IMPROVE 2022 International Meeting on Pathway-Related Obesity: Vision of Excellence.

Nearly 90 clinicians and researchers from around the world attended the first IMPROVE 2022 International Meeting on Pathway-Related Obesity. Delegates attended in person or online from across Europe, Argentina and Israel to hear the latest scientific and clinical developments in hyperphagia and severe, early-onset obesity, and set out a vision of excellence for the future for improving the diagnosis, treatment, and care of patients with melanocortin-4 receptor (MC4R) pathway-related obesity. The meeting co-chair Peter Kühnen, Charité Universitätsmedizin Berlin, Germany, indicated that change was needed with the rapidly increasing prevalence of obesity and the associated complications to improve the understanding of the underlying mechanisms and acknowledge that monogenic forms of obesity can play an important role, providing insights that can be applied to a wider group of patients with obesity. World-leading experts presented the latest research and led discussions on the underlying science of obesity, diagnosis (including clinical and genetic approaches such as the role of defective MC4R signalling), and emerging clinical data and research with targeted pharmacological approaches. The aim of the meeting was to agree on the questions that needed to be addressed in future research and to ensure that optimised diagnostic work-up was used with new genetic testing tools becoming available. This should aid the planning of new evidence-based treatment strategies for the future, as explained by co-chair Martin Wabitsch, Ulm University Medical Center, Germany.

Obesity and thinness: insights from genetics.

Genetic disruption of key molecular components of the hypothalamic leptin-melanocortin pathway causes severe obesity in mice and humans. Physiological studies in people who carry these mutations have shown that the adipose tissue-derived hormone leptin primarily acts to defend against starvation. A lack of leptin causes an intense drive to eat and increases the rewarding properties of food, demonstrating that human appetite has a strong biological basis. Genetic studies in clinical- and population-based cohorts of people with obesity or thinness continue to provide new insights into the physiological mechanisms involved in weight regulation and identify molecular targets for weight loss therapy. This article is part of a discussion meeting issue 'Causes of obesity: theories, conjectures and evidence (Part II)'.

Halloysite nanotubes-cellulose ether based biocomposite matrix, a potential sustained release system for BCS class I drug verapamil hydrochloride: Compression characterization, in-vitro release kinetics, and in-vivo mechanistic physiologically based pharmacokinetic modeling studies.

This study investigated the ability of natural nanotubular clay mineral (Halloysite) and cellulose ether based biocomposite matrix as a controlled release agent for Verapamil HCl (BCS Class-I). Drug-loaded halloysite was prepared and tablet formulations were designed by varying amount of hydroxy propyl methyl cellulose (HPMC K4M). Physical characterization was carried out using SEM, FTIR, and DSC. Tabletability profiles were evaluated using USP1062 guidelines. Drug release kinetics were studied, and physiologically based pharmacokinetic (PBPK) modeling was performed. Compressed tablets possess satisfactory yield pressure of 625 MPa with adequate hardness and disintegration within 30 min. The initial release of the drug was due to surface drug on tablets, while the prolonged release at later time points (around 80 % drug release at 12 h) were due to halloysite loading. The FTIR spectra exhibited electrostatic attraction between the positively charged drug and the negatively charged Si-O-Si functional group of halloysite, while the thermogram showed Verapamil HCl melting point at ~146 °C with enthalpy change of -126.82 J/g. PBPK modeling exhibited PK parameters of optimized matrix formulation (VER-HNT3%) comparable to in vivo data. The study effectively demonstrated the potential of prepared biocomposite matrix as a commercially viable oral release modifying agent for highly soluble drugs.

Natural History of Obesity Due to POMC, PCSK1, and LEPR Deficiency and the Impact of Setmelanotide.

