Sixteen years have passed since the description of the nuclear factor-кB (NF-кB) as a regulator of к light-chain gene expression in murine B lymphocytes (Sen & Baltimore, 1986a) During that time, over 4,000 publications have appeared, characterizing the family of Rel/NF-кB transcription factors involved in the control of a large number of normal and pathological cellular processes The physiological functions of NF-кB proteins include immunological and inflammatory responses, developmental processes, cellular growth and modulating effects on apoptosis In addition, these factors are activated in a number of diseases, including cancer, arthritis, acute and chronic inflammatory states, asthma, as well as neurodegenerative and heart diseases

Activators and target genes of Rel/NF-kappaB transcription factors.

The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism

Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and similar to 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 x 10(-8)), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.

/pdf/association-analyses-of-249-796-individuals-reveal-18-new-1h49rus1hh.pdf

Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index

Gene families are growing rapidly, but standard methods for inferring phylogenies do not scale to alignments with over 10,000 sequences. We present FastTree, a method for constructing large phylogenies and for estimating their reliability. Instead of storing a distance matrix, FastTree stores sequence profiles of internal nodes in the tree. FastTree uses these profiles to implement neighbor-joining and uses heuristics to quickly identify candidate joins. FastTree then uses nearest-neighbor interchanges to reduce the length of the tree. For an alignment with N sequences, L sites, and a different characters, a distance matrix requires O(N^2) space and O(N^2 L) time, but FastTree requires just O( NLa + N sqrt(N) ) memory and O( N sqrt(N) log(N) L a ) time. To estimate the tree's reliability, FastTree uses local bootstrapping, which gives another 100-fold speedup over a distance matrix. For example, FastTree computed a tree and support values for 158,022 distinct 16S ribosomal RNAs in 17 hours and 2.4 gigabytes of memory. Just computing pairwise Jukes-Cantor distances and storing them, without inferring a tree or bootstrapping, would require 17 hours and 50 gigabytes of memory. In simulations, FastTree was slightly more accurate than neighbor joining, BIONJ, or FastME; on genuine alignments, FastTree's topologies had higher likelihoods. FastTree is available at http://microbesonline.org/fasttree.

/pdf/fast-tree-computing-large-minimum-evolution-trees-with-4grq0gwfpy.pdf

Fast Tree: Computing Large Minimum-Evolution Trees with Profiles instead of a Distance Matrix

The prevalence of obesity has increased worldwide in the past ~50 years, reaching pandemic levels. Obesity represents a major health challenge because it substantially increases the risk of diseases such as type 2 diabetes mellitus, fatty liver disease, hypertension, myocardial infarction, stroke, dementia, osteoarthritis, obstructive sleep apnoea and several cancers, thereby contributing to a decline in both quality of life and life expectancy. Obesity is also associated with unemployment, social disadvantages and reduced socio-economic productivity, thus increasingly creating an economic burden. Thus far, obesity prevention and treatment strategies - both at the individual and population level - have not been successful in the long term. Lifestyle and behavioural interventions aimed at reducing calorie intake and increasing energy expenditure have limited effectiveness because complex and persistent hormonal, metabolic and neurochemical adaptations defend against weight loss and promote weight regain. Reducing the obesity burden requires approaches that combine individual interventions with changes in the environment and society. Therefore, a better understanding of the remarkable regional differences in obesity prevalence and trends might help to identify societal causes of obesity and provide guidance on which are the most promising intervention strategies.

Obesity: global epidemiology and pathogenesis.

Glucagon in Islet and Metabolic Regulation

Vertical sleeve gastrectomy (VSG) is one of several bariatric procedures that substantially improves glycemia and energy homeostasis. Increased secretion of multiple gut peptides has been hypothesized to be a critical contributor to VSG’s potent effects to reduce body weight and improve glucose regulation. VSG results in an increase in the number of hormone-secreting enteroendocrine cells (EECs) in the intestinal epithelium, but whether this increase is via proliferation or differentiation of EECs and their subtypes remains unclear. Notably, the beneficial effects of VSG are lost in a mouse model lacking the bile acid nuclear receptor, farnesoid X receptor (FXR). FXR is a nuclear transcription factor that has been shown to regulate intestinal stem cell (ISC) function in cancer models, but whether it plays a role specifically in normal intestinal differentiation remains unknown. Therefore, we hypothesized that the VSG-induced increase in EECs is due to changes in intestinal differentiation driven by an increase in bile acid signaling through FXR. To test this, we performed VSG in mice that express eGFP in ISC/progenitor cells and performed RNAseq on GFP-positive cells sorted from the intestinal epithelia. We also assessed changes in EEC number (marked by GLP-1) in mouse intestinal organoids following treatment with bile acids and/or an FXR antagonist. RNA-seq revealed that FXR is expressed in ISCs and that VSG explicitly alters ISC expression of several genes that regulate intestinal secretory cell development, including EEC differentiation. Mouse intestinal organoids treated with bile acids increased GLP-1-positive cell numbers, whereas a potent FXR antagonist blocked this effect. Taken together, these data indicate that VSG drives ISC fate towards EEC differentiation through FXR signaling.

