Obese Research Articles

L-aspartate ameliorates diet-induced obesity by increasing adipocyte energy expenditure.

Obesity always leads to profound perturbation of metabolome. Metabolome studies enrich the knowledge on associations between endogenous metabolites and obesity, potentially providing innovative strategies for the development of novel anti-obesity pharmacotherapy. This study aims to identify an endogenous metabolite that regulates energy expenditure and to explore its application for obesity treatment. C57BL/6 mice were fed with a high-fat and high-cholesterol (HFC) diet, comprising 60% fat and 1.2% cholesterol, for 12 weeks to induce obesity. Significant metabolites were identified in the livers of both health and obese mice through comparative hepatic metabolomics analysis. Correlation between serum or adipose L-aspartate level and body weight in obese mice, as well as human body mass index (BMI), was evaluated. In addition, saline or 200 mg/kg L-aspartate was orally administrated to HFC diet mice and HFC diet-induced obese mice for 6-7 weeks. Body weight, adipose tissue weight, glucose tolerance and liver damage were assessed to evaluate the effect on obesity prevention and treatment. Comprehensive lab animal monitoring system (CLAMS) and seahorse assay were employed to investigate the regulatory effect of L-aspartate on energy metabolism in vivo and in vitro, respectively. 3T3-L1 preadipocytes and murine white adipose tissue (WAT) were utilized to examine the impact of L-aspartate on adipocyte adipogenesis and lipogenesis and cellular signalling pathway in vitro and in vivo. L-aspartate, an approved drug for liver injury and chronic fatigue, was identified as an endogenous inducer of energy expenditure. Serum or adipose L-aspartate levels were found to be negatively correlated with the severity of obesity in both humans and mice. Administration of L-aspartate to HFC diet mice led to a significant reduction in body weight, with decreases of 14.5% in HFC diet mice and 8.5% in HFC diet-induced obese mice, respectively. In addition, the treatment improved related metabolic syndrome (Figure 2 and Figure S3). These therapeutics were associated with enhancements in whole-body energy expenditure and suppression of adipocyte adipogenesis along with activation of Adenosine 5'-monophosphate-activated protein kinase (AMPK) signalling pathway. L-aspartate may serve as a novel endogenous inducer of energy expenditure and suppressor of adipogenesis and lipogenesis along with activation of AMPK, thereby offering a promising therapeutic strategy for obesity prevention and treatment.

In silico and functional analysis identifies key gene networks and novel gene candidates in obesity-linked human visceral fat.

Visceral adiposity is associated with increased proinflammatory activity, insulin resistance, diabetes risk, and mortality rate. Numerous individual genes have been associated with obesity, but studies investigating gene regulatory networks in human visceral obesity have been lacking. We analyzed gene regulatory networks in human visceral adipose tissue (VAT) from 48 and 11 Chinese patients with and without obesity, respectively, using gene coexpression and gene regulatory network construction from RNA-sequencing data. We also conducted RNA interference-based functional tests on selected genes for effects on adipocyte differentiation. A scale-free gene coexpression network was constructed from 360 differentially expressed genes between VAT samples from patients with and without obesity (absolute log fold change > 1, false discovery rate [FDR] < 0.05), with edge probability > 0.8. Gene regulatory network analysis identified candidate transcription factors associated with differentially expressed genes. A total of 15 subnetworks (communities) displayed altered connectivity patterns between obesity and nonobesity networks. Genes in proinflammatory pathways showed increased network connectivity in VAT samples with obesity, whereas the oxidative phosphorylation pathway displayed reduced connectivity (enrichment FDR < 0.05). Functional screening via RNA interference identified genes such as SOX30, SIRPB1, and OSBPL3 as potential network-derived candidates influencing adipocyte differentiation. This approach highlights the network architecture in human obesity, identifies novel candidate genes, and generates new hypotheses regarding network-assisted gene regulation in VAT.