Context: Rare homozygous or biallelic variants in POMC, PCSK1, and LEPR can disrupt signaling through the melanocortin-4 receptor (MC4R) pathway, resulting in hyperphagia and severe early-onset obesity. In pivotal Phase 3 clinical trials, treatment with the MC4R agonist setmelanotide reduced hunger and weight in patients with obesity due to proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency. Objective: To characterize the historical weight trajectory in these patients. Methods: This analysis included data from 2 pivotal single-arm, open-label, Phase 3 trials (NCT02896192, NCT03287960). These were multicenter trials. Patients had obesity due to POMC/PCSK1 or LEPR deficiency. During the trial, patients were treated with setmelanotide. Historical data on measured weight and height were obtained during screening. Results: A total of 17 patients (POMC, n = 8; PCSK1, n = 1; LEPR, n = 8) with historical weight and height data were included in this analysis. Before setmelanotide treatment, patients with obesity due to POMC/PCSK1 or LEPR deficiency were above the 95th percentile for weight throughout childhood, demonstrated continuous weight gain, and did not show long-term weight loss upon interventions (eg, diet, surgery, exercise). Setmelanotide treatment attenuated weight and body mass index trajectories over the observation period of 1 year. Conclusion: In patients with POMC, PCSK1, or LEPR deficiency, traditional interventions for weight loss had limited impact on the trajectory of severe early-onset obesity. However, setmelanotide treatment attenuated weight and body mass index trajectories and led to weight loss associated with health benefits in most individuals.

Central obesity is selectively associated with cerebral gray matter atrophy in 15,634 subjects in the UK Biobank.

BACKGROUND: Obesity is a risk factor for both cardiovascular disease and dementia, but the mechanisms underlying this association are not fully understood. We examined associations between obesity, including estimates of central obesity using different modalities, with brain gray matter (GM) volume in the UK Biobank, a large population-based cohort study. METHODS: To determine relationships between obesity and the brain we used brain MRI, abdominal MRI, dual-energy X-ray absorptiometry (DXA), and bioelectric whole-body impedance. We determined whether obesity was associated with any change in brain gray matter (GM) and white matter (WM) volumes, and brain network efficiency derived from the structural connectome (wiring of the brain) as determined from diffusion-tensor MRI tractography. Using Waist-Hip Ratio (WHR), abdominal MRI and DXA we determined whether any associations were primarily with central rather than peripheral obesity, and whether associations were mediated by known cardiovascular risk factors. We analyzed brain MRI data from 15,634. RESULTS: We found that central obesity, was associated with decreased GM volume (anthropometric data: p = 6.7 × 10-16, DXA: p = 8.3 × 10-81, abdominal MRI: p = 0.0006). Regional associations were found between central obesity and with specific GM subcortical nuclei (thalamus, caudate, pallidum, nucleus accumbens). In contrast, no associations were found with WM volume or structure, or brain network efficiency. The effects of central obesity on GM volume were not mediated by C-reactive protein or blood pressure, glucose, lipids. CONCLUSIONS: Central body-fat distribution rather than the overall body-fat percentage is associated with gray matter changes in people with obesity. Further work is required to identify the factors that mediate the association between central obesity and GM atrophy.

Frequency and impact of slow flow / no flow in primary percutaneous coronary intervention.

OBJECTIVE: To determine the frequency of slow/no flow in primary percutaneous coronary intervention, to know the clinical and angiographical predictors of the phenomenon, and to investigate the immediate impact of slow/no flow on haemodnamics. METHOD: The cross-sectional study was conducted at the National Institute of Cardiovascular Diseases, Karachi, from June 2018 to July 2019, and comprised patients presenting with ST elevation myocardial infarction who underwent primary percutaneous coronary intervention. Demographic and clinical details of the patients were recorded. The antegrade flow was assessed and determined using the thrombolysis in myocardial infarction criterion. Patients were assessed for the occurrence, predictors and impact of slow/no flow. Data was analysed using SPSS 21. RESULTS: Of the 559 patients, 441(78.9%) were males. The overall mean age of the sample was 55.86±11.07 years. Angiographical slow/no flow during the procedure occurred in 53 (9.5%) patients, while normal flow was achieved in 506(90.5%). The thrombolysis in myocardial infarction grade in the affected patients was 0 in 10(1.8%), 1 in 15(2.7%), and 2 in 28(5%) patients. Smoking status, prior myocardial infarction, prior heart failure, no history of pre-infarct angina, cerebrovascular disease, New York Heart Association class III or IV, Killip class III or IV, and lower ejection fraction were significant predictors of slow/no flow (p<0.05). The angiographical and procedural predictors were total occlusion of culprit vessel and high thrombus burden (p<0.05). Direct stenting and use of bare metal stents had significantly less chance of developing slow/no flow (p<0.05). The most common immediate impact was hypotension 26(49.1%) and bradyarrhythmia 5(9.4%). However, 2(3.8%) patients developed haemodnamically unstable ventricular tachycardia that resulted in mortality. CONCLUSIONS: Predictors on the basis of history and angiographical features can be taken into account to anticipate the occurrence of slow/no flow phenomenon.

