Two Adverse Early Life Events Induce Differential Changes in Brain CRH and Serotonin Systems in Rats along with Hyperphagia and Depression.

BACKGROUND: Different types of stress inflicted in early stages of life elevate the risk, among adult animals and humans, to develop disturbed emotional-associated behaviors, such as hyperphagia or depression. Early-life stressed (ELS) adults present hyperactivity of the hypothalamus-pituitary-adrenal (HPA) axis, which is a risk factor associated with mood disorders. However, the prevalence of hyperphagia (17%) and depression (50%) is variable among adults that experienced ELS, suggesting that the nature, intensity, and chronicity of the stress determines the specific behavioral alteration that those individuals develop. METHODS: We analyzed corticosterone serum levels, Crh, GR, Crhr1 genes expression in the hypothalamic paraventricular nucleus, amygdala, and hippocampus due to their regulatory role on HPA axis in adult rats that experienced maternal separation (MS) or limited nesting material (LNM) stress; as well as the serotonergic system activity in the same regions given its association with the corticotropin-releasing hormone (CRH) pathway functioning and with the hyperphagia and depression development. RESULTS: Alterations in dams' maternal care provoked an unresponsive or hyper-responsive HPA axis function to an acute stress in MS and LNM adults, respectively. The differential changes in amygdala and hippocampal CRH system seemed compensating alterations to the hypothalamic desensitized glucocorticoids receptor (GR) in MS or hypersensitive in LNM. However, both adult animals developed hyperphagia and depression-like behavior when subjected to the forced-swimming test, which helps to understand that both hypo and hypercortisolemic patients present those disorders. CONCLUSION: Different ELS types induce neuroendocrine, brain CRH and 5-hydroxytriptamine (5-HT) systems' alterations that may interact converging to develop similar maladaptive behaviors.

Separate gut-brain circuits for fat and sugar reinforcement combine to promote overeating.

Food is a powerful natural reinforcer that guides feeding decisions. The vagus nerve conveys internal sensory information from the gut to the brain about nutritional value; however, the cellular and molecular basis of macronutrient-specific reward circuits is poorly understood. Here, we monitor in vivo calcium dynamics to provide direct evidence of independent vagal sensing pathways for the detection of dietary fats and sugars. Using activity-dependent genetic capture of vagal neurons activated in response to gut infusions of nutrients, we demonstrate the existence of separate gut-brain circuits for fat and sugar sensing that are necessary and sufficient for nutrient-specific reinforcement. Even when controlling for calories, combined activation of fat and sugar circuits increases nigrostriatal dopamine release and overeating compared with fat or sugar alone. This work provides new insights into the complex sensory circuitry that mediates motivated behavior and suggests that a subconscious internal drive to consume obesogenic diets (e.g., those high in both fat and sugar) may impede conscious dieting efforts.

A human obesity-associated MC4R mutation with defective Gq/11α signaling leads to hyperphagia in mice.

Melanocortin 4 receptor (MC4R) mutations are the most common cause of human monogenic obesity and are associated with hyperphagia and increased linear growth. While MC4R is known to activate Gsα/cAMP signaling, a substantial proportion of obesity-associated MC4R mutations do not affect MC4R/Gsα signaling. To further explore the role of specific MC4R signaling pathways in the regulation of energy balance, we examined the signaling properties of one such mutant, MC4R (F51L), as well as the metabolic consequences of MC4RF51L mutation in mice. The MC4RF51L mutation produced a specific defect in MC4R/Gq/11α signaling and led to obesity, hyperphagia, and increased linear growth in mice. The ability of a melanocortin agonist to acutely inhibit food intake when delivered to the paraventricular nucleus (PVN) was lost in MC4RF51L mice, as well as in WT mice in which a specific Gq/11α inhibitor was delivered to the PVN; this provided evidence that a Gsα-independent signaling pathway, namely Gq/11α, significantly contributes to the actions of MC4R on food intake and linear growth. These results suggest that a biased MC4R agonist that primarily activates Gq/11α may be a potential agent to treat obesity with limited untoward cardiovascular and other side effects.

