Body Weight Homeostasis Research Articles

Abstract PS18-51: Leptin receptor expression in breast tumors and chromatin modulators: A comparative study

Abstract Metabolic dysregulation and carcinogenesis are strongly linked. Leptin signaling acts as a metabolic switch that maintains body weight and energy homeostasis and gets impacted during metabolic dysregulation. Leptin signaling mediates its effect on breast cancer cells through downstream effectors like JAK-STAT, MAPK and PI3K pathways. At the molecular level, leptin exerts its effects through its receptor, LEPR, encoded by LEPR gene. Leptin signaling has been shown to contribute towards progression of breast cancer. Obese post-menopausal women are considered to be a high-risk category for breast cancer and dysregulated leptin signaling contributes towards it. We in this study focused on comparative molecular analysis of Leptin high (LEPRhi) and low (LEPRlow) expressing breast tumors.Breast cancer data from METABRIC (Molecular Taxonomy of Breast Cancer International Consortium) study was used through the cBioPortal (http://cbioportal.org) platform for cancer genomics. The METABRIC study includes clinical and molecular data from over 2500 breast cancer cases. The LEPRhi and LEPRlow expressing breast tumors in RNA-seq dataset were queried using cBioPortal embedded SQL feature as LEPR: EXP>1 and LEPR: EXP<-1 respectively. This query enabled us to create LEPRhi and LEPRlow expressing breast tumor cohorts from 243 and 234 patients respectively. Comparative analysis of LEPRhi and LEPRlow expressing breast tumors was performed for mRNA expression profiles. The mRNA data was further analyzed for integrated networks using GSEA pathway enrichment and CR2-cancer algorithms.The analysis indicated unique mRNA expression signature for LEPRhi and LEPRlow breast tumors. CR2-Cancer analysis of the mRNA dataset revealed chromatin modulators like- EZH2 (Enhancer of Zeste homolog 2), MEN1 (Menin), UHRF1 (Ubiquitin Like with PHD And Ring Finger Domains 1), TTF2 (Transcription termination factor 2), LMNB2 (Lamin B2), and RUVBL2 (RuvB Like AAA ATPase 2) had significantly higher mRNA expression in LEPRlow compared to LEPRhi tumor group. GSEA pathway enrichment analysis indicated PLK1 and Aurora A signaling as the most significant signaling pathways with an FDR q-value of less than 0.05.This preliminary study provides us with mechanistic insight into the unique molecular signatures of LEPRhi and LEPRlow expressing breast tumors. The results of this study leads to the basis of our hypothesis that leptin receptor signaling in breast cancer mediates epigenetic modifications of key genes that impact promotion and progression of breast cancer through chromatin modulators. Citation Format: Sara Pacheco, Maria E. Juarez, Sushmita Nandy. Leptin receptor expression in breast tumors and chromatin modulators: A comparative study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS18-51.

Sodium acetate, propionate, and butyrate reduce fat accumulation in mice via modulating appetite and relevant genes

ObjectivesAcetate, propionate, and butyrate, three of the most common short-chain fatty acids (SCFAs), can be produced when some non-digestible carbohydrates enter the large intestine and undergo bacterial fermentation. The aim of this study was to investigate the effects of these three SCFAs on appetite regulation and lipid metabolism and to determine the extent that appetite contributes to the beneficial influences of SCFAs. MethodsIn a 35-d study, 48 C57BL/6J male mice were randomly allocated to six groups: control; 5% sodium acetate; 5% sodium propionate; 5% sodium butyrate; pair fed 1; and pair fed 2. ResultsThe study showed that dietary supplementation of sodium acetate reduced serum triacylglycerol, free fatty acids, glucose, and interleukin (IL)-6 levels (P < 0.05), increased serum glucagon-like peptide 1, and leptin levels (P < 0.05), downregulated the mRNA expressions of fatty acid synthase, peroxisome proliferator-activated receptor, and lipoprotein lipase (P < 0.05), and upregulated the mRNA expressions of fasting-induced adipose factor, nuclear respiratory factor 1, mitochondrial transcription factor A, tumor necrosis factor receptor superfamily member 9, cytochrome-C oxidase IV and free fatty acid receptor 2 (P < 0.05). Sodium propionate also reduced serum IL-1β level (P < 0.05), increased serum peptide YY level (P < 0.05), downregulated the mRNA expressions of acetyl-coenzyme A carboxylase and sterol regulatory element-binding protein 1c (P < 0.05), and upregulated the mRNA expression of transmembrane protein 26 (P < 0.05). Additionally, sodium butyrate decreased average daily feed intake (P < 0.05) downregulated the mRNA expression of myosin heavy-chain (MyHc) Ⅱb (P < 0.05), and upregulated the mRNA expressions of lipase hormone-sensitive, MyHC Ⅱa and carnitine palmitoyltransferase-1α (P < 0.05). Moreover, the metabolic benefits of SCFAs were partly attributed to the reduction of feed intake. ConclusionTaken together, SCFAs could reduce appetite and fat accumulation via modulating relevant genes and hormones, which might further illustrate the potential mechanisms that underlay the effects of SCFAs on lipid homeostasis and control of body weight.