Modification and validation of liquid chromatographic method for the quantification of ciprofloxacin in human plasma and its application to a bioavailability study.

A new simple, accurate, precise and sensitive liquid chromatographic method for the analysis of Ciprofloxacin in human plasma, suitable for quantification of drug was developed and validated using HPLC-UV method. The analyte was chromatographically separated from endogenous plasma components on a C-18 reversed phase column (5µm, 25cm × 0.46cm) and detected at 278nm. The sample pretreatment was carried out with acetonitrile on 200µl of plasma. The Lower limit of quantification (LLOQ) was 0.04 µg/ml with linearity in the range 0.04-4 µg/ml and coefficient of correlation value (R2)>0.995. The method was successfully validated as per current FDA guidance for necessary parameters and applied to a pilot bioavailability study conducted on six healthy volunteers with marketed Ciprofloxacin 250mg immediate release tablets. The plasma concentrations were subjected to non-compartmental analysis for calculation of pharmacokinetic parameters like Cmax, Tmax, AUCo-t, AUC 0-∞ and t½ etc. The mean values of Cmax and Tmax were found to be 1.35±0.09µg/ml and 1.25±0.27h respectively while for other pharmacokinetic parameters including AUCo-t, AUC0-∞ were found to be 5.98±0.96 µg/ml×h and 6.34±1.07µg/ml×h. The drug exhibited half-life (t½) of 3.94±0.33h. The obtained results proved the suitability of the method for routine pharmacokinetic studies of Ciprofloxacin.

Investigating Halloysite Nanotubes as a Potential Platform for Oral Modified Delivery of Different BCS Class Drugs: Characterization, Optimization, and Evaluation of Drug Release Kinetics.

PURPOSE: This study systematically investigated the potential of four model drugs (verapamil HCl, flurbiprofen, atenolol, and furosemide), each belonging to a different class of Biopharmaceutics Classification Systems (BCS) to be developed into oral modified release dosage forms after loading with halloysite nanotubes (HNTs). METHODS: The drugs were studied for their loading (mass gain %) by varying solvent system, method, pH, and ratios of loading into the nanotubes using D-optimal split-plot design with the help of Design Expert software. Drug-loaded halloysites were characterized by XRD, DTA, FTIR, SEM, and HPLC-UV-based assay procedures. Dissolution studies were also performed in dissolution media with pH 1.2, 4.5, and 6.8. Moreover, the optimized samples were evaluated under stress stability conditions for determining prospects for the development of oral dosage forms. RESULTS: As confirmed with the results of XRD and DTA, the drugs were found to be converted into amorphous form after loading with halloysite (HNTs). The drugs were loaded in the range of ~7-9% for the four drugs, with agitation providing satisfactory and equivalent loading as compared to vacuum plus agitation based reported methods. FTIR results revealed either only weak electrostatic (verapamil HCl and flurbiprofen) or no interaction with the surface structure of the HNTs. The dissolution profiling depicted significantly retarded release of drugs with Fickian diffusion from a polydisperse system as a model that suits well for the development of oral dosage forms. HPLC-UV-based assay indicated that except furosemide (BCS class IV), the other three drugs are quite suitable for development for oral dosage forms. CONCLUSION: The four drugs investigated undergo phase transformation with HNTs. While agitation is an optimum method for loading drugs with various physicochemical attributes into HNTs; solvent system, loading ratios and pH play an important role in the loading efficiency respective to the drug properties. The study supports the capability of developing HNT-based modified release oral dosage forms for drugs with high solubility.