Microbiota-gut-brain axis drives overeating disorders.

Overeating disorders (ODs), usually stemming from dieting history and stress, remain a pervasive issue in contemporary society, with the pathological mechanisms largely unresolved. Here, we show that alterations in intestinal microbiota are responsible for the excessive intake of palatable foods in OD mice and patients with bulimia nervosa (BN). Stress combined with a history of dieting causes significant changes in the microbiota and the intestinal metabolism, which disinhibit the vagus nerve terminals in the gut and thereby lead to a subsequent hyperactivation of the gut-brain axis passing through the vagus, the solitary tract nucleus, and the paraventricular nucleus of the thalamus. The transplantation of a probiotic Faecalibacterium prausnitzii or dietary supplement of key metabolites restores the activity of the gut-to-brain pathway and thereby alleviates the OD symptoms. Thus, our study delineates how the microbiota-gut-brain axis mediates energy balance, unveils the underlying pathogenesis of the OD, and provides potential therapeutic strategies.

Regulation of Satiety by Bdnf-e2-Expressing Neurons through TrkB Activation in Ventromedial Hypothalamus.

The transcripts for Bdnf (brain-derived neurotrophic factor), driven by different promoters, are expressed in different brain regions to control different body functions. Specific promoter(s) that regulates energy balance remain unclear. We show that disruption of Bdnf promoters I and II but not IV and VI in mice (Bdnf-e1-/-, Bdnf-e2-/-) results in obesity. Whereas Bdnf-e1-/- exhibited impaired thermogenesis, Bdnf-e2-/- showed hyperphagia and reduced satiety before the onset of obesity. The Bdnf-e2 transcripts were primarily expressed in ventromedial hypothalamus (VMH), a nucleus known to regulate satiety. Re-expressing Bdnf-e2 transcript in VMH or chemogenetic activation of VMH neurons rescued the hyperphagia and obesity of Bdnf-e2-/- mice. Deletion of BDNF receptor TrkB in VMH neurons in wildtype mice resulted in hyperphagia and obesity, and infusion of TrkB agonistic antibody into VMH of Bdnf-e2-/- mice alleviated these phenotypes. Thus, Bdnf-e2-transcripts in VMH neurons play a key role in regulating energy intake and satiety through TrkB pathway.

Hypomethylation of the dopamine transporter (DAT) gene promoter is associated with hyperphagia-related behavior in Prader-Willi syndrome: A case-control study.

Prader-Willi syndrome (PWS), a neurodevelopmental disorder based on the loss of paternally derived but maternally imprinted genes on chromosome 15q11-13, is typically associated with hyperphagia-related behavior leading to massive obesity. Recently, there has been increasing evidence for dysregulated expression patterns of genes outside the PWS locus that influence the behavioral phenotype and for alterations in the dopaminergic system associated with weight regulation in PWS. In this study, we investigated the epigenetic regulation of the promoter regions of the dopamine transporter (DAT) and dopamine receptor D2 (DRD2) genes and their association with hyperphagia-related behavior in PWS. Methylation of the DAT and DRD2 promoter regions was examined by DNA bisulfite sequencing in 32 individuals with PWS and compared with a control group matched for sex, age, and body mass index (BMI). Hyperphagia-related behavior was assessed using the Hyperphagia Questionnaire for Clinical Trials (HQ-CT). Analysis by linear mixed models revealed a significant effect of factor group on mean DAT promoter methylation rate with decreased mean methylation in PWS (7.3 ± 0.4%) compared to controls (18.8 ± 0.6%), p < 0.001. In the PWS group, we further identified effects of HQ-CT score and BMI on DAT promoter methylation. Although also statistically significantly different (8.4 ± 0.2 in PWS, 10.5 ± 0.3 in controls, p < 0.001), DRD2 promoter methylation visually appeared to be evenly distributed between groups, raising concerns regarding a biological effect. Here, we provide evidence for altered epigenetic regulation of the DAT gene in PWS, which is associated with PWS-typical hyperphagia-related behaviors.

