The Nucleolar δ Isoform of Adapter Protein SH2B1 Enhances Morphological Complexity and Function of Cultured Neurons

The adapter protein SH2B1 is recruited to neurotrophin receptors including TrkB, receptor for brain-derived neurotrophic factor (BDNF). Herein, we demonstrate that the four alternatively spliced isoforms of SH2B1 are important determinants of neuronal architecture and neurotrophin-induced gene expression. Primary hippocampal neurons from Sh2b1−/- (KO) mice exhibit decreased neurite complexity and length and BDNF-induced expression of synapse-related immediate early genes Egr1 and Arc. Reintroduction of each SH2B1 isoform into KO neurons increases neurite complexity; the brain-specific δ isoform also increases total neurite length. Human obesity-associated variants, when expressed in SH2B1δ, alter neurite complexity, suggesting that a decrease or increase in neurite branching may have deleterious effects that contribute to the severe childhood obesity and neurobehavioral abnormalities associated with these variants. Surprisingly, in contrast to SH2B1α, β, and γ, which localize primarily in the cytoplasm and plasma membrane, SH2B1δ localizes primarily in nucleoli. Some SH2B1δ is also present in the plasma membrane and nucleus. Nucleolar localization, driven by two highly basic regions unique to SH2B1δ, is required for SH2B1δ to maximally increase neurite complexity and BDNF-induced expression of Egr1, Arc, and FosL1.

Asymmetric Relationship of Global Human Obesity and Political Globalization Through World Human Development Levels

Background: Political globalization is a crucial and distinct component of strengthening global organizations. Obesity is a global epidemic in a few nations, and it is on the verge of becoming a pandemic that would bring plenty of diseases. The focus of this research is to see how the political globalization index affects worldwide human obesity in relation to global human development levels. Methods: In order to assess any cross-sectional dependence among observed 109 nations, the yearly period from 1990 to 2017 is analyzed using second generation panel data methods. KAO panel cointegration test and Feasible Generalized Least Square model were used to meet our objectives. Results: Low level of political Globalization tends to increase global human obesity because countries cannot sway international decisions and resources towards them. While the high level of political Globalization tends to reduce obesity because they can control and amends the international decisions. For the regression model, a feasible Generalized Least Square model was utilized. The study observed that the R squared values for all models are healthy, with a minimum of 87 percent variables explaining differences in global obesity at the country level. Conclusion: There is a very important to tackle globalization issue to reduce global human obesity. Simplicity of dietary options and the amount of physical labour they undergo in their agricultural duties, an increase in rural population percentage tends to lower the average national obesity value.

Integrative genomic analyses in adipocytes implicate DNA methylation in human obesity and diabetes

DNA methylation variations are prevalent in human obesity, but evidence of a causative role in disease pathogenesis is limited. In this study, we combine epigenome-wide association and integrative genomics to investigate the impact of subcutaneous and visceral adipocyte DNA methylation variations in extreme human obesity. We identify extensive DNA methylation changes that are robustly associated with extreme obesity in combined discovery and replication analyses (N=190 samples, 691 loci in subcutaneous and 173 loci in visceral adipocytes, P<1x10-7). Using functional interaction maps and methylation-expression association testing in human adipocytes, we connect extreme obesity-associated methylation variations to transcriptomic changes at >500 target genes. We find that disease-associated methylation variations localise to active genomic regions and transcription factor binding sites, at which DNA methylation influences transcription factor-target gene co-expression relationships. In Mendelian Randomisation analyses, we infer causal effects of DNA methylation on human obesity and obesity-induced metabolic disturbances, under genetic control, at 28 independent loci. Silencing of two target genes of causal DNA methylation variations, the PRRC2A and LIMD2 genes, further reveals novel metabolic effects in adipocytes. Our results indicate DNA methylation is an important determinant of human obesity and its metabolic complications, and reveal genomic and molecular mechanisms through which altered DNA methylation may impact adipocyte cellular functions.

scEMC10, a novel circulating inhibitor of adipocyte thermogenesis, is upregulated in human obesity and its neutralizing antibody prevents diet-induced obesity

Secreted isoform of endoplasmic reticulum membrane complex subunit 10 (scEMC10) is a poorly characterised secreted protein of largely unknown physiological function. Here we demonstrate that scEMC10 is upregulated in humans with obesity and is positively associated with insulin resistance. Consistent with a causal role for scEMC10 in obesity, Emc10-/- mice are resistant to diet-induced obesity due to an increase in energy expenditure. Furthermore, neutralization of circulating scEMC10 using a monoclonal antibody reduces body weight and enhances insulin sensitivity in obese mice. Mechanistically, we provide evidence that scEMC10 binds to the catalytic subunit of PKA and inhibits its stimulatory action on CREB while ablation of EMC10 promotes thermogenesis in adipocytes via activation of the PKA signalling pathway and its downstream targets. Taken together, our data identify scEMC10 as a novel circulating inhibitor of thermogenesis and a potential therapeutic target for obesity and its cardiometabolic complications.

