointestinal Research (DK034933). The remaining authors declare no conflict of interest. ACKNOWLEDGMENTS We thank Dr Celine Cansell, Ms Raffaella Chianese and the staff of the Medical Research Facility for technical assistance. We thank Dr Vladimir Orduña for the scientific advice and technical assistance.Peer reviewedPublisher PD

The 5-HT2C receptor agonist meta-chlorophenylpiperazine (mCPP) reduces palatable food consumption and BOLD fMRI responses to food images in healthy female volunteers

RATIONALE: Brain 5-HT2C receptors form part of a neural network that controls eating behaviour. 5-HT2C receptor agonists decrease food intake by activating proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus, but recent research in rodents has suggested that 5-HT2C receptor agonists may also act via dopaminergic circuitry to reduce the rewarding value of food and other reinforcers. No mechanistic studies on the effects of 5-HT2C agonists on food intake in humans have been conducted to date. OBJECTIVES: The present study examined the effects of the 5-HT2C receptor agonist meta-chlorophenylpiperazine (mCPP) on food consumption, eating microstructure and blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) responses to food pictures in healthy female volunteers. METHODS: In a double-blind, placebo-controlled, crossover design, participants were randomized immediately after screening to receive oral mCPP (30mg) in a single morning dose, or placebo, in a counterbalanced order. Test foods were served from a Universal Eating Monitor (UEM) that measured eating rate and fMRI BOLD signals to the sight of food and non-food images were recorded. RESULTS: mCPP decreased rated appetite and intake of a palatable snack eaten in the absence of hunger but had no significant effect on the consumption of a pasta lunch (although pasta eating rate was reduced). mCPP also decreased BOLD fMRI responses to the sight of food pictures in areas of reward-associated circuitry. A post hoc analysis identified individual variability in the response to mCPP (exploratory responder-non-responder analysis). Some participants did not reduce their cookie intake after treatment with mCPP and this lack of response was associated with enhanced ratings of cookie pleasantness and enhanced baseline BOLD responses to food images in key reward and appetite circuitry. CONCLUSIONS: These results suggest that 5-HT2C receptor activation in humans inhibits food reward-related responding and that further investigation of stratification of responding to mCPP and other 5-HT2C receptor agonists is warranted

Adherence to cardioprotective medications and mortality among patients with diabetes and ischemic heart disease

BACKGROUND: Patients with diabetes and ischemic heart disease (IHD) are at high risk for adverse cardiac outcomes. Clinical practice guidelines recommend multiple cardioprotective medications to reduce recurrent events. We evaluated the association between cardioprotective medication adherence and mortality among patients with diabetes and IHD. METHODS: In a retrospective cohort study of 3,998 patients with diabetes and IHD, we evaluated use of ACE inhibitors or angiotensin receptor blockers, β-blockers, and statin medications. Receipt of cardioprotective medications was based on filled prescriptions. Medication adherence was calculated as the proportion of days covered (PDC) for filled prescriptions. The primary outcome of interest was all-cause mortality. RESULTS: The majority of patients (92.8%) received at least 1 cardioprotective medication. Patients receiving any medications had lower unadjusted mortality rates compared to patients not receiving any medications (7.9% vs. 11.5%; p = 0.03). In multivariable analysis, receipt of any cardioprotective medication remained associated with lower all-cause mortality (OR 0.65; 95% CI 0.43–0.99). Among patients receiving cardioprotective medications, the majority (80.3%) were adherent (PDC ≥ 0.80). Adherent patients had lower unadjusted mortality rates (6.7% vs. 12.1%; p < 0.01). In multivariable analysis, medication adherence remained associated with lower all-cause mortality (OR 0.52; 95% CI 0.39–0.69) compared to non-adherence. In contrast, there was no mortality difference between patients receiving cardioprotective medications who were non-adherent compared to patients not receiving any medications (OR 1.01; 95% CI 0.64–1.61). CONCLUSION: In conclusion, medication adherence is associated with improved outcomes among patients with diabetes and IHD. Quality improvement interventions are needed to increase medication adherence in order for patients to maximize the benefit of cardioprotective medications

Development of a peer support intervention to encourage dietary behaviour change towards a Mediterranean diet in adults at high cardiovascular risk.

BACKGROUND: Mediterranean diet (MD) interventions are demonstrated to significantly reduce cardiovascular disease (CVD) risk but are typically resource intensive and delivered by health professionals. There is considerable interest to develop interventions that target sustained dietary behaviour change and that are feasible to scale-up for wider public health benefit. The aim of this paper is to describe the process used to develop a peer support intervention to encourage dietary behaviour change towards a MD in non-Mediterranean adults at high CVD risk. METHODS: The Medical Research Council (MRC) and Behaviour Change Wheel (BCW) frameworks and the COM-B (Capability, Opportunity, Motivation, Behaviour) theoretical model were used to guide the intervention development process. We used a combination of evidence synthesis and qualitative research with the target population, health professionals, and community health personnel to develop the intervention over three main stages: (1) we identified the evidence base and selected dietary behaviours that needed to change, (2) we developed a theoretical basis for how the intervention might encourage behaviour change towards a MD and selected intervention functions that could drive the desired MD behaviour change, and (3) we defined the intervention content and modelled outcomes. RESULTS: A theory-based, culturally tailored, peer support intervention was developed to specifically target behaviour change towards a MD in the target population. The intervention was a group-based program delivered by trained peer volunteers over 12-months, and incorporated strategies to enhance social support, self-efficacy, problem-solving, knowledge, and attitudes to address identified barriers to adopting a MD from the COM-B analysis. CONCLUSIONS: The MRC and BCW frameworks provided a systematic and complementary process for development of a theory-based peer support intervention to encourage dietary behaviour change towards a MD in non-Mediterranean adults at high CVD risk. The next step is to evaluate feasibility, acceptability, and diet behaviour change outcomes in response to the peer support intervention (change towards a MD and nutrient biomarkers) using a randomized controlled trial design