MC4R in Central and Peripheral Systems.

Obesity has emerged as a critical and urgent health burden during the current global pandemic. Among multiple genetic causes, melanocortin receptor-4 (MC4R), involved in food intake and energy metabolism regulation through various signaling pathways, has been reported to be the lead genetic factor in severe and early onset obesity and hyperphagia disorders. Most previous studies have illustrated the roles of MC4R signaling in energy intake versus expenditure in the central system, while some evidence indicates that MC4R is also expressed in peripheral systems, such as the gut and endocrine organs. However, its physiopathological function remains poorly defined. This review aims to depict the central and peripheral roles of MC4R in energy metabolism and endocrine hormone homeostasis, the diversity of phenotypes, biased downstream signaling caused by distinct MC4R mutations, and current drug development targeting the receptor.

Nuclear receptor 5A2 regulation of Agrp underlies olanzapine-induced hyperphagia.

Antipsychotic (AP) drugs are efficacious treatments for various psychiatric disorders, but excessive weight gain and subsequent development of metabolic disease remain serious side effects of their use. Increased food intake leads to AP-induced weight gain, but the underlying molecular mechanisms remain unknown. In previous studies, we identified the neuropeptide Agrp and the transcription factor nuclear receptor subfamily 5 group A member 2 (Nr5a2) as significantly upregulated genes in the hypothalamus following AP-induced hyperphagia. While Agrp is expressed specifically in the arcuate nucleus of the hypothalamus and plays a critical role in appetite stimulation, Nr5a2 is expressed in both the CNS and periphery, but its role in food intake behaviors remains unknown. In this study, we investigated the role of hypothalamic Nr5a2 in AP-induced hyperphagia and weight gain. In hypothalamic cell lines, olanzapine treatment resulted in a dose-dependent increase in gene expression of Nr5a2 and Agrp. In mice, the pharmacological inhibition of NR5A2 decreased olanzapine-induced hyperphagia and weight gain, while the knockdown of Nr5a2 in the arcuate nucleus partially reversed olanzapine-induced hyperphagia. Chromatin-immunoprecipitation studies showed for the first time that NR5A2 directly binds to the Agrp promoter region. Lastly, the analysis of single-cell RNA seq data confirms that Nr5a2 and Agrp are co-expressed in a subset of neurons in the arcuate nucleus. In summary, we identify Nr5a2 as a key mechanistic driver of AP-induced food intake. These findings can inform future clinical development of APs that do not activate hyperphagia and weight gain.

Role of astroglial ACBP in energy metabolism flexibility and feeding responses to metabolic challenges in male mice.

Acyl-CoA binding protein (ACBP), also known as diazepam binding inhibitor (DBI), has recently emerged as a hypothalamic and brainstem gliopeptide regulating energy balance. Previous work has shown that the ACBP-derived octadecaneuropeptide exerts strong anorectic action via proopiomelanocortin (POMC) neuron activation and the melanocortin-4 receptor. Importantly, targeted ACBP loss-of-function in astrocytes promotes hyperphagia and diet-induced obesity while its overexpression in arcuate astrocytes reduces feeding and body weight. Despite this knowledge, the role of astroglial ACBP in adaptive feeding and metabolic responses to acute metabolic challenges has not been investigated. Using different paradigms, we found that ACBP deletion in glial fibrillary acidic protein (GFAP)-positive astrocytes does not affect weight loss when obese male mice are transitioned from a high fat diet to a chow diet, nor metabolic parameters in mice fed with a normal chow diet (e.g., energy expenditure, body temperature) during fasting, cold exposure and at thermoneutrality. In contrast, astroglial ACBP deletion impairs meal pattern and feeding responses during refeeding after a fast and during cold exposure, thereby showing that ACBP is required to stimulate feeding in states of increased energy demand. These findings challenge the general view that astroglial ACBP exerts anorectic effects and suggest that regulation of feeding by ACBP is dependent on metabolic status.