Genetic ablation of C-reactive protein gene confers resistance to obesity and insulin resistance in rats.

Besides serving as a traditional inflammatory marker, C-reactive protein (CRP) is closely associated with the development of obesity, diabetes and cardiovascular diseases as a metabolic and inflammatory marker. We hypothesise that CRP protein directly participates in the regulation of energy and glucose metabolism rather than just being a surrogate marker, and that genetic deficiency of CRP will lead to resistance to obesity and insulin resistance. Crp gene deletion was achieved by transcription activator-like effector nuclease (TALEN) technology in rats. The Crp knockout animals were placed on either a standard chow diet or a high-fat diet. Phenotypic changes in body weight, glucose metabolism, insulin sensitivity, energy expenditure and inflammation condition were examined. The central impact of CRP deficiency on leptin and insulin hypothalamic signalling, as well as glucose homeostasis, were examined via intracerebral ventricular delivery of leptin and CRP plus glucose clamp studies in the wild-type and Crp knockout rats. CRP deficiency led to a significant reduction in weight gain and food intake, elevated energy expenditure and improved insulin sensitivity after exposure to high-fat diet. Glucose clamp studies revealed enhanced hepatic insulin signalling and actions. Deficiency of CRP enhanced and prolonged the weight-reducing effect of central injected leptin and promoted the central and peripheral roles of leptin. By contrast, reinstatement of CRP into the hypothalamus of the knockout rats attenuated the effects of central leptin signalling on insulin sensitivity and peripheral glucose metabolism. This study represents the first line of genetic evidence that CRP is not merely a surrogate blood marker for inflammation and metabolic syndromes but directly regulates energy balance, body weight, insulin sensitivity and glucose homeostasis through direct regulation of leptin's central effect and hypothalamic signalling.

An overview of obesity mechanisms in humans: Endocrine regulation of food intake, eating behaviour and common determinants of body weight.

Obesity is one of the biggest health challenges of the 21st century, already affecting close to 700 million people worldwide, debilitating and shortening lives and costing billions of pounds in healthcare costs and loss of workability. Body weight homeostasis relies on complex biological mechanisms and the development of obesity occurs on a background of genetic susceptibility and an environment promoting increased caloric intake and reduced physical activity. The pathophysiology of common obesity links neuro-endocrine and metabolic disturbances with behavioural changes, genetics, epigenetics and cultural habits. Also, specific causes of obesity exist, including monogenetic diseases and iatrogenic causes. In this review, we provide an overview of obesity mechanisms in humans with a focus on energy homeostasis, endocrine regulation of food intake and eating behavior, as well as the most common specific causes of obesity.

Sexually dimorphic roles for the type 2 diabetes-associated C2cd4b gene in murine glucose homeostasis