Glycated haemoglobin association with severity of thrombus burden in non-diabetic versus diabetic patients with ST-elevation myocardial infarction.

OBJECTIVE: To determine and compare the relationship between glycated haemoglobin level on admission and the angiographic thrombus burden in diabetic and non-diabetic patients with ST-segment elevation myocardial infarction. METHODS: The cross-sectional study was conducted at the National Institute of Cardiovascular Diseases, Karachi, from June 2018 to July 2019, and comprised patients presenting with ST-elevation myocardial infarction. Demographic details and self-reported duration of diabetes was recorded. The thrombus burden was assessed on angiography classifying 0 = no thrombus, 1 = possible thrombus, 2 = small thrombus, 3 = moderate thrombus, 4 = large thrombus, and 5 = total occlusion. The data was analysed using SPSS 21. RESULTS: Of the 212 patients, 173(81.6%) were men, and 75(35.4%) had body mass index ≥30kg/m2. The overall mean age of the sample was 54.62±11.75 years. Known diabetic cases were 82(38.7%) and 20(24.4%) were insulin-dependent. Mean glycated haemoglobin level was 7.18±2.03% and 96(45.3%) patients had the critical value >6.5%. Pre-procedure thrombus score in 118(55.7%) patients was 3 and 4 and 57(26.9%) had total occlusion. A significant relationship between glycated haemoglobin level and thrombus score was found in the overall sample as well as in diabetic and non-diabetic groups (p<0.001). CONCLUSIONS: Increased glycated haemoglobin level was found to have a positive correlation with thrombus score in both diabetic and non-diabetic patients.

Quality by Design (QbD)-Based Numerical and Graphical Optimization Technique for the Development of Osmotic Pump Controlled-Release Metoclopramide HCl Tablets.

PURPOSE: To develop the osmotically controlled-release gastroprokinetic metoclopramide HCl tablets, using quality by design (QbD)-numerical and graphical optimization technique for the treatment of gastroparesis and prophylaxis of delayed nausea and vomiting induced by low-high emetogenic chemotherapy. METHODS: Formulations were designed by central composite design using Design Expert version 11.0.0, with osmogen concentration (X1), orifice size (X2), and tablet weight gain after coating (X3) as input and in-vitro drug release at 1hr. (Y1), 6 hrs. (Y2), and 12 hrs. (Y3), and the regression coefficient of drug release data fitted to zero-order, RSQ zero (Y4) as output variables. Core tablets prepared by direct compression were coated with Opadry® CA. The experimental design was validated by the polynomial equation. A correlation between predicted and observed values was evaluated by random checkpoint analysis. The optimized formulations were characterized for drug release, pH effect, osmolarity, agitation intensity, surface morphology, and stability study, and were subjected to accelerated studies according to ICH guidelines. RESULTS: The interaction charts and response surface plots deduced a significant simultaneous effect of X variables on in vitro drug release and RSQ zero. The numerical optimization model predicted >90% drug release with X1 (13.30%), X2 (0.6 mm), and X3 (7.96%). Random checkpoint analysis showed a good correlation between predicted and observed values. The optimized formulation followed zero-order kinetics (r2=0.9703) drug release. Shelf life calculated was 2.8 years as per ICH guidelines. CONCLUSION: The QbD-based approach was found successful in developing controlled release osmotic tablets of metoclopramide HCl, for reducing the dosage frequency, better emetic control, and improve patient compliance.

Drug utilization evaluation of Piperacillin/Tazobactam: A prospective and cross sectional investigation in tertiary care setup.