CRTC1 deficiency, specifically in melanocortin-4 receptor-expressing cells, induces hyperphagia, obesity, and insulin resistance.

Melanocortin-4 receptor (MC4R) is a critical regulator of appetite and energy expenditure in rodents and humans. MC4R deficiency causes hyperphagia, reduced energy expenditure, and impaired glucose metabolism. Ligand binding to MC4R activates adenylyl cyclase, resulting in increased levels of intracellular cyclic adenosine monophosphate (cAMP), a secondary messenger that regulates several cellular processes. Cyclic adenosine monophosphate responsive element-binding protein-1-regulated transcription coactivator-1 (CRTC1) is a cytoplasmic coactivator that translocates to the nucleus in response to cAMP and is reportedly involved in obesity. However, the precise mechanism through which CRTC1 regulates energy metabolism remains unknown. Additionally, there are no reports linking CRTC1 and MC4R, although both CRTC1 and MC4R are known to be involved in obesity. Here, we demonstrate that mice lacking CRTC1, specifically in MC4R cells, are sensitive to high-fat diet (HFD)-induced obesity and exhibit hyperphagia and increased body weight gain. Moreover, the loss of CRTC1 in MC4R cells impairs glucose metabolism. MC4R-expressing cell-specific CRTC1 knockout mice did not show changes in body weight gain, food intake, or glucose metabolism when fed a normal-chow diet. Thus, CRTC1 expression in MC4R cells is required for metabolic adaptation to HFD with respect to appetite regulation. Our results revealed an important protective role of CRTC1 in MC4R cells against dietary adaptation.

Hindbrain insulin controls feeding behavior.

OBJECTIVE: Pancreatic insulin was discovered a century ago, and this discovery led to the first lifesaving treatment for diabetes. While still controversial, nearly one hundred published reports suggest that insulin is also produced in the brain, with most focusing on hypothalamic or cortical insulin-producing cells. However, specific function for insulin produced within the brain remains poorly understood. Here we identify insulin expression in the hindbrain's dorsal vagal complex (DVC), and determine the role of this source of insulin in feeding and metabolism, as well as its response to diet-induced obesity in mice. METHODS: To determine the contribution of Ins2-producing neurons to feeding behavior in mice, we used the cross of transgenic RipHER-cre mouse and channelrhodopsin-2 expressing animals, which allowed us to optogenetically stimulate neurons expressing Ins2 in vivo. To confirm the presence of insulin expression in Rip-labeled DVC cells, in situ hybridization was used. To ascertain the specific role of insulin in effects discovered via optogenetic stimulation a selective, CNS applied, insulin receptor antagonist was used. To understand the physiological contribution of insulin made in the hindbrain a virogenetic knockdown strategy was used. RESULTS: Insulin gene expression and presence of insulin-promoter driven fluorescence in rat insulin promoter (Rip)-transgenic mice were detected in the hypothalamus, but also in the DVC. Insulin mRNA was present in nearly all fluorescently labeled cells in DVC. Diet-induced obesity in mice altered brain insulin gene expression, in a neuroanatomically divergent manner; while in the hypothalamus the expected obesity-induced reduction was found, in the DVC diet-induced obesity resulted in increased expression of the insulin gene. This led us to hypothesize a potentially divergent energy balance role of insulin in these two brain areas. To determine the acute impact of activating insulin-producing neurons in the DVC, optic stimulation of light-sensitive channelrhodopsin 2 in Rip-transgenic mice was utilized. Optogenetic photoactivation induced hyperphagia after acute activation of the DVC insulin neurons. This hyperphagia was blocked by central application of the insulin receptor antagonist S961, suggesting the feeding response was driven by insulin. To determine whether DVC insulin has a necessary contribution to feeding and metabolism, virogenetic insulin gene knockdown (KD) strategy, which allows for site-specific reduction of insulin gene expression in adult mice, was used. While chow-fed mice failed to reveal any changes of feeding or thermogenesis in response to the KD, mice challenged with a high-fat diet consumed less food. No changes in body weight were identified, possibly resulting from compensatory reduction in thermogenesis. CONCLUSIONS: Together, our data suggest an important role for hindbrain insulin and insulin-producing cells in energy homeostasis.