Increased susceptibility to diet-induced obesity in female mice impairs ovarian steroidogenesis: the role of elevated leptin signalling on Nodal activity inhibition in theca cells

ObjectiveSusceptibility to obesity in humans is driven by the intricate interplay of genetic, environmental and behavioural factors. Moreover, the mechanisms linking maternal obesity to infertility remain largely understudied. In this study, we investigated how variable susceptibility to obesity in mice affects ovarian steroidogenesis, with a particular focus on the leptin-mediated dysregulation of Nodal signalling pathway in theca cells (TC). MethodsC56BL/6J (B6) and 129S1/SvlmJ (129) mice, models of maternal obesity (MO), were fed a chow diet (CD) and a high fat diet (HFD) for 16 weeks. To investigate the contrasting effects of leptin on ovarian steroidogenesis, B6 mice pharmacologically treated with leptin for 16 days on CD were used to model hyperleptinemia, while homozygous ob/ob (-/-) mice with genetic leptin deficiency, also on a CD, were used to examine the effects of obesity in the absence of leptin. Following the characterisation of the mouse phenotype, gonadal fat (GON), whole ovaries (WO), ovarian TC and granulosa cell (GC) fractions were collected for mRNA transcription and protein expression analysis. Finally, in vitro treated ovarian explants obtained from B6 mice were used to further elucidate the effects of Nodal on steroidogenesis. ResultsThe significant gain in body weight (BW) and fat mass (FM) in HFD-fed B6 mice (p<0.05), was associated with increased mRNA transcription of the adipose tissue expansion genes Polymerase I and transcript release factor (Cavin), Secreted frizzled- related protein 5 (Sfrp5) and Mesoderm specific transcript (Mest) in GON (p<0.05). Furthermore, the HFD-fed B6 mice presented also impaired glucose metabolism and insulin sensitivity (p<0.05). In contrast, the HFD-fed 129 mice exhibited no changes in BW and FM, maintaining glucose and insulin metabolism. At the ovarian level, decreased protein expression of Steroidogenic Acute Regulatory Protein (StAR) in WO obtained from HFD-fed B6 mice (p=0.05), was followed by reduced transcription of key steroidogenic genes like Star and Cytochrome P450 17a1 (Cyp17a) in TC (p<0.05). Furthermore, the transcription of Nodal and its receptors was downregulated (p<0.05), whereas mRNA levels of Suppressor of cytokine signalling 3 (Socs3) and SMAD family member 7 (Smad7) were upregulated in TC obtained from HFD-fed B6 mice (p<0.05). No changes were seen in the genes regulating steroidogenesis, Nodal signalling, or Socs3 and Smad7 activity in the ovaries of HFD-fed 129 mice. Importantly, the pharmacological treatment of lean mice with leptin, upregulated the ovarian transcription of Socs3 and Smad7, while downregulating Nodal and its receptors (p<0.05). Finally, in vitro pharmacological inhibition of Nodal signalling pathway in ovarian explants isolated from CD-fed B6 mice decreased the transcription of Star and Cyp17a in TC (p<0.05), whereas Nodal treatment of explants obtained from HFD-fed B6 mice restored the transcription of both genes (p<0.05). ConclusionsIncreased susceptibility to obesity in MO is associated with systemic hyperleptinemia and hypoestrogenism due to compromised ovarian steroidogenesis, largely driven by the inhibitory effects of leptin-Smad7 pathway on Nodal signalling activity in the TC compartment of ovarian follicles.

Paradoxıcal effect of body mass index ranges on pedobarographic evaluatıon

Although there is evidence suggesting that obesity alters plantar pressure distribution, the specific effects of certain body mass index (BMI) ranges on pedobarographic measures in healty individuals has been poorly investigated. A cross-sectional study with 167 healthy participants was conducted to assess plantar pressure changes across 4 BMI ranges: Under/normal weight (NW), overweight (OW), obese (OB), severe obese (SO). Subjects walked on the Footscan® pressure plate at a self-selected speed, and peak plantar pressure (PPP), load rate, and contact area values were recorded. The foot was divided into 10 zones: hallux (T1), toes 2–5 (T2-5), metatarsals 1–5 (M1-M5), midfoot (MF), medial hindfoot (MH) and lateral hindfoot (LH). PPP underneath M2-M4 was lowest in the NW group (p = 0.011), and although PPP values for the SO group were lower than those for the OW and OB groups, these differences were not statistically significant. Load rate values of M2-M3 were lower in both the NW and SO groups (p = 0.008) compared to the OW and OB groups. In addition, the metatarsal load rate values for the SO group were generally lower than those for the NW group. The total metatarsal contact area of both the NW and SO groups was lower (p = 0.019) than that of the OW and OB groups in both feet. These findings suggest that as BMI increases, PPP, load rate, and contact area in the middle metatarsal region initially increase, stabilize early in obesity, and then decrease at advanced stages, indicating a shift of the load to the midfoot.