Drug utilization evaluation (DUE) is an arrangement of continuous, orderly, criteria-based assessment of medication utilizes to guarantee that medicines are utilized suitably. In the event that treatment is regarded to be improper, provider and patient intervention may be important to optimize therapeutic efficacy. In the present study drug utilization evaluation of Piperacillin/Tazobactam was carried out in prospective manner. A well structured data collection form was constructed to collect the related information regarding demographic, clinical use, indication, culture sensitivity criteria, outcomes of therapy, renal impairment cases of dose adjustments and appropriate use. Results of chi square indicated insignificant relationship between gender and as p value was found to be p=0.446 and 0.111 for use of drug alone and in combination. Similarly insignificant relationship between gender and use of drug in combination with other antibiotics as p value was found to be p=0.111. It was found that from 61-70 years (Therapeutic Effectiveness; n=12, 9.37%), (Therapeutic Failure; n=10, 45.45%) and mortality (n=1, 50%) were quite higher. The prescription pattern was in accordance with standard guidelines. Study indicated need to elevate prescribers to pursue generic prescribing and rationally utilize antibiotics to avert advancement of resistance at the level of hospital and community. These sorts of studies are valuable for acquiring data about medication utilize designs and for recognizing inconceivable expense of medicines.

Potential role of gender specific effect of leptin receptor deficiency in an extended consanguineous family with severe early-onset obesity.

Congenital Leptin receptor (LEPR) deficiency is a rare genetic cause of early-onset morbid obesity characterised by severe early onset obesity, major hyperphagia, hypogonadotropic hypogonadism and immune and neuroendocrine/metabolic dysfunction. We identified a homozygous loss-of-function mutation, NM_002303.5:c.464 T > G; p.(Tyr155*), in the LEPR in an extended consanguineous family with multiple individuals affected by early-onset severe obesity and hyperphagia. Interestingly, the LEPR-deficient adult females have extremely high body mass index (BMI) with hypogonadal infertility, the BMI of the affected males began to decline around the onset of puberty (13-15 years) with fertility being preserved. These findings lead to the speculation that LEPR deficiency may have a gender-specific effect on the regulation of body weight. In order to elucidate gender-specific effects of LEPR deficiency on reproduction further investigations are needed. The limitations of this study are that our conclusion is based on observations of two males and two females. Further LEPR deficient males and females are required for comparison in order to support this finding more confidently.

Impact of different organic acids on solubility enhancement of cefpodxime proxetil immediate release tablet and its stability studies.

Cefpodoxime proxetil is a third generation cephalosporin antibiotic demonstrates pH dependent solubility and is highly soluble only in acidic pH. The purpose of this investigation was to design and develop immediate release tablets of cefpodoxime proxetil by direct compression method and determine the effect of different solid buffers (organic acids) such as fumaric acid (formulations F1-F4), maleic acid (formulations M1-M4) and citric acid (formulations C1-C4) by using cefpodoxime and acid in the ratios of 4:1, 2:1, 1:1 and 1:2 to achieve pH-independent release of the drug. Physical parameters and assay were found to be within the acceptable range as prescribed in USP 36 / NF 31. In vitro dissolution studies of each formulation were performed in distilled water, USP dissolution medium, HCl buffer solution of pH 1.2, phosphate buffer solutions of pH 4.5 and 6.8 to observe the drug release. The formulations F3, F4, M4 were selected for film coating on the basis of better drug release profile, to protect the drug from chemical degradation through hydrolysis. Film coated formulation F3, F4 and M4 showed a remarkable in vitro release of the drug (72.88±0.43 to 92.67±0.71%) within 30min of observation in all dissolution media and further evaluated by model independent and model dependent approaches. The drug release was found to be best fit to Weibull model as highest r2adjusted (0.924-0.998) and lowest AIC (18.416-54.710) values were obtained in all dissolution media. R Gui® applied for stability studies of F3 and F4 formulations, showing shelf lives of 28 & 27months at ambient and 33 months at accelerated temperatures. Formulation F4 was chosen as best formulation on the basis of physical properties, highest dissolution rate and stability studies.

Obesity associated with increased brain age from midlife.