Dysregulated adipose tissue expansion and impaired adipogenesis in Prader-Willi syndrome children before obesity-onset.

OBJECTIVE: Prader-Willi syndrome (PWS) is a rare genetic imprinting disorder resulting from the expression loss of genes on the paternally inherited chromosome 15q11-13. Early-onset life-thriving obesity and hyperphagia represent the clinical hallmarks of PWS. The noncoding RNA gene SNORD116 within the minimal PWS genetic lesion plays a critical role in the pathogenesis of the syndrome. Despite advancements in understanding the genetic basis for PWS, the pathophysiology of obesity development in PWS remains largely uncharacterized. Here, we aimed to investigate the signatures of adipose tissue development and expansion pathways and associated adipose biology in PWS children without obesity-onset at an early stage, mainly from the perspective of the adipogenesis process, and further elucidate the underlying molecular mechanisms. METHODS: We collected inguinal (subcutaneous) white adipose tissues (ingWATs) from phase 1 PWS and healthy children with normal weight aged from 6 M to 2 Y. Adipose morphology and histological characteristics were assessed. Primary adipose stromal vascular fractions (SVFs) were isolated, cultured in vitro, and used to determine the capacity and function of white and beige adipogenic differentiation. High-throughput RNA-sequencing (RNA-seq) was performed in adipose-derived mesenchymal stem cells (AdMSCs) to analyze transcriptome signatures in PWS subjects. Transient repression of SNORD116 was conducted to evaluate its functional relevance in adipogenesis. The changes in alternative pre-mRNA splicing were investigated in PWS and SNORD116 deficient cells. RESULTS: In phase 1 PWS children, impaired white adipose tissue (WAT) development and unusual fat expansion occurred long before obesity onset, which was characterized by the massive enlargement of adipocytes accompanied by increased apoptosis. White and beige adipogenesis programs were impaired and differentiated adipocyte functions were disturbed in PWS-derived SVFs, despite increased proliferation capacity, which were consistent with the results of RNA-seq analysis of PWS AdMSCs. We also experimentally validated disrupted beige adipogenesis in adipocytes with transient SNORD116 downregulation. The transcript and protein levels of PPARγ, the adipogenesis master regulator, were significantly lower in PWS than in control AdMSCs as well as in SNORD116 deficient AdMSCs/adipocytes than in scramble (Scr) cells, resulting in the inhibited adipogenic program. Additionally, through RNA-seq, we observed aberrant transcriptome-wide alterations in alternative RNA splicing patterns in PWS cells mediated by SNORD116 loss and specifically identified a changed PRDM16 gene splicing profile in vitro. CONCLUSIONS: Imbalance in the WAT expansion pathway and developmental disruption are primary defects in PWS displaying aberrant adipocyte hypertrophy and impaired adipogenesis process, in which SNORD116 deficiency plays a part. Our findings suggest that dysregulated adiposity specificity existing at an early phase is a potential pathological mechanism exacerbating hyperphagic obesity onset in PWS. This mechanistic evidence on adipose biology in young PWS patients expands knowledge regarding the pathogenesis of PWS obesity and may aid in developing a new therapeutic strategy targeting disturbed adipogenesis and driving AT plasticity to combat abnormal adiposity and associated metabolic disorders for PWS patients.