Aims/hypothesisVariants close to the VPS13C/C2CD4A/C2CD4B locus are associated with altered risk of type 2 diabetes in genome-wide association studies. While previous functional work has suggested roles for VPS13C and C2CD4A in disease development, none has explored the role of C2CD4B.MethodsCRISPR/Cas9-induced global C2cd4b-knockout mice and zebrafish larvae with c2cd4a deletion were used to study the role of this gene in glucose homeostasis. C2 calcium dependent domain containing protein (C2CD)4A and C2CD4B constructs tagged with FLAG or green fluorescent protein were generated to investigate subcellular dynamics using confocal or near-field microscopy and to identify interacting partners by mass spectrometry.ResultsSystemic inactivation of C2cd4b in mice led to marked, but highly sexually dimorphic changes in body weight and glucose homeostasis. Female C2cd4b mice displayed unchanged body weight compared with control littermates, but abnormal glucose tolerance (AUC, p = 0.01) and defective in vivo, but not in vitro, insulin secretion (p = 0.02). This was associated with a marked decrease in follicle-stimulating hormone levels as compared with wild-type (WT) littermates (p = 0.003). In sharp contrast, male C2cd4b null mice displayed essentially normal glucose tolerance but an increase in body weight (p < 0.001) and fasting blood glucose (p = 0.003) after maintenance on a high-fat and -sucrose diet vs WT littermates. No metabolic disturbances were observed after global inactivation of C2cd4a in mice, or in pancreatic beta cell function at larval stages in C2cd4a null zebrafish. Fasting blood glucose levels were also unaltered in adult C2cd4a-null fish. C2CD4B and C2CD4A were partially localised to the plasma membrane, with the latter under the control of intracellular Ca2+. Binding partners for both included secretory-granule-localised PTPRN2/phogrin.Conclusions/interpretationOur studies suggest that C2cd4b may act centrally in the pituitary to influence sex-dependent circuits that control pancreatic beta cell function and glucose tolerance in rodents. However, the absence of sexual dimorphism in the impact of diabetes risk variants argues for additional roles for C2CD4A or VPS13C in the control of glucose homeostasis in humans.Data availabilityThe datasets generated and/or analysed during the current study are available in the Biorxiv repository (www.biorxiv.org/content/10.1101/2020.05.18.099200v1). RNA-Seq (GSE152576) and proteomics (PXD021597) data have been deposited to GEO (www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE152576) and ProteomeXchange (www.ebi.ac.uk/pride/archive/projects/PXD021597) repositories, respectively.Graphical abstract

BDNF Gene as a Precision Skill of Obesity Management.

The scarcity of the results obtained for the treatment of obesity leads us to consider new strategies, contemplating all the factors involved in the development of the disease. One of the key molecules for controlling body weight and energy homeostasis is the brain-derived neurotrophic factor (BDNF). This work summarizes the mechanisms in which BDNF gene regulates this multifactorial disease. In addition, we discuss the role of other BDNF polymorphisms as genetic determinants of obesity. In this context, a total of 14 SNPs near or inside BDNF/BDNF-AS related to BMI were identified in various GWASs. Finally, we assess gene-diet interaction as a novel tool to prevent obesity and formulate solid and personalized nutritional management. Our research group has performed the first study on the association of BDNF-AS rs925946 polymorphism and calcium intake as potential modulators of the nutritional status. Although these results should be confirmed in future studies, they open the path for new prevention opportunities.

LRP1 regulates food intake and energy balance in GABAergic neurons independently of leptin action.

Low-density lipoprotein receptor-related protein 1 (LRP1) is a member of LDL receptor family that plays a key role in systemic glucose and lipid homeostasis. LRP1 also regulates energy balance in the hypothalamus by mediating leptin's anorexigenic action, although the underlying neurocircuitry involved is still unclear. Because GABAergic neurons are a major mediator of hypothalamic leptin action, we studied the role of GABAergic LRP1 in energy balance and leptin action using mice lacking LRP1 in Vgat- or AgRP-expressing neurons (Vgat-Cre; LRP1loxP/loxP or AgRP-Cre; LRP1loxP/loxP). Here, we show that LRP1 deficiency in GABAergic neurons results in severe obesity in male and female mice fed a normal-chow diet. This effect is most likely due to increased food intake and decreased energy expenditure and locomotor activity. Increased adiposity in GABAergic neuron-specific LRP1-deficient mice is accompanied by hyperleptinemia and hyperinsulinemia. Insulin resistance and glucose intolerance in these mice are occurred without change in body weight. Importantly, LRP1 in GABAergic neurons is not required for leptin action, as evidenced by normal leptin's anorexigenic action and leptin-induced hypothalamic Stat3 phosphorylation. In contrast, LRP1 deficiency in AgRP neurons has no effect on adiposity and caloric intake. In conclusion, our data identify GABAergic neurons as a key neurocircuitry that underpins LRP1-dependent regulation of systemic energy balance and body-weight homeostasis. We further find that the GABAergic LRP1 signaling pathway modulates food intake and energy expenditure independently of leptin signaling and AgRP neurons.

Two co-inherited novel SNPs in the MC4R gene related to live body weight and hormonal assays in Awassi and Arabi sheep breeds of Iraq.