/pdf/vertical-sleeve-gastrectomy-induces-enteroendocrine-cell-1mv4zvl39d.pdf

Vertical Sleeve Gastrectomy Induces Enteroendocrine Cell Differentiation of Intestinal Stem Cells Through Farnesoid X Receptor Activation

Historically, intracellular function and metabolic adaptation within the α-cell has been understudied, with most of the attention being placed on the insulin-producing β-cells due to their role in the pathophysiology of Type 2 Diabetes Mellitus. However, there is a growing interest in understanding the function of other endocrine cell types within the islet and their paracrine role in regulating insulin secretion. For example, there is greater appreciation for α-cell products and their contributions to overall glucose homeostasis. Several recent studies have addressed a paracrine role for α-cell derived glucagon-like peptide-1 (GLP-1) in regulating glucose homeostasis and responses to metabolic stress. Further, other studies have demonstrated the ability of glucagon to impact insulin secretion by acting through the GLP-1 receptor. These studies challenge the central dogma surrounding α-cell biology describing glucagon's primary role in glucose counter-regulation to one where glucagon is critical in regulating both hyper- and hypoglycemic responses. Herein, this review will update the current understanding of the role of glucagon and α-cell derived GLP-1 placing emphasis on their roles in regulating glucose homeostasis, insulin secretion, and β-cell mass.

Preproglucagon Products and Their Respective Roles Regulating Insulin Secretion.

To change the future you need a firm grip on history. Successful implementation of strategies to catalyze evolution of gender parity requires a coherent plan with clear deliverables. The article by Dunne et al. (1,2), simultaneously published in Diabetes and Diabetes Care , provides a much-needed foundation that defines the scope of the problem within the field of diabetes, documents stagnated progress over recent years, and offers suggestions for intervention. We applaud the authors and are encouraged that the American Diabetes Association (ADA) leadership is fully invested in being part of an effective solution. As nationally funded and internationally recognized women leaders in diabetes research, we are compelled to initiate the process of addressing the inequities brought to light by Dunne et al. to enhance the development and retention of female talent in our field. To intiate that process, here we discuss the observations by Dunne et al. and propose a set of concrete measures for achieving gender equity within diabetes-related professions.

Dunne et al. observe that almost half (43%) of the attendees of the annual ADA Scientific Sessions national conference are women, demonstrating strong active participation of women. Women are also well represented in education-focused leadership positions comprising 83% of the then Vice Presidents and now Presidents of Health Care and Education over the last five decades and 89% and 49% of the editorial boards for Diabetes Spectrum and Clinical Diabetes , respectively. In striking contrast, in the last 20 years, only 9% of ADA Presidents of Medicine and Science have been women (1,2), and since the inception of the ADA, only 5 of 81 ADA Presidents of Medicine and Science have been women. Further, women represent one-third or fewer of editorial board members for the highest-impact diabetes journals ( Diabetes Care, Diabetes , and Diabetologia …

/pdf/career-advancement-for-women-in-diabetes-related-research-2lutlaqznu.pdf

Career Advancement for Women in Diabetes-Related Research: Developing and Retaining Female Talent

Obesity and type 2 diabetes mellitus (T2D) are growing epidemics resulting in increased morbidity and mortality. An emerging body of evidence has shown that elevated levels of branched-chain amino acids (BCAA) and their metabolites are strongly positively associated with obesity, insulin-resistance and T2D. Bariatric surgery is among the best treatments for weight loss and the alleviation of T2D. Additionally, clinical studies have reported that bariatric surgery decreases the circulating levels of BCAA. The objective of these studies was to test the hypothesis that reduced BCAA levels contribute to the metabolic improvements after VSG. We find that, as in humans, circulating BCAA levels are significantly lower in VSG rats and mice compared to Sham controls. In order to increase circulating BCAA levels, we tested mice with either increased dietary intake of BCAA or impaired BCAA catabolism by total body deletion of mitochondrial phosphatase 2C, Pp2cm, a key enzyme in the rate-limiting step in BCAA catabolism. Our results show that a decrease in circulating BCAA levels is not necessary for sustained body weight loss and improved glucose tolerance after VSG. While it is clear that circulating levels of BCAAs are excellent biomarkers for metabolic status, the current data do not support a causal role in determining metabolic regulation and the response to VSG.

https://biorxiv.org/content/10.1101/2020.06.01.128157v1.full.pdf

The role of elevated branched chain amino acids in the potent effects of vertical sleeve gastrectomy to reduce weight and improve glucose regulation in mice

Darleen A. Sandoval

Papers

Glucagon in Islet and Metabolic Regulation

Vertical Sleeve Gastrectomy Induces Enteroendocrine Cell Differentiation of Intestinal Stem Cells Through Farnesoid X Receptor Activation

Preproglucagon Products and Their Respective Roles Regulating Insulin Secretion.

Career Advancement for Women in Diabetes-Related Research: Developing and Retaining Female Talent

The role of elevated branched chain amino acids in the potent effects of vertical sleeve gastrectomy to reduce weight and improve glucose regulation in mice