Hyperphagia and hyperleptinemia induced by low-protein, high-carbohydrate diet is reversed at a later stage of development in rats.

This study investigated whether increased food intake after 15 days of low-protein, high-carbohydrate (LPHC) and its normalization in the later period of development change the content of key proteins related to leptin or adiponectin signaling in the hypothalamus. Male rats were divided into five groups: Control groups received a control diet (17% protein, 63% carbohydrate) for 15 (C15) or 45 (C45) days; LPHC groups received an LPHC diet (6% protein, 74% carbohydrate) for 15 (LPHC15) or 45 (LPHC45) days; and Reverse group (R): received LPHC diet for 15 days followed by control diet for another 30 days. The LPHC15 group showed increased adiposity index, leptin level, and adiponectin level, as well as decreased the leptin receptor (ObRb) and pro-opiomelanocortin (POMC) content in the hypothalamus compared with the C15 group. LPHC diet for 45 days or diet reversion (R group) rescued these alterations, except the adiponectin level in LPHC45 rats, which was higher. In summary, LPHC diet reduced hypothalamic leptin action by diminishing ObRb and POMC levels, leading to hyperphagia and adiposity body. Medium-term administration of LPHC diet or reverting to control diet restored the levels of these proteins, thereby improving body lipid mass rearrangement in adulthood.

AgRP neurons control feeding behaviour at cortical synapses via peripherally derived lysophospholipids.

Phospholipid levels are influenced by peripheral metabolism. Within the central nervous system, synaptic phospholipids regulate glutamatergic transmission and cortical excitability. Whether changes in peripheral metabolism affect brain lipid levels and cortical excitability remains unknown. Here, we show that levels of lysophosphatidic acid (LPA) species in the blood and cerebrospinal fluid are elevated after overnight fasting and lead to higher cortical excitability. LPA-related cortical excitability increases fasting-induced hyperphagia, and is decreased following inhibition of LPA synthesis. Mice expressing a human mutation (Prg-1R346T) leading to higher synaptic lipid-mediated cortical excitability display increased fasting-induced hyperphagia. Accordingly, human subjects with this mutation have higher body mass index and prevalence of type 2 diabetes. We further show that the effects of LPA following fasting are under the control of hypothalamic agouti-related peptide (AgRP) neurons. Depletion of AgRP-expressing cells in adult mice decreases fasting-induced elevation of circulating LPAs, as well as cortical excitability, while blunting hyperphagia. These findings reveal a direct influence of circulating LPAs under the control of hypothalamic AgRP neurons on cortical excitability, unmasking an alternative non-neuronal route by which the hypothalamus can exert a robust impact on the cortex and thereby affect food intake.

Mechanisms of Weight Control by Primary Cilia.

A primary cilium, a hair-like protrusion of the plasma membrane, is a pivotal organelle for sensing external environmental signals and transducing intracellular signaling. An interesting linkage between cilia and obesity has been revealed by studies of the human genetic ciliopathies Bardet-Biedl syndrome and Alström syndrome, in which obesity is a principal manifestation. Mouse models of cell type-specific cilia dysgenesis have subsequently demonstrated that ciliary defects restricted to specific hypothalamic neurons are sufficient to induce obesity and hyperphagia. A potential mechanism underlying hypothalamic neuron cilia-related obesity is impaired ciliary localization of G protein-coupled receptors involved in the regulation of appetite and energy metabolism. A well-studied example of this is melanocortin 4 receptor (MC4R), mutations in which are the most common cause of human monogenic obesity. In the paraventricular hypothalamus neurons, a blockade of ciliary trafficking of MC4R as well as its downstream ciliary signaling leads to hyperphagia and weight gain. Another potential mechanism is reduced leptin signaling in hypothalamic neurons with defective cilia. Leptin receptors traffic to the periciliary area upon leptin stimulation. Moreover, defects in cilia formation hamper leptin signaling and actions in both developing and differentiated hypothalamic neurons. The list of obesity-linked ciliary proteins is expending and this supports a tight association between cilia and obesity. This article provides a brief review on the mechanism of how ciliary defects in hypothalamic neurons facilitate obesity.