Eubacterium siraeum suppresses fat deposition via decreasing the tyrosine-mediated PI3K/AKT signaling pathway in high-fat diet-induced obesity.

Obesity in humans can lead to chronic diseases such as diabetes and cardiovascular disease. Similarly, subcutaneous fat (SCF) in pigs affects feed utilization, and excessive SCF can reduce the feed efficiency of pigs. Therefore, identifying factors that suppress fat deposition is particularly important. Numerous studies have implicated the gut microbiome in pigs' fat deposition, but research into its suppression remains scarce. The Lulai black pig (LL) is a hybrid breed derived from the Laiwu pig (LW) and the Yorkshire pig, with lower levels of SCF compared to the LW. In this study, we focused on these breeds to identify microbiota that regulate fat deposition. The key questions were: Which microbial populations reduce fat in LL pigs compared to LW pigs, and what is the underlying regulatory mechanism? In this study, we identified four different microbial strains, Eubacterium siraeum, Treponema bryantii, Clostridium sp. CAG:413, and Jeotgalibaca dankookensis, prevalent in both LW and LL pigs. Blood metabolome analysis revealed 49 differential metabolites, including tanshinone IIA and royal jelly acid, known for their anti-adipogenic properties. E. siraeum was strongly correlated with these metabolites, and its genes and metabolites were enriched in pathways linked to fatty acid degradation, glycerophospholipid, and glycerolipid metabolism. In vivo mouse experiments confirmed that E. siraeum metabolites curb weight gain, reduce SCF adipocyte size, increase the number of brown adipocytes, and regulate leptin, IL-6, and insulin secretion. Finally, we found that one important pathway through which E. siraeum inhibits fat deposition is by suppressing the phosphorylation of key proteins in the PI3K/AKT signaling pathway through the reduction of tyrosine. We compared LW and LL pigs using fecal metagenomics, metabolomics, and blood metabolomics, identifying E. siraeum as a strain linked to fat deposition. Oral administration experiments in mice demonstrated that E. siraeum effectively inhibits fat accumulation, primarily through the suppression of the PI3K/AKT signaling pathway, a critical regulator of lipid metabolism. These findings provide a valuable theoretical basis for improving pork quality and offer insights relevant to the study of human obesity and related chronic metabolic diseases. Video Abstract.

Alzheimer’s Disease, Obesity, and Type 2 Diabetes: Focus on Common Neuroglial Dysfunctions (Critical Review and New Data on Human Brain and Models)