Reduced Serotonin Reuptake Transporter (SERT) Function Causes Insulin Resistance and Hepatic Steatosis Independent of Food Intake

Serotonin reuptake transporter (SERT) is a key regulator of serotonin neurotransmission and a major target of antidepressants. Antidepressants, such as selectively serotonin reuptake inhibitors (SSRIs), that block SERT function are known to affect food intake and body weight. Here, we provide genetic evidence that food intake and metabolism are regulated by separable mechanisms of SERT function. SERT-deficient mice ate less during both normal diet and high fat diet feeding. The reduced food intake was accompanied with markedly elevated plasma leptin levels. Despite reduced food intake, SERT-deficient mice exhibited glucose intolerance and insulin resistance, and progressively developed obesity and hepatic steatosis. Several lines of evidence indicate that the metabolic deficits of SERT-deficient mice are attributable to reduced insulin-sensitivity in peripheral tissues. First, SERT-deficient mice exhibited beta-cell hyperplasia and islet-mass expansion. Second, biochemical analyses revealed constitutively elevated JNK activity and diminished insulin-induced AKT activation in the liver of SERT-deficient mice. SERT-deficient mice exhibited hyper-JNK activity and hyperinsulinemia prior to the development of obesity. Third, enhancing AKT signaling by PTEN deficiency corrected glucose tolerance in SERT-deficient mice. These findings have potential implications for designing selective SERT drugs for weight control and the treatment of metabolic syndromes

A short history of the 5-HT2C receptor: from the choroid plexus to depression, obesity and addiction treatment

This paper is a personal account on the discovery and characterization of the 5-HT2C receptor (first known as the 5- HT1C receptor) over 30 years ago and how it translated into a number of unsuspected features for a G protein-coupled receptor (GPCR) and a diversity of clinical applications. The 5-HT2C receptor is one of the most intriguing members of the GPCR superfamily. Initially referred to as 5-HT1CR, the 5-HT2CR was discovered while studying the pharmacological features and the distribution of [3H]mesulergine-labelled sites, primarily in the brain using radioligand binding and slice autoradiography. Mesulergine (SDZ CU-085), was, at the time, best defined as a ligand with serotonergic and dopaminergic properties. Autoradiographic studies showed remarkably strong [3H]mesulergine-labelling to the rat choroid plexus. [3H]mesulergine-labelled sites had pharmacological properties different from, at the time, known or purported 5-HT receptors. In spite of similarities with 5-HT2 binding, the new binding site was called 5-HT1C because of its very high affinity for 5-HT itself. Within the following 10 years, the 5-HT1CR (later named 5- HT2C) was extensively characterised pharmacologically, anatomically and functionally: it was one of the first 5-HT receptors to be sequenced and cloned. The 5-HT2CR is a GPCR, with a very complex gene structure. It constitutes a rarity in theGPCR family: many 5-HT2CR variants exist, especially in humans, due to RNA editing, in addition to a few 5-HT2CR splice variants. Intense research led to therapeutically active 5-HT2C receptor ligands, both antagonists (or inverse agonists) and agonists: keeping in mind that a number of antidepressants and antipsychotics are 5- HT2CR antagonists/inverse agonists. Agomelatine, a 5-HT2CR antagonist is registered for the treatment of major depression. The agonist Lorcaserin is registered for the treatment of aspects of obesity and has further potential in addiction, especially nicotine/ smoking. There is good evidence that the 5-HT2CR is involved in spinal cord injury-induced spasms of the lower limbs, which can be treated with 5-HT2CR antagonists/inverse agonists such as cyproheptadine or SB206553. The 5-HT2CR may play a role in schizophrenia and epilepsy. Vabicaserin, a 5-HT2CR agonist has been in development for the treatment of schizophrenia and obesity, but was stopped. As is common, there is potential for further indications for 5-HT2CR ligands, as suggested by a number of preclinical and/or genome-wide association studies (GWAS) on depression, suicide, sexual dysfunction, addictions and obesity. The 5-HT2CR is clearly affected by a number of established antidepressants/antipsychotics and may be one of the culprits in antipsychotic-induced weight gain

Tailoring pharmacotherapy to specific eating behaviours in obesity: Can recommendations for personalised therapy be made from the current data?

Pharmacotherapy provides an adjunct to behaviour modification in the management of obesity. There are a number of new drug therapies purportedly targeting appetite; liraglutide, and bupropion/naltrexone, which are European Medicines Agency and US Food and Drug Administration (FDA) approved, and lorcaserin and phentermine/topiramate, which have FDA approval only. Each of the six drugs, used singly or in combination, has distinct pharmacological, and presumably distinct behavioural, mechanisms of action, thus the potential to provide defined therapeutic options to personalise the management of obesity. Yet, with regard to pharmacotherapy for obesity, we are far from true personalised medicine. We review the limited mechanistic data with four mono and combination pharmacotherapies, to assess the potential for tailoring their use to target specific obesogenic behaviours. Potential treatment options are considered, but in the absence of adequate research in respect to effects of these drugs on eating behaviour, neural activity and psychological substrates that underlie poorly controlled eating, we are far from definitive therapeutic recommendations. Specific mechanistic studies and broader behavioural phenotyping, possibly in conjunction with pharmacogenetic research, are required to characterise responders for distinct pharmacotherapeutic options