Melanocortin‐4 receptor (MC4R) gene plays a key role in the regulation of body weight and energy homeostasis. This study aims to evaluate the association of single nucleotide polymorphisms (SNPs) of the MC4R gene with live body weight and hormonal assays in two breeds of sheep that differ in productive performance, Awassi and Arabi. All known coding sequences of the MC4R gene were covered in this study. DNA samples from 150 animals (Awassi and Arabi breed) were genotyped by PCR‐single‐strand conformation polymorphism (PCR‐SSCP) to assess their pattern of genetic variation. Concerning exon 1, clear heterogeneity was detected with three different SSCP‐banding patterns. The sequencing reactions confirmed these variations by detecting the presence of the two novel SNPs, 107G/C and 138A/C, and three genotypes, GC, AC and AA. The 107G/C SNP was detected in GC genotype, while the 138A/C was detected on both GC and AC genotypes. The other SSCP‐banding pattern (AA genotype) did not show any detectable unique variation. Both SNPs were closely and strongly linked in both breeds (D' and r 2 values were 1.00), which signifies that both loci were co‐inherited as one unit. Association analysis indicated that both breeds with GC/AC haplotype showed higher live body weight (37.250 ± 0.790) relative to the GG/AA (30.244 ± 0.968) and CC/CC (47.231 ± 1.230) haplotypes (p < .05). Concerning the genotyping of exon 2, only 362 bp showed heterogeneity with a missense mutation, with no significant association (p > .05) with the measured traits. In conclusion, the two novel SNPs (107G/C and 138 A/C) were highly associated with live body weight in both breeds. Haplotype analysis confirmed that these two novel SNPs were in strong linkage disequilibrium (LD) and could be used as genetic markers for sheep phenotypic trait improvement.

Dietary Management of Obesity: A Review of the Evidence.

Obesity is a multi-factorial disease and its prevention and management require knowledge of the complex interactions underlying it and adopting a whole system approach that addresses obesogenic environments within country specific contexts. The pathophysiology behind obesity involves a myriad of genetic, epigenetic, physiological, and macroenvironmental factors that drive food intake and appetite and increase the obesity risk for susceptible individuals. Metabolically, food intake and appetite are regulated via intricate processes and feedback systems between the brain, gastrointestinal system, adipose and endocrine tissues that aim to maintain body weight and energy homeostasis but are also responsive to environmental cues that may trigger overconsumption of food beyond homeostatic needs. Under restricted caloric intake conditions such as dieting, these processes elicit compensatory metabolic mechanisms that promote energy intake and weight regain, posing great challenges to diet adherence and weight loss attempts. To mitigate these responses and enhance diet adherence and weight loss, different dietary strategies have been suggested in the literature based on their differential effects on satiety and metabolism. In this review article, we offer an overview of the literature on obesity and its underlying pathological mechanisms, and we present an evidence based comparative analysis of the effects of different popular dietary strategies on weight loss, metabolic responses and diet adherence in obesity.

Identification and characterization of distinct brown adipocyte subtypes in C57BL/6J mice.

Brown adipose tissue (BAT) plays an important role in the regulation of body weight and glucose homeostasis. Although increasing evidence supports white adipose tissue heterogeneity, little is known about heterogeneity within murine BAT. Recently, UCP1 high and low expressing brown adipocytes were identified, but a developmental origin of these subtypes has not been studied. To obtain more insights into brown preadipocyte heterogeneity, we use single-cell RNA sequencing of the BAT stromal vascular fraction of C57/BL6 mice and characterize brown preadipocyte and adipocyte clonal cell lines. Statistical analysis of gene expression profiles from brown preadipocyte and adipocyte clones identify markers distinguishing brown adipocyte subtypes. We confirm the presence of distinct brown adipocyte populations in vivo using the markers EIF5, TCF25, and BIN1. We also demonstrate that loss of Bin1 enhances UCP1 expression and mitochondrial respiration, suggesting that BIN1 marks dormant brown adipocytes. The existence of multiple brown adipocyte subtypes suggests distinct functional properties of BAT depending on its cellular composition, with potentially distinct functions in thermogenesis and the regulation of whole body energy homeostasis.

Hyperleptinemia as a contributing factor for the impairment of glucose intolerance in obesity.