The model of litter size reduction induces long-term disruption of the gut-brain axis: An explanation for the hyperphagia of Wistar rats of both sexes.

The gut microbiota affects the host's metabolic phenotype, impacting health and disease. The gut-brain axis unites the intestine with the centers of hunger and satiety, affecting the eating behavior. Deregulation of this axis can lead to obesity onset. Litter size reduction is a well-studied model for infant obesity because it causes overnutrition and programs for obesity. We hypothesize that animals raised in small litters (SL) have altered circuitry between the intestine and brain, causing hyperphagia. We investigated vagus nerve activity, the expression of c-Fos, brain-derived neurotrophic factor (BDNF), gastrointestinal (GI) hormone receptors, and content of bacterial phyla and short-chain fatty acids (SCFAs) in the feces of adult male and female Wistar rats overfed during lactation. On the 3rd day after birth, litter size was reduced to 3 pups/litter (SL males or SL females) until weaning. Controls had normal litter size (10 pups/litter: 5 males and 5 females). The rats were killed at 5 months of age. The male and female offspring were analyzed separately. The SL group of both sexes showed higher food consumption and body adiposity than the respective controls. SL animals presented dysbiosis (increased Firmicutes, decreased Bacteroidetes) and had increased vagus nerve activity. Only the SL males had decreased hypothalamic GLP-1 receptor expression, while only the SL females had lower acetate and propionate in the feces and higher CCK receptor expression in the hypothalamus. Thus, overfeeding during lactation differentially changes the gut-brain axis, contributing to hyperphagia of the offspring of both sexes.

Approach to the Patient With Prader-Willi Syndrome.

Prader-Willi syndrome (PWS) is a rare, multisystemic, genetic disorder involving the hypothalamus. It is caused by loss of expression of paternally inherited genes in chromosome 15 q11-13 region. The estimated incidence is around 1 in 20.000 births. PWS is characterized by a complex lifelong trajectory involving neurodevelopmental, nutritional, endocrine, metabolic, and behavioral changes. The major symptoms are hypotonia, short stature, hypogonadism, and eating disorders ranging from anorexia in infancy to hyperphagia, a deficit of satiety, and a high risk of severe obesity. The patients display intellectual disability comprising cognitive deficit, delayed motor and language development, learning deficits, impaired social skills, and emotional regulation. Behavioral features including temper outbursts, anxiety, obsessive-compulsive symptoms and rigidity are common and become more apparent with increasing age. Almost all have hypogonadism and growth hormone deficiency. Central adrenal insufficiency is rare whereas central hypothyroidism occurs in up to 30% of children with PWS. The prevalence of obesity increases with age from almost none in early childhood to more than 90% in adulthood. Up to 25% of adults with obesity have type 2 diabetes. Obesity and its complications are the major causes of comorbidity and mortality in PWS. As there is no specific treatment, care consists of comprehensive management of feeding disorders, a restricted, controlled diet, regular exercise, hormone substitution, and screening and treatment of comorbidities. Here we present the course of PWS from birth to adulthood in 2 patients and discuss their symptoms in relation to the literature.

Disruption of CRTC1 and CRTC2 in Sim1 cells strongly increases high-fat diet intake in female mice but has a modest impact on male mice.