Background/Objectives. Obesity, type 2 diabetes (T2D), and Alzheimer’s disease (AD) are pathologies that affect millions of people worldwide. They have no effective therapy and are difficult to prevent and control when they develop. It has been known for many years that these diseases have many pathogenic aspects in common. We highlight in this review that neuroglial cells (astroglia, oligodendroglia, and microglia) play a vital role in the origin, clinical–pathological development, and course of brain neurodegeneration. Moreover, we include the new results of a T2D-AD mouse model (APP+PS1 mice on a high-calorie diet) that we are investigating. Methods. Critical bibliographic revision and biochemical neuropathological study of neuroglia in a T2D-AD model. Results. T2D and AD are not only “connected” by producing complex pathologies in the same individual (obesity, T2D, and AD), but they also have many common pathogenic mechanisms. These include insulin resistance, hyperinsulinemia, hyperglycemia, oxidative stress, mitochondrial dysfunction, and inflammation (both peripheral and central—or neuroinflammation). Cognitive impairment and AD are the maximum exponents of brain neurodegeneration in these pathological processes. both due to the dysfunctions induced by metabolic changes in peripheral tissues and inadequate neurotoxic responses to changes in the brain. In this review, we first analyze the common pathogenic mechanisms of obesity, T2D, and AD (and/or cerebral vascular dementia) that induce transcendental changes and responses in neuroglia. The relationships between T2D and AD discussed mainly focus on neuroglial responses. Next, we present neuroglial changes within their neuropathological context in diverse scenarios: (a) aging involution and neurodegenerative disorders, (b) human obesity and diabetes and obesity/diabetes models, (c) human AD and in AD models, and (d) human AD-T2D and AD-T2D models. An important part of the data presented comes from our own studies on humans and experimental models over the past few years. In the T2D-AD section, we included the results of a T2D-AD mouse model (APP+PS1 mice on a high-calorie diet) that we investigated, which showed that neuroglial dysfunctions (astrocytosis and microgliosis) manifest before the appearance of amyloid neuropathology, and that the amyloid pathology is greater than that presented by mice fed a normal, non-high-caloric diet A broad review is finally included on pharmacological, cellular, genic, and non-pharmacological (especially diet and lifestyle) neuroglial-related treatments, as well as clinical trials in a comparative way between T2D and AD. These neuroglial treatments need to be included in the multimodal/integral treatments of T2D and AD to achieve greater therapeutic efficacy in many millions of patients. Conclusions. Neuroglial alterations (especially in astroglia and microglia, cornerstones of neuroinflammation) are markedly defining brain neurodegeneration in T2D and A, although there are some not significant differences between each of the studied pathologies. Neuroglial therapies are a very important and p. promising tool that are being developed to prevent and/or treat brain dysfunction in T2D-AD. The need for further research in two very different directions is evident: (a) characterization of the phenotypic changes of astrocytes and microglial cells in each region of the brain and in each phase of development of each isolated and associated pathology (single-cell studies are mandatory) to better understand the pathologies and define new therapeutic targets; (b) studying new therapeutic avenues to normalize the function of neuroglial cells (preventing neurotoxic responses and/or reversing them) in these pathologies, as well as the phenotypic characteristics in each moment of the course and place of the neurodegenerative process.

Adipose Tissue-Resident Sphingomonas Paucimobilis Suppresses Adaptive Thermogenesis by Reducing 15-HETE Production and Inhibiting AMPK Pathway.

Obesity represents a low-grade chronic inflammation status, which is associated with compromised adaptive thermogenesis. However, the mechanisms underlying the defective activation of thermogenesis in chronic inflammation remain unclear. Here, a chronic inflammatory model is first estabolished by injecting mice with low-dose lipopolysaccharide (LPS) before cold exposure, and then it is verified that LPS treatment can decrease the core body temperature of mice and alter the microbial distribution in epididymal white adipose tissue (eWAT). An adipose tissue-resident bacterium Sphingomonas paucimobilis is identified as a potential inhibitor on the activation of brown fat and browning of inguinal WAT, resulting in defective adaptive thermogenesis. Mechanically, LPS and S. paucimobilis inhibit the production and release of 15-HETE by suppressing its main metabolic enzyme 12 lipoxygenase (12-LOX) and 15- Hydroxyeicosatetraenoic acid (15-HETE) rescues the impaired thermogenesis. Interestingly, 15-HETE directly binds to AMP-activated protein kinase α (AMPKα) and elevates the phosphorylation of AMPK, leading to the activation of uncoupling protein 1 (UCP1) and mitochondrial oxidative phosphorylation (OXPHOS) complexes. Further analysis with human obesity subjects reveals that individuals with high body mass index displayed lower 15-HETE levels. Taken together, this work improves the understanding of how chronic inflammation impairs adaptive thermogenesis and provides novel targets for alleviating obesity.

