Melanocortin Receptor 4 Deficiency Affects Body Weight Regulation, Grooming Behavior, and Substrate Preference in the Rat

Obesity is caused by an imbalance between energy intake and expenditure and has become a major health-care problem in western society. The central melanocortin system plays a crucial role in the regulation of feeding and energy expenditure, and functional loss of melanocortin receptor 4 (MC4R) is the most common genetic cause of human obesity. In this study, we present the first functional Mc4r knockout model in the rat, resulting from an N-ethyl-N-nitrosourea mutagenesis–induced point mutation. In vitro observations revealed impaired membrane-binding and subsequent nonfunctionality of the receptor, whereas in vivo observations showed that functional loss of MC4R increased body weight, food intake, white adipose mass, and changed substrate preference. In addition, intracerebroventricular (ICV) administration of Agouti-Related Protein79–129 (AgRP79–129), an MC4R inverse agonist, or Melanotan-II (MTII), an MC4R agonist, did affect feeding behavior in wild-type rats but not in homozygous mutant rats, confirming complete loss of MC4R function in vivo. Finally, ICV administration of MTII induced excessive grooming behavior in wild-type rats, whereas this effect was absent in homozygous mutant rats, indicating that MTII-induced grooming behavior is exclusively regulated via MC4R pathways. Taken together, we expect that the MC4R rat model described here will be a valuable tool for studying monogenic obesity in humans. More specifically, the relative big size and increased cognitive capacity of rats as compared to mice will facilitate complex behavioral studies and detailed mechanistic studies regarding central function of MC4R, both of which ultimately may help to further understand the specific mechanisms that induce obesity during loss of MC4R function

Development and body mass inversely affect children’s brain activation in dorsolateral prefrontal cortex during food choice

Childhood obesity is a rising problem caused in part by unhealthy food choices. Food choices are based on a neural value signal encoded in the ventromedial prefrontal cortex, and self-control involves modulation of this signal by the dorsolateral prefrontal cortex (dlPFC). We determined the effects of development, body mass (BMI Cole score) and body mass history on the neural correlates of healthy food choice in children. 141 children (aged 10-17y) from Germany, Hungary and Sweden were scanned with fMRI while performing a food choice task. Afterwards health and taste ratings of the foods were collected. In the food choice task children were asked to consider the healthiness or tastiness of the food or to choose naturally. Overall, children made healthier choices when asked to consider healthiness. However, children who had a higher weight gain per year chose less healthy foods when considering healthiness but not when choosing naturally. Pubertal development stage correlated positively while current body mass correlated negatively with dlPFC activation when accepting foods. Pubertal development negatively and current body mass positively influenced the effect of considering healthiness on activation of brain areas involved in salience and motivation. In conclusion, children in earlier stages of pubertal development and children with a higher body weight exhibited less activation in the dlPFC, which has been implicated in self-control during food choice. Furthermore, pubertal development and body mass influenced neural responses to a health cue in areas involved in salience and motivation. Thus, these findings suggest that children in earlier stages of pubertal development, children with a higher body mass gain and children with overweight may possibly be less susceptible to healthy eating interventions that rely on self-control or that highlight health aspects of food.</p

Common Genetic Variation And Age at Onset Of Anorexia Nervosa

Background Genetics and biology may influence the age at onset of anorexia nervosa (AN). The aims of this study were to determine whether common genetic variation contributes to AN age at onset and to investigate the genetic associations between age at onset of AN and age at menarche. Methods A secondary analysis of the Psychiatric Genomics Consortium genome-wide association study (GWAS) of AN was performed which included 9,335 cases and 31,981 screened controls, all from European ancestries. We conducted GWASs of age at onset, early-onset AN (< 13 years), and typical-onset AN, and genetic correlation, genetic risk score, and Mendelian randomization analyses. Results Two loci were genome-wide significant in the typical-onset AN GWAS. Heritability estimates (SNP-h2) were 0.01-0.04 for age at onset, 0.16-0.25 for early-onset AN, and 0.17-0.25 for typical-onset AN. Early- and typical-onset AN showed distinct genetic correlation patterns with putative risk factors for AN. Specifically, early-onset AN was significantly genetically correlated with younger age at menarche, and typical-onset AN was significantly negatively genetically correlated with anthropometric traits. Genetic risk scores for age at onset and early-onset AN estimated from independent GWASs significantly predicted age at onset. Mendelian randomization analysis suggested a causal link between younger age at menarche and early-onset AN. Conclusions Our results provide evidence consistent with a common variant genetic basis for age at onset and implicate biological pathways regulating menarche and reproduction.Peer reviewe

Shared genetic risk between eating disorder- and substance-use-related phenotypes:Evidence from genome-wide association studies

First published: 16 February 202

Reinforcement learning across the rat estrous cycle

Reinforcement learning, the process by which an organism flexibly adapts behavior in response to reward and punishment, is vital for the proper execution of everyday behaviors, and its dysfunction has been implicated in a wide variety of mental disorders. Here, we use computational trial-by-trial analysis of data of female rats performing a probabilistic reward learning task and demonstrate that core computational processes underlying value-based decision making fluctuate across the estrous cycle, providing a neuroendocrine substrate by which gonadal hormones may influence adaptive behavior

Genetic predisposition to obesity affects behavioural traits including food reward and anxiety-like behaviour in rats

Here we sought to define behavioural traits linked to anxiety, reward, and exploration in different strains of rats commonly used in obesity research. We hypothesized that genetic variance may contribute not only to their metabolic phenotype (that is well documented) but also to the expression of these behavioural traits. Rat strains that differ in their susceptibility to develop an obese phenotype (Sprague-Dawley, Obese Prone, Obese Resistant, and Zucker rats) were exposed to a number of behavioural tests starting at the age of 8 weeks. We found a similar phenotype in the obesity susceptible models, Obese Prone and Zucker rats, with a lower locomotor activity, exploratory activity, and higher level of anxiety-like behaviour in comparison to the leaner Obese Resistant strain. We did not find evidence that rat strains with a genetic predisposition to obesity differed in their ability to experience reward from chocolate (in a condition place preference task). However, Zucker rats show higher motivated behaviour for sucrose compared to Obese Resistant rats when the effort required to obtain palatable food is relatively low. Together our data demonstrate that rat strains that differ in their genetic predisposition to develop obesity also differ in their performance in behavioural tests linked to anxiety, exploration, and reward and that these differences are independent of body weight. We conclude that genetic variations which determine body weight and the aforementioned behaviours co-exist but that future studies are required to identify whether (and which) common genes are involved

AgRP(83—132) and SHU9119 differently affect activity-based anorexia

Activity-based anorexia (ABA) mimics starvation and hyperactivity of anorexia nervosa patients in rats. Activation of the melanocortin (MC) system leads to hypophagia and increased energy expenditure in ad libitum fed rats. Therefore, activation of the MC system might underlie the development and propagation of ABA. Pro-opiomelanocortin (POMC) gene expression is normally decreased during negative energy balance. Strikingly, we found a transient up-regulation of POMC mRNA levels in the arcuate nucleus during the development of ABA, indicating a hyperactive MC system. However, wheel running and food intake were not influenced by treating ABA rats with the competitive antagonist SHU9119. This suggests that agonism of MC receptors by endogenous α-melanocyte-stimulating hormone (α-MSH) levels does not underlie ABA. Instead, treatment with the inverse agonist AgRP(83—132) did ameliorate signs of ABA. This implies that modulation of constitutive MC receptor activity rather than antagonizing putative α-MSH release contributes to the development and propagation of ABA.

Peptoid-peptide hybrids as potent novel melanocortin receptor ligands

No abstract available