Common mechanisms in aging and obesity are hypothesized to increase susceptibility to neurodegeneration, however, direct evidence in support of this hypothesis is lacking. We therefore performed a cross-sectional analysis of magnetic resonance image-based brain structure on a population-based cohort of healthy adults. Study participants were originally part of the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) and included 527 individuals aged 20-87 years. Cortical reconstruction techniques were used to generate measures of whole-brain cerebral white-matter volume, cortical thickness, and surface area. Results indicated that cerebral white-matter volume in overweight and obese individuals was associated with a greater degree of atrophy, with maximal effects in middle-age corresponding to an estimated increase of brain age of 10 years. There were no similar body mass index-related changes in cortical parameters. This study suggests that at a population level, obesity may increase the risk of neurodegeneration.

Mutation in human selenocysteine transfer RNA selectively disrupts selenoprotein synthesis.

Selenium is a trace element that is essential for human health and is incorporated into more than 25 human selenocysteine-containing (Sec-containing) proteins via unique Sec-insertion machinery that includes a specific, nuclear genome-encoded, transfer RNA (tRNA[Ser]Sec). Here, we have identified a human tRNA[Ser]Sec mutation in a proband who presented with a variety of symptoms, including abdominal pain, fatigue, muscle weakness, and low plasma levels of selenium. This mutation resulted in a marked reduction in expression of stress-related, but not housekeeping, selenoproteins. Evaluation of primary cells from the homozygous proband and a heterozygous parent indicated that the observed deficit in stress-related selenoprotein production is likely mediated by reduced expression and diminished 2'-O-methylribosylation at uridine 34 in mutant tRNA[Ser]Sec. Moreover, this methylribosylation defect was restored by cellular complementation with normal tRNA[Ser]Sec. This study identifies a tRNA mutation that selectively impairs synthesis of stress-related selenoproteins and demonstrates the importance of tRNA modification for normal selenoprotein synthesis.

Assessment of Eating Behavior Disturbance and Associated Neural Networks in Frontotemporal Dementia.

IMPORTANCE: Abnormal eating behaviors are common in patients with frontotemporal dementia (FTD), yet their exact prevalence, severity, and underlying biological mechanisms are not understood. OBJECTIVE: To define the severity of abnormal eating behavior and sucrose preference and their neural correlates in patients with behavioral variant FTD (bvFTD) and semantic dementia. DESIGN, SETTING, AND PARTICIPANTS: Forty-nine patients with dementia (19 with bvFTD, 15 with semantic dementia, and 15 with Alzheimer disease) were recruited, and their eating behavior was compared with that of 25 healthy controls. The study was conducted from November 1, 2013, through May 31, 2015, and data analyzed from June 1 to August 31, 2015. MAIN OUTCOMES AND MEASURES: Patients participated in an ad libitum breakfast test meal, and their total caloric intake and food preferences were measured. Changes in eating behavior were also measured using the Appetite and Eating Habits Questionnaire (APEHQ) and the Cambridge Behavioral Inventory (CBI). Sucrose preference was tested by measuring liking ratings of 3 desserts of varying sucrose content (A: 26%, B: 39%, C: 60%). Voxel-based morphometry analysis of whole-brain 3-T high-resolution brain magnetic resonance imaging was used to determine the gray matter density changes across groups and their relations to eating behaviors. RESULTS: Mean (SD) ages of patients in all 4 groups ranged from 62 (8.3) to 66 (8.4) years. At the ad libitum breakfast test meal, all patients with bvFTD had increased total caloric intake (mean, 1344 calories) compared with the Alzheimer disease (mean, 710 calories), semantic dementia (mean, 573 calories), and control groups (mean, 603 calories) (P < .001). Patients with bvFTD and semantic dementia had a strong sucrose preference compared with the other groups. Increased caloric intake correlated with atrophy in discrete neural networks that differed between patients with bvFTD and semantic dementia but included the cingulate cortices, thalami, and cerebellum in patients with bvFTD, with the addition of the orbitofrontal cortices and nucleus accumbens in patients with semantic dementia. A distributed network of neural correlates was associated with sucrose preference in patients with FTD. CONCLUSIONS AND RELEVANCE: Marked hyperphagia is restricted to bvFTD, present in all patients with this diagnosis, and supports its diagnostic value. Differing neural networks control eating behavior in patients with bvFTD and semantic dementia and are likely responsible for the differences seen, with a similar network controlling sucrose preference. These networks share structures that control cognitive-reward, autonomic, neuroendocrine, and visual modulation of eating behavior. Delineating the neural networks involved in mediating these changes in eating behavior may enable treatment of these features in patients with complex medical needs and aid in our understanding of structures that control eating behavior in patients with FTD and healthy individuals.