Serum expression of mirnas in obese and lean patients with heart failure

Abstract Background Heart Failure (HF) is a progressive disease that results in increased morbidity and mortality, and clinical studies have demonstrated that body mass index (BMI) is an independent risk factor for the development of HF. Evidence has suggested that human obesity is associated with reduced mortality among patients with HF, a clinical phenomenon known as the "Obesity Paradox." MicroRNAs (miRNAs) have been underscored for their pivotal regulatory roles in numerous diseases, particularly in the context of HF. Nevertheless, our understanding of the impact of these miRNAs on obesity in conjunction with HF remains limited. Purpose The objective of this study was to evaluate the serum expression of miRNAs in obese and lean patients with HF and establish the relationship between these miRNAs and BMI. Additionally, we explored this association within two distinct phenotypes: HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). Methods Sixty-five patients with symptomatic HF (all NYHA &amp;gt;/=II, mean-LVFE 44.4 %), 29 lean (BMI= 25.87 ± 2.52 Kg/m2) and 36 obese (BMI= 34.52 ± 4.15 Kg/m2), were prospectively evaluated by clinical, laboratory and echocardiographic analyses. Serum expression of miRNAs was assessed by the TaqMan OpenArray Human MicroRNA system, a polymerase chain reaction-based quantitative platform that contains 754 microRNAs in a microfluidic platform. Results Among the studied miRNAs, seventeen were upregulated and one downregulated in obese HF patients compared to lean HF patients (Figure 1A). Ten miRNAs were differentially expressed in the serum of obese HFpEF patients compared to lean HFrEF patients (Figure 1B) and five were differentially expressed in the serum of obese HFpEF patients when compared to lean HFpEF patients (Figure 1C). miR-132 was upregulated in obese patients with HFrEF and HFpEF compared to lean patients, whereas miR-1291 was downregulated only in obese patients with HFpEF. Correlation analysis demonstrated a positive association between BMI and miR-132 (r=0.502; p=0.001), miR-148b (r=0.510; p&amp;lt;0.001), miR-103a-3p (r=0.373; p =0.011) and miR-374b-5p (r=0.325; p=0.034) in HF patients and gene set enrichment analysis identified seventy-nine potential target genes common to at least three of these four miRNAs, with the EIF4E3 and TRA2B genes common to the four miRNAs. Conclusions Our study reveals a profile of miRNAs that are differentially expressed in obese patients with HF when compared to lean patients with HF. Furthermore, four of these miRNAs showed a positive correlation with BMI in patients with HF. Although the literature indicates that miR-132 presents reduced expression in obesity models, our study identified increased serum expression of this miRNA, suggesting that it might be a potential "missing link" in the obesity paradox in patients with HF. Further studies with a larger sample are needed to confirm and explore the mechanisms linking these miRNAs to the obesity paradox.

Modern approaches in the diagnosis, treatment and prevention from obesity

Today, from 1.0 to 1.9 billion adults are overweight, including 312-650 million of them, and 124 million children and adolescents are obese. In Russia and Europe, about 60% of residents are obese and overweight. According to WHO forecasts, by 2025 the number of obese patients will double and will account for 30-50% of the population of economically developed countries. Morbid obesity is usually a multifactorial disease that is acquired and progresses under the influence of many factors (geography, level of economic development, cultural values, lifestyle, and others) as well as hereditary predisposition. Among people suffering from comorbid obesity, there is an atypical course of concomitant comorbid diseases. Against the background of morbid obesity, the likelihood of acquiring other diseases of organs and systems increases: the cardiovascular system, hormonal system, digestive tract, erosive esophagitis, fatty liver dystrophy, cirrhosis of the liver, obstructive sleep apnea, osteoarthritis, etc. To confirm the presence of morbid obesity in humans, the following indicators are evaluated: the number of kilograms per square meter of human body area (BMI calculation), waist circumference, triglyceride index, as well as the use of instrumental diagnostics: radiation and ultrasound methods to study the level of obesity of internal organs. To date, orlistat, sibutramine and liraglutide have been registered in Russia for the conservative therapy of morbid obesity, i.e. the choice of drugs is very limited. Surgical methods and electrical stimulation of the stomach are also used. Obesity ranked 5th in the world ranking of risk factors for premature death. A targeted policy and an integrated approach aimed at improving the system of medical care for overweight and obese patients should become key factors in achieving the national goal of improving people's health and well-being. The expansion of preventive measures at the local, regional and federal levels will help significantly reduce the spread of this pathology and prevent the development of an "obesity pandemic".