Obesity has emerged as a major risk factor for insulin resistance leading to the development of type 2 diabetes (T2D). The condition is characterized by high circulating levels of the adipose-derived hormone leptin and a state of chronic low-grade inflammation. Pro-inflammatory signaling in the hypothalamus is associated with a decrease of central leptin- and insulin action leading to impaired systemic glucose tolerance. Intriguingly, leptin not only regulates body weight and glucose homeostasis but also acts as a pro-inflammatory cytokine. Here we demonstrate that increasing leptin levels (62,5µg/kg/d, PEGylated leptin) in mice fed a high-fat diet (HFD) exacerbated body weight gain and aggravated hypothalamic micro- as well as astrogliosis. In contrast, administration of a predetermined dose of a long-acting leptin antagonist (100 µg/kg/d, PESLAN) chosen to block excessive leptin signaling during diet-induced obesity (DIO) showed the opposite effect and significantly improved glucose tolerance as well as decreased the total number of microglia and astrocytes in the hypothalamus of mice fed HFD. These results suggest that high levels of leptin, such as in obesity, worsen HFD-induced micro-and astrogliosis, whereas the partial reduction of hyperleptinemia in DIO mice may have beneficial metabolic effects and improves hypothalamic gliosis.

Elevated GDF-15 levels may indicate malnutrition in chronic compensated heart failure with or without diabetes mellitus

Abstract Background/Introduction Malnutrition is common in chronic heart failure (HF) and is associated with adverse outcomes. Elevated NT-proBNP may indicate increased cardiac stress, whereas growth differentiation factor 15 (GDF-15) is increased in response to tissue injury, inflammation and in diabetes mellitus (DM). GDF-15 also negatively regulates appetite, body weight and skeletal muscle homeostasis. Purpose We aim to assess the nutritional status of HF patients with or without DM, and determine if GDF-15 is associated with malnutrition. Methods We did a cross-sectional analysis on chronic HF patients in a prospective cohort study, forecAsting Heart Failure decompensation (AHF). Chronic compensated HF was defined as a state following hospital discharge for &amp;gt;30 days, or where there had not been hospitalisation for 30 days preceding phenotyping. Patients with a history of HF decompensation were included. Geriatric Nutritional Risk Index (GNRI), including body mass index (BMI) and serum albumin, was used to assess and categorise nutritional status. Patients were classified as being “malnourished” or “well-nourished” based on GNRI scores of &amp;lt;92 and ≥92, respectively. NT-proBNP and GDF-15 levels were measured and echocardiography was done. The study was approved by institutional review board and complied with Declaration of Helsinki. Results Among 73 patients (mean age 66 y, 58.9% male), 32.7% exhibited malnutrition as determined by GNRI. There was no difference in age, sex ratio and NYHA functional class between the malnourished and the well-nourished. BMI (22.1 vs 25.6, P&amp;lt;0.001) and levels of GDF-15 (7216.0 vs 2469.0, P&amp;lt;0.001) and NT-proBNP (7158.0 vs 1321.0, P=0.01) were different between the malnourished and well-nourished. Both GDF-15 and NT-proBNP were inversely correlated with GNRI (GDF-15, r=−0.39, P&amp;lt;0.001; NT-proBNP, r=−0.46, P&amp;lt;0.0001). As expected, DM HF patients had significantly higher levels of GDF-15 than non-DM HF patients. In subgroup analysis of DM HF patients, GDF-15 and NT-proBNP levels were higher in the malnourished than well-nourished (median log-[GDF-15], 9.15 vs 8.10, P&amp;lt;0.01; median log-[NT-proBNP], 9.44 vs 7.00, P&amp;lt;0.01). Whereas in non-DM HF, NT-proBNP levels were not different between the malnourished and well-nourished. Age- and sex-adjusted logistic regression model determined that per log increment in GDF-15 level there was a 5.8-fold increased risk of malnutrition (OR 5.81 [2.43–17.62], P&amp;lt;0.001), and for every log increment in NT-proBNP level there was a 1.8-fold increase in the risk of malnutrition (OR 1.82 [1.23–2.88], P&amp;lt;0.01). Conclusion(s) Malnutrition is common in chronic compensated HF patients with a history of hospitalisation, and is associated with elevated NT-proBNP and GDF-15 levels. Elevated GDF-15 levels independently predicted poor nutritional status, and with NT-proBNP may indicate a particularly high-risk HF subgroup Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): 1) Health and Medical Research Fund, Food and Health Bureau, 2) Direct Grant, Faculty of Medicine, CUHK

Effect of physiological factors, pathologies, and acquired habits on the sweet taste threshold: A systematic review and meta-analysis.

