Issue 21 – Spring 2013

Deconstruction of a neural circuit for hunger atasoy D, Betley JN, Su hh & Sternson Sm Nature 2012 488 172–177 coNTexT: hunger is a complex behavioural state that elicits intense food seeking and consumption. These behaviours are rapidly recapitulated by activation of starvation-sensitive agouti-related peptide (aGrP) neurones, which present an entry point for reverse engineering neural circuits for hunger. meThoDS: here they mapped synaptic interactions of aGrP neurones with multiple cell populations in mice and probed the contribution of these distinct circuits to feeding behaviour using optogenetic and pharmacogenetic techniques. reSulTS: an inhibitory circuit with paraventricular hypothalamus (Pvh) neurones substantially accounted for acute aGrP neurone evoked eating, whereas two other prominent circuits were insufficient. Within the Pvh, they found that aGrP neurones target and inhibit oxytocin neurones, a small population that is selectively lost in Prader Willi syndrome, a condition involving insatiable hunger. coNcluSIoNS: By developing strategies for evaluating molecularly defined circuits, this paper shows that aGrP neurone suppression of oxytocin neurones is critical for evoked feeding. These experiments reveal a new neural circuit that regulates hunger state and pathways associated with over-eating disorders. COMMENTARY by Ze’ev Hochberg It was known that stimulation of the agouti-related peptide (aGrP) neurones evokes hunger and its behavioural responses: an intense search for food and hedonic eating. If starvation-sensitive neurones and behaviours can be elicited by a single molecule, aGrP, then genetic manipulation allows for ‘reverse engineering’ of the neural circuit for hunger. Stimulation of aGrP-expressing neurones by optogenetics and pharmacogenetics is shown here to suppress oxytocin-releasing neurones. It was previously reported that oxytocin-releasing neurones are lost in Prader-Willi syndrome. It follows that the inhibitory circuit involving oxytocin neurones is a prerequisite for aGrP-expressing neurone-evoked eating. Thus, here we have a previously unknown neural circuit in the regulation of hunger and its behavioural responses, which may be associated with over-eating disorders that we now call hypothalamic obesity. Efficacy and safety of lorcaserin in obese adults: a meta-analysis of 1-year randomised controlled trials (RCTs) and narrative review on short-term RCTs chan eW, he Y, chui cS, Wong aY, lau Wc & Wong Ic Obesity Reviews 2013 Jan 21. doi: 10.1111/obr.12015. coNTexT: lorcaserin is a new anti-obesity drug recently approved by the uS Food and Drug administration. meThoDS: This was a systematic review and meta-analysis of randomised controlled trials (rcTs) to evaluate the association of lorcaserin therapy with weight loss and adverse events in obese adults (18-65 years old). reSulTS: Weight loss of 3.23 kg (95% confidence interval [cI]: 2.70, 3.75) and body mass index reduction of 1.16 kg m-2 (95% cI: 0.98, 1.34) was observed compared with placebo in rcTs of 1 year duration. The use of lorcaserin for 8 and 12 weeks reduced weight by 1.60 kg (95% cI: 0.34, 2.86) and 2.9 kg (95% cI: 2.2, 3.5) respectively. In comparison with placebo, lorcaserin decreased waist circumference, blood pressure, total cholesterol, low-density lipoprotein-cholesterol and triglycerides. however, it did not statistically affect heart rate or high-density lipoprotein-cholesterol. headache, nausea and dizziness were found to be significantly higher in the patients receiving lorcaserin than in patients receiving placebo, whereas diarrhoea is no more likely than in patients receiving placebo. coNcluSIoN: lorcaserin achieves modest weight loss and appears to be well-tolerated. clinical and pharmacovigilance studies with longer study duration are needed to inform us of the long-term efficacy and safety of lorcaserin. COMMENTARY by Ze’ev Hochberg In spite of the growing burden of obesity worldwide, anti-obesity drug development and approval have lagged behind. lorcaserin has been in trials for several years now, and is suggested to induce satiety by a selective agonistic effect on the serotonin 5-hT2c receptor. It deserves special attention as it was recently approved by the uS Food and Drug administration (FDa). It was previously rejected by the FDa because of evidence that it increased cancer incidence in rats, and because of its modest efficacy (loss of 3% body weight after 1 year of treatment). The FDa advisory panel has now concluded that the cancer findings did not apply to humans, and our desperation has reached a state when even modest efficacy is welcome. Since the 2012 Yearbook, the FDa has also approved Qsymia, a combination of two older drugs, phentermine and topiramate, that reduces hunger by targeting different neurotransmitter systems, mainly norepinephrine but also dopamine and serotonin. Qsymia is more potent that lorcaserin (an average of 8.9% at the highest dose compared with placebo), yet it may cause more serious side effects, including an increased heart rate and increased risk of birth defects. The FDa was convinced that the benefits outweigh the risks. These are not perfect drugs. a healthy lifestyle and low carbohydrate diets work better when they are introduced; it is only that we fail to introduce them Training for North Africa The eSPe maGhreB School PromoTeS the training of young paediatric endocrinologists in the French-speaking countries of North africa and from other parts of africa such as cameroon. The scheme was founded in recognition of the underdevelopment of paediatric endocrinology in these countries, and because the language barrier makes it difficult for paediatricians in these areas to attend eSPe educational activities such as the Winter and Summer Schools. The eSPe maghreb School began a 3-year teaching programme in october 2011 in morocco. Subsequently, 6 students spent between 10 weeks and 1 year training in paediatric endocrinology at european centres during 2012 (by means of eSPe clinical Fellowships), while paediatric endocrinologists from the maghreb School also successfully presented at the eSPe annual meeting. The 2nd eSPe maghreb School was held in Tunisia in December 2012 with 26 students (50% of whom had attended the 1st eSPe maghreb School). The 4½ day course had an extended programme, including topics that were not covered in detail previously, such as growth, thyroid, disorders of sex development, diabetes mellitus, obesity, pituitary and adrenals. The teaching comprised interactive lectures, case presentations from the students and teachers, a small group of workshops on proposal research projects from students, and presentation of selected projects to the plenum. all participants worked hard from 8.00 am to 8.30 pm! The programme was supported by a faculty consisting of six members of eSPe and teachers from the three maghreb countries, algeria, morocco and Tunisia. maghreb School participants also have access to a web-based French educational programme, where they can refer to slides of the conferences and case presentations. The next eSPe maghreb School will be in algeria (20–25 November 2013). application details are at www.eurospe.org/education/ education_maghrebProject.html. We are extremely grateful to Pfizer, who have funded the programme, and have kindly agreed to sponsor another 3-year cycle of teaching. The eSPe maghreb project will have huge benefits in terms of developing a paediatric endocrine infrastructure, with effective networks for research and development, in the North african countries