Effect of obesity and NAFLD on leukocyte telomere length and hTERT gene MNS16A VNTR variant

It is known that telomere length (TL) (evaluated with T/S ratio) is shortened in the presence of obesity. In this study, we aimed to investigate how obesity in adolescents and non-alcoholic liver disease (NAFLD) within the obese group affect TL and the clinical significance of the human telomerase reverse transcriptase (hTERT) gene MNS16A VNTR variant in terms of NAFLD. Adolescents with exogenous obesity and healthy controls (aged 10–19 years) who applied to our adolescent outpatient clinic between May-October 2023 were included in this study. We performed upper abdominal ultrasonography to investigate the presence of NAFLD in adolescents with obesity and divided into two groups: those without hepatosteatosis (obese NAFLD (-)) and those with hepatosteatosis (obese NAFLD (+)). We recorded body weight, height, waist circumference, and blood pressure measurements and measured the T/S ratio (telomere sequence copy number/gene single copy number) by the Quantitative Polymerase Chain Reaction method. The groups were compared using frequentist and Bayesian methods. Eighty-three obese adolescents [63 NAFLD(+) 20 NAFLD(-)] and 69 lean controls were included in the study. Pairwise comparisons revealed that T/S ratio was significantly lower in the obese NAFLD (-) group than the obese NAFLD (+) and the control group (p = 0.025, p = 0.007, respectively). T/S ratio was lower in the LL allele group than in the other alleles (p = 0.022) and slightly higher in the obese group with metabolic syndrome compared to the obese group without metabolic syndrome (p = 0.072). hTERT-MNS16A-VNTR gene variant LL allele had a negative correlation with T/S ratio among the obese adolescent group. Patients with LL alleles had higher ALT, GGT, HOMA-IR, and ALT/AST. Diastolic blood pressure had a significant correlation with the T/S ratio. The T/S ratio was shorter in the obese adolescent group compared to healthy ones but was higher in the NAFLD (+) obese compared to the NAFLD (-) obese. ALT level and ALT/AST ratio were higher, T/S ratio was lower in the hTERT MNS16A VNTR variant LL allele group among obese adolescents. In addition, there was a significant correlation between the T/S ratio and diastolic blood pressure in obese adolescents.

Challenging Childhood Obesity: The Influence of Education and Close Monitoring on Obesity-Related Behaviors.

We aimed to evaluate the role of nutrition and behavior education intervention in the prevention and treatment of childhood obesity by comparing changes in obesity-related characteristics among obese children during a follow-up period of 12 months. This study was designed as a prospective cohort study in children aged between 6 and 18 years, with exogenous obesity who applied to Istanbul Research and Training Hospital, Pediatrics Department, between January 2018 and July 2019. Beginning at the sixth month, a program for nutrition and behavior education for obesity prevention and treatment was initiated and continued during the second half of the study period. The mean age of 59 children (29 females, 30 males) was 11.73 ± 2.78. BMI levels did not show a significant difference in the first 6 months, but decreased significantly during the second 6 months of the study. Screen time, fast eating behavior, overeating behavior and food score index scores also demonstrated significant improvements during the intervention period of the study, between 6 and 12 months. It was concluded that nutrition and behavior education for the prevention and treatment of childhood obesity could be a successful intervention with close follow-up.

Loss of adipose ATF3 promotes adipose tissue lipolysis and the development of MASH

The crosstalk between adipose tissue and the liver is finely controlled to maintain metabolic health. Yet, how adipose tissue controls toxic free fatty acid overflow into the liver remains incompletely understood. Here, we show that adipocyte activating transcription factor 3 (ATF3) was induced in human or mouse obesity. Adipocyte Atf3−/− (Atf3Adi−/−) mice developed obesity, glucose intolerance, and metabolic dysfunction-associated steatohepatitis (MASH) in chow diet, high-fat diet, or Western diet-fed mice. Blocking fatty acid flux by inhibiting hepatocyte CD36, but not the restoration of hepatic AMPK signaling, prevented the aggravation of MASH in Atf3Adi−/− mice. Further studies show that the loss of adipocyte ATF3 increased lipolysis via inducing adipose triglyceride lipase, which in turn induced lipogenesis and inflammation in hepatocytes. Moreover, Atf3Adi−/− mice had reduced energy expenditure and increased adipose lipogenesis and