Sweet taste perception is a key factor in the establishment of the food pattern with nonstatic thresholds. Indeed, taste sensitivity can be influenced by physiological factors (age and sex), pathologies (obesity and type 2 diabetes mellitus), and acquired habits (tobacco and alcohol consumption). In order to elucidate how these variables influence the sucrose detection threshold (DT) and recognition threshold (RT), a systematic review and meta-analysis of the relevant literature were performed. After a comprehensive search in the PubMed and Scopus databases, a total of 48 studies were qualitatively considered, and 44 were meta-analyzed. The factors of aging (standard mean difference [SMD]: -0.46; 95% confidence interval (CI), -0.74 to -0.19; I2 : 73%; Tau2 : 0.18) and type 2 diabetes mellitus (SMD: 0.30; 95% CI, 0.06 to 0.55; I2 : 0%; Tau2 : 0.00) were found to significantly increase the sucrose RT, whereas the DT only increased in subjects with a higher body mass index (SMD: 0.58; 95% CI, 0.35 to 0.82; I2 : 0%; Tau2 : 0.00). No effects of sex and tobacco smoking were found, and associations with alcohol consumption could not be assessed, as it was included as a variable in only one study. Feasible mechanisms underlying changes in sucrose thresholds include the modulation of hormones involved in energy and body weight homeostasis, taste bud abundance, taste brain signaling, and the gut-brain axis. The present work provides insights into the variables that should be considered when assessing sweet taste sensitivity, discusses the mechanisms underlying differences in sweet taste, and highlights the need for further research in the field of personalized nutrition.

Discovery and preclinical efficacy of HSG4112, a synthetic structural analog of glabridin, for the treatment of obesity

BackgroundHSG4112 is a clinical-stage drug candidate for the treatment of obesity. Here, we report its discovery and preclinical efficacy.MethodsIn high-fat diet (HFD)-induced obese male C57BL/6J mice, we tested the weight loss effect of synthetic compounds derived from a structure–activity relationship (SAR) study of glabridin, a natural compound known to reduce body weight and influence energy homeostasis. After selecting HSG4112 as our optimized compound from this discovery method, we characterized its pharmacological effects on parameters related to obesity through in vivo metabolic and biochemical measurements, histology and gene expression analysis, and indirect calorimetry.ResultsThrough the SAR study, we identified four novel components of glabridin pertinent for its anti-obesity activity, and found that HSG4112, an optimized structural analog of glabridin, markedly supersedes glabridin in weight reduction efficacy and chemical stability. Six-week administration of HSG4112 to HFD-induced obese mice led to dose-dependent normalization of obesity-related parameters, including body weight, muscle and adipose tissue weight, adipocyte size, and serum leptin/insulin/glucose levels. The weight reduction induced by HSG4112 was partially mediated by decreased food intake and mainly mediated by increased energy expenditure, with no change in physical activity. Accordingly, the pattern of transcriptional changes was aligned with increased energy expenditure in the liver and muscles. Following significant body weight reduction, robust amelioration of histopathology and blood markers of fatty liver were also observed.ConclusionsOur study demonstrates the key chemical components of glabridin pertinent to its weight loss effects and suggests HSG4112 as a promising novel drug candidate for the pharmacological treatment of obesity.

IGFBP-2 Partly Mediates the Early Metabolic Improvements Caused by Bariatric Surgery

Insulin-like growth factor-binding protein (IGFBP)-2 is a circulating biomarker of cardiometabolic health. Here, we aimed at evaluating its levels following different bariatric procedures, and whether it directly contributes to their beneficial effects on body weight and glucose homeostasis. In humans, plasma IGFBP-2 levels increased to higher levels after biliopancreatic diversion with duodenal switch (BPD-DS), compared to Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG). This increase was closely associated with insulin sensitization. In mice and rats, BPD-DS and RYGB operations also increased circulating IGFBP-2 levels, which were not affected by SG or caloric restriction. In mice, Igfbp2 deficiency significantly blunted surgery-induced loss in adiposity and early improvement in insulin sensitivity but did not impact long-term enhancement in glucose homeostasis. This study demonstrated that the modulation of circulating IGFBP-2 may play a role in the early improvement of insulin sensitivity and loss of adiposity brought about by bariatric surgery.