Amyotrophic lateral sclerosis and frontotemporal dementia: distinct and overlapping changes in eating behaviour and metabolism.

Metabolic changes incorporating fluctuations in weight, insulin resistance, and cholesterol concentrations have been identified in several neurodegenerative disorders. Whether these changes result from the neurodegenerative process affecting brain regions necessary for metabolic regulation or whether they drive the degenerative process is unknown. Emerging evidence from epidemiological, clinical, pathological, and experimental studies emphasises a range of changes in eating behaviours and metabolism in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In ALS, metabolic changes have been linked to disease progression and prognosis. Furthermore, changes in eating behaviour that affect metabolism have been incorporated into the diagnostic criteria for FTD, which has some clinical and pathological overlap with ALS. Whether the distinct and shared metabolic and eating changes represent a component of the proposed spectrum of the two diseases is an intriguing possibility. Moreover, future research should aim to unravel the complex connections between eating, metabolism, and neurodegeneration in ALS and FTD, and aim to understand the potential for targeting modifiable risk factors in disease development and progression.

Role of melanocortin signalling in the preference for dietary macronutrients in human beings.

BACKGROUND: Signalling though the melanocortin 4 receptor (MC4R), which is widely expressed in the hypothalamus, mediates food intake and macronutrient preference in rodents. Studies in patients with MC4R deficiency can provide insights into the role of this pathway in man. We investigated the role of melanocortin signalling in fat and sucrose preference in human beings by studying patients with loss of function mutations in MC4R. METHODS: We studied 24 obese patients with MC4R deficiency, and 80 healthy controls (40 obese, 40 lean). We used an ad-libitum meal protocol consisting of three meals covertly manipulated to provide 20% (low), 40% (medium), and 60% (high) fat content. We used the same procedure for meals manipulated to provide 8% (low), 26% (medium), and 54% (high) sucrose content. We measured food intake and rated liking for the meals with visual analogue scores. Data were analysed by ANOVA and Tukey's post-hoc tests or a linear mixed-effects model with an interaction term for study group and study meal when appropriate. FINDINGS: Although the liking of the three different fat meals did not differ between the three groups, patients with MC4R mutations consumed 95% more of the high fat meal than did lean controls and 65% more of the high fat meal than did obese controls (p=0·0222 for the interaction of group by meal). By contrast, although liking ratings for low and medium sucrose meals were comparable in the individuals with MC4R deficiency, liking ratings for the high sucrose meal were significantly reduced (p=0·0252 in linear mixed-effects model, intercept 57·8, MC4R group factor -26·2, factors in the model for MC4R-low sucrose 27·7, MC4R-medium sucrose 22·6). Similarly, patients with MC4R deficiency consumed less of all three sucrose meals than did healthy controls (p=0·0064). INTERPRETATION: Our study shows that the central melanocortin system has divergent effects on macronutrient preference and intake in human beings. FUNDING: Wellcome Trust, NIHR Cambridge Biomedical Research Centre, Bernard Wolfe Health Neuroscience Fund, NeuroFAST consortium, which is funded by the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement no 245009.

Food reward system: current perspectives and future research needs.

This article reviews current research and cross-disciplinary perspectives on the neuroscience of food reward in animals and humans, examines the scientific hypothesis of food addiction, discusses methodological and terminology challenges, and identifies knowledge gaps and future research needs. Topics addressed herein include the role of reward and hedonic aspects in the regulation of food intake, neuroanatomy and neurobiology of the reward system in animals and humans, responsivity of the brain reward system to palatable foods and drugs, translation of craving versus addiction, and cognitive control of food reward. The content is based on a workshop held in 2013 by the North American Branch of the International Life Sciences Institute.