Dynamic regulation of N6,2′-O-dimethyladenosine (m6Am) in obesity

The prevalent m6Am mRNA cap modification was recently identified as a valid target for removal by the human obesity gene FTO along with the previously established m6A mRNA modification. However, the deposition and dynamics of m6Am in regulating obesity are unknown. Here, we investigate the liver m6A/m methylomes in mice fed on a high fat Western-diet and in ob/ob mice. We find that FTO levels are elevated in fat mice, and that genes which lost m6Am marking under obesity are overly downregulated, including the two fatty-acid-binding proteins FABP2, and FABP5. Furthermore, the cellular perturbation of FTO correspondingly affect protein levels of its targets. Notably, generally m6Am- but not m6A-methylated genes, are found to be highly enriched in metabolic processes. Finally, we deplete all m6A background via Mettl3 knockout, and unequivocally uncover the association of m6Am methylation with increased mRNA stability, translation efficiency, and higher protein expression. Together, these results strongly implicate a dynamic role for m6Am in obesity-related translation regulation.

Predicting novel candidate human obesity genes and their site of action by systematic functional screening in Drosophila

The discovery of human obesity-associated genes can reveal new mechanisms to target for weight loss therapy. Genetic studies of obese individuals and the analysis of rare genetic variants can identify novel obesity-associated genes. However, establishing a functional relationship between these candidate genes and adiposity remains a significant challenge. We uncovered a large number of rare homozygous gene variants by exome sequencing of severely obese children, including those from consanguineous families. By assessing the function of these genes in vivo in Drosophila, we identified 4 genes, not previously linked to human obesity, that regulate adiposity (itpr, dachsous, calpA, and sdk). Dachsous is a transmembrane protein upstream of the Hippo signalling pathway. We found that 3 further members of the Hippo pathway, fat, four-jointed, and hippo, also regulate adiposity and that they act in neurons, rather than in adipose tissue (fat body). Screening Hippo pathway genes in larger human cohorts revealed rare variants in TAOK2 associated with human obesity. Knockdown of Drosophila tao increased adiposity in vivo demonstrating the strength of our approach in predicting novel human obesity genes and signalling pathways and their site of action.

Insects as a New Complex Model in Hormonal Basis of Obesity

Nowadays, one of the biggest problems in healthcare is an obesity epidemic. Consumption of cheap and low-quality energy-rich diets, low physical activity, and sedentary work favor an increase in the number of obesity cases within many populations/nations. This is a burden on society, public health, and the economy with many deleterious consequences. Thus, studies concerning this disorder are extremely needed, including searching for new, effective, and fitting models. Obesity may be related, among other factors, to disrupting adipocytes activity, disturbance of metabolic homeostasis, dysregulation of hormonal balance, cardiovascular problems, or disorders in nutrition which may lead to death. Because of the high complexity of obesity, it is not easy to find an ideal model for its studies which will be suitable for genetic and physiological analysis including specification of different compounds’ (hormones, neuropeptides) functions, as well as for signaling pathways analysis. In recent times, in search of new models for human diseases there has been more and more attention paid to insects, especially in neuro-endocrine regulation. It seems that this group of animals might also be a new model for human obesity. There are many arguments that insects are a good, multidirectional, and complex model for this disease. For example, insect models can have similar conservative signaling pathways (e.g., JAK-STAT signaling pathway), the presence of similar hormonal axis (e.g., brain–gut axis), or occurrence of structural and functional homologues between neuropeptides (e.g., neuropeptide F and human neuropeptide Y, insulin-like peptides, and human insulin) compared to humans. Here we give a hint to use insects as a model for obesity that can be used in multiple ways: as a source of genetic and peptidomic data about etiology and development correlated with obesity occurrence as well as a model for novel hormonal-based drug activity and their impact on mechanism of disease occurrence.