Gut microbiome alterations induced by tributyltin exposure are associated with increased body weight, impaired glucose and insulin homeostasis and endocrine disruption in mice

Tributyltin (TBT), an organotin compound once widely used in agriculture and industry, has been reported to induce obesity and endocrine disruption. Gut microbiota has a strong connection with the host’s physiology. Nevertheless, the influences of TBT exposure on gut microbiota and whether TBT-influenced gut microbiota is related to TBT-induced toxicity remain unclear. To fill these gaps, ICR (CD-1) mice were respectively exposed to TBT at NOEL (L-TBT) and tenfold NOEL (H-TBT) daily by gavage for 8 weeks in the current study. The results showed that TBT exposure significantly increased body weight as well as epididymal fat, and led to adipocyte hypertrophy, dyslipidemia and impaired glucose and insulin homeostasis in mice. Additionally, TBT exposure significantly decreased the levels of T4, T3 and testosterone in serum. Also of note, TBT exposure changed gut microbiota composition mainly by decreasing Bacteroidetes and increasing Firmicutes proportions. To confirm the role of gut microbiota in TBT-induced overweight and hormonal disorders, fecal microbiota transplantation was performed and the mice receiving gut microbiota from H-TBT mice had similar phenotypes with their donor mice including significant body weight and epididymal fat gain, glucose and insulin dysbiosis and hormonal disorders. These results suggested that gut microbiome altered by TBT exposure was involved in the TBT-induced increased body weight, impaired glucose and insulin homeostasis and endocrine disruption in mice, providing significant evidence and a novel perspective for better understanding the mechanism by which TBT induces toxicity.

Perinatal exposure to a dietary pesticide cocktail does not increase susceptibility to high-fat diet-induced metabolic perturbations at adulthood but modifies urinary and fecal metabolic fingerprints in C57Bl6/J mice

BackgroundWe recently demonstrated that chronic dietary exposure to a mixture of pesticides at low-doses induced sexually dimorphic obesogenic and diabetogenic effects in adult mice. Perinatal pesticide exposure may also be a factor in metabolic disease etiology. However, the long-term consequences of perinatal pesticide exposure remain controversial and largely unexplored. ObjectivesHere we assessed how perinatal exposure to the same low-dose pesticide cocktail impacted metabolic homeostasis in adult mice. MethodsSix pesticides (boscalid, captan, chlopyrifos, thiachloprid, thiophanate, and ziram) were incorporated in food pellets. During the gestation and lactation periods, female (F0) mice were fed either a pesticide-free or a pesticide-enriched diet at doses exposing them to the tolerable daily intake (TDI) level for each compound, using a 1:1 body weight scaling from humans to mice. All male and female offsprings (F1) were then fed the pesticide-free diet until 18 weeks of age, followed by challenge with a pesticide-free high-fat diet (HFD) for 6 weeks. Metabolic parameters, including body weight, food and water consumption, glucose tolerance, and urinary and fecal metabolomes, were assessed over time. At the end of the experiment, we evaluated energetic metabolism and microbiota activity using biochemical assays, gene expression profiling, and 1H NMR-based metabolomics in the liver, urine, and feces. ResultsPerinatal pesticide exposure did not affect body weight or energy homeostasis in 6- and 14-week-old mice. As expected, HFD increased body weight and induced metabolic disorders as compared to a low-fat diet. However, HFD-induced metabolic perturbations were similar between mice with and without perinatal pesticide exposure. Interestingly, perinatal pesticide exposure induced time-specific and sex-specific alterations in the urinary and fecal metabolomes of adult mice, suggesting long-lasting changes in gut microbiota. ConclusionsPerinatal pesticide exposure induced sustained sexually dimorphic perturbations of the urinary and fecal metabolic fingerprints, but did not significantly influence the development of HFD-induced metabolic diseases.

MC4R Variant rs17782313 Associates With Increased Levels of DNAJC27, Ghrelin, and Visfatin and Correlates With Obesity and Hypertension in a Kuwaiti Cohort.

Melanocortin 4 receptor (MC4R), a notable component of the melanocortin system, regulates appetite, body weight, and energy homeostasis. Genome-wide association studies have identified several MC4R variants associated with adiposity; of these, rs17782313, which is associated with increased body mass index (BMI) and overeating behavior, is of particular interest. Another gene associated with increased adiposity in global genome-wide association studies is DNAJC27, a heat shock protein known to be elevated in obesity. The detailed mechanisms underlying the role of MC4R variants in the biological pathways underlying metabolic disorders are not well-understood. To address this, we assessed variations of rs17782313 in a cohort of 282 Arab individuals from Kuwait, who are deeply phenotyped for anthropometric and metabolic traits and various biomarkers, including DNAJC27. Association tests showed that the rs17782313_C allele was associated with BMI and DNAJC27 levels. Increased levels of DNAJC27 reduced the MC4R-mediated formation of cAMP in MC4R ACTOne stable cells. In conclusion, this study demonstrated an association between the rs17782313 variant near MC4R and increased BMI and DNAJC27 levels and established a link between increased DNAJC27 levels and lower cAMP levels. We propose that regulation of MC4R activity by DNAJC27 enhances appetite through its effect on cAMP, thereby regulating obesity.