cAMP responsive element binding protein (CREB)-regulated transcription coactivators (CRTCs) regulate gene transcription in response to an increase in intracellular cAMP or Ca2+ levels. To date, three isoforms of CRTC have been identified in mammals. All CRTCs are widely expressed in various regions of the brain. Numerous studies have shown the importance of CREB and CRTC in energy homeostasis. In the brain, the paraventricular nucleus of the hypothalamus (PVH) plays a critical role in energy metabolism, and CRTC1 and CRTC2 are highly expressed in PVH neuronal cells. The single-minded homolog 1 gene (Sim1) is densely expressed in PVH neurons and in some areas of the amygdala neurons. To determine the role of CRTCs in PVH on energy metabolism, we generated mice that lacked CRTC1 and CRTC2 in Sim1 cells using Sim-1 cre mice. We found that Sim1 cell-specific CRTC1 and CRTC2 double-knockout mice were sensitive to high-fat diet (HFD)-induced obesity. Sim1 cell-specific CRTC1 and CRTC2 double knockout mice showed hyperphagia specifically for the HFD, but not for the normal chow diet, increased fat mass, and no change in energy expenditure. Interestingly, these phenotypes were stronger in female mice than in male mice, and a weak phenotype was observed in the normal chow diet. The lack of CRTC1 and CRTC2 in Sim1 cells changed the mRNA levels of some neuropeptides that regulate energy metabolism in female mice fed an HFD. Taken together, our findings suggest that CRTCs in Sim1 cells regulate gene expression and suppress excessive fat intake, especially in female mice.

Rapid PCR-based method for herbivore dietary evaluation using plant-specific primers.

Polyphagous pests cause significant economic loss worldwide through feeding damage on various cash crops. However, their diets in agricultural landscapes remain largely unexplored. Pest dietary evaluation in agricultural fields is a challenging task currently approached through visual observation of plant feeding and microscopic identification of semi-digested plant material in pest's guts. While molecular gut content analysis using metabarcoding approaches using universal primers (e.g., rbcl and trnL) have been successful in evaluating polyphagous pest diet, this method is relatively costly and time-consuming. Hence, there is a need for a rapid, specific, sensitive, and cost-effective method to screen for crops in the gut of pests. This is the first study to develop plant-specific primers that target various regions of their genomes, designed using a whole plant genome sequence. We selected Verticillium wilt disease resistance protein (VE-1) and pathogenesis related protein-coding genes 1-5 (PR-1-5) as our targets and designed species-specific primers for 14 important crops in the agroecosystems. Using amplicon sizes ranging from 115 to 407 bp, we developed two multiplex primer mixes that can separate nine and five plant species per PCR reaction, respectively. These two designed primer mixes provide a rapid, sensitive and specific route for polyphagous pest dietary evaluation in agroecosystems. This work will enable future research to rapidly expand our knowledge on the diet preference and range of crops that pests consume in various agroecosystems, which will help in the redesign and development of new crop rotation regimes to minimize polyphagous pest pressure and damage on crops.

Influence of betahistine repeated administration on a weight gain and selected metabolic parameters in the model of excessive eating in rats.

It is important to search for a promising therapeutic target or small molecules that can control excessive eating since limiting the intake of foods, especially tasty ones, could be effective in the treatment or prevention of obesity. Some studies indicate betahistine as an unique drug having the ability to ameliorate, for example, antipsychotic-induced weight gain. This study aimed to determine whether repeated administration of betahistine (histamine H1R agonist and H3R antagonist) could be beneficial in reducing the intake of tasty foods or the body's response to overeating via mechanisms such as by influencing the levels of hormones involved in the regulation of food intake or the levels of selected metabolic parameters. Studies were performed in the excessive eating model in rats, which perfectly illustrates the harmful high-caloric intake from freely available tasty products rich in sugar and fat. Our results indicated that repeated administration of betahistine to rats caused lower gain of body mass compared to the control rats fed palatable feed. Interestingly, betahistine treatment increased the consumption of cheese, which is a source of histamine. Although betahistine did not prevent the development of metabolic disorders, such as reduced glucose tolerance, in test animals, it significantly increased the level of high-density lipoprotein cholesterol, which could certainly be considered beneficial. Further studies should be conducted to investigate the effect of repeated administration of betahistine on satiety, gastrointestinal disorders, and the preference for histamine-containing foods.