Lack of AR in LepRb Cells Disrupts Ambulatory Activity and Neuroendocrine Axes in a Sex-Specific Manner in Mice.

Disorders of androgen imbalance, such as hyperandrogenism in females or hypoandrogenism in males, increase risk of visceral adiposity, type 2 diabetes, and infertility. Androgens act upon androgen receptors (AR) which are expressed in many tissues. In the brain, AR are abundant in hypothalamic nuclei involved in regulation of reproduction and energy homeostasis, yet the role of androgens acting via AR in specific neuronal populations has not been fully elucidated. Leptin receptor (LepRb)-expressing neurons coexpress AR predominantly in hypothalamic arcuate and ventral premammillary nuclei (ARH and PMv, respectively), with low colocalization in other LepRb neuronal populations, and very low colocalization in the pituitary gland and gonads. Deletion of AR from LepRb-expressing cells (LepRbΔAR) has no effect on body weight, energy expenditure, and glucose homeostasis in male and female mice. However, LepRbΔAR female mice show increased body length later in life, whereas male LepRbΔAR mice show an increase in spontaneous ambulatory activity. LepRbΔAR mice display typical pubertal timing, estrous cycles, and fertility, but increased testosterone levels in males. Removal of sex steroid negative feedback action induced an exaggerated rise in luteinizing hormone in LepRbΔAR males and follicle-stimulating hormone in LepRbΔAR females. Our findings show that AR can directly affect a subset of ARH and PMv neurons in a sex-specific manner and demonstrate specific androgenic actions in the neuroendocrine hypothalamus.

Effects of leptin on HPG axis and reproductive function in male rat in simulated altitude of 5500 m hypoxia environment

High altitude hypobaric hypoxia environment impairs male’s reproductive function. Leptin is an adipose tissue-derived hormone which regulates body weight homeostasis. Its receptor (LepR) has been found in all levels of male reproductive axis, indicating that it can affect male reproductive system in a direct or (and) indirect way. However, the role of leptin signaling in hypobaric hypoxia induced male reproductive dysfunction remains to be elucidated. In this study, we investigated the changes of leptin levels in male SD rats in stimulated altitude of 5500 m hypobaric hypoxia environment and their effects on the hypothalamus-pituitary-gonad axis (HPG axis). A hypoxia animal model was established using a hypobaric hypoxia chamber. Rats were divided randomly into 1, 7, 14, 28-day hypoxia group, recovery group (14 days hypoxia+14 days normoxia) and their control groups. Hypoxia groups displayed obvious changes of testicular and epididymis index compared to control groups. The total number of sperm and sperm motility rate decreased dramatically, while sperm deformity rate increased in hypoxia groups. The flow cytometry analysis showed that the percentage of haploid in 1-day, 7-day and 28-day hypoxia groups increased while the proportion of diploid decreased in 14-day and 28-day hypoxia group. TUNEL staining showed that the testis cells apoptosis index (AI) of hypoxia groups increased significantly, and the apoptosis of cells mainly focus on spermatogonia and spermatocytes. The expression of GnRH in hypothalamus decreased dramatically under hypoxia condition, accompanied with the reduction of serum testosterone (T) level in 1-day and 28-day hypoxia groups and free-testosterone level (FT) in 1-day and 14-day hypoxia groups. Importantly, ELISA analysis showed that serum leptin level decreased in 7-day hypoxia groups and acylated-ghrelin, gastrin also changed, accompanying with reduction of LepR in hypothalamus in hypoxia groups. Immunohistochemical staining exhibited increased leptin and LepR in testis under hypobaric hypoxia conditions. Our results suggested that simulated high altitude hypobaric hypoxia environment decreased male reproductive function, depressed HPG axis activity and altered the serum concentration of hormones related to food intake in adult male rats. Additionally, hypobaric hypoxia induced the leptin-LepR expression in adult male rats’ testis, suggesting leptin-LepR signaling may mediate hypoxia-induced impairment in male rats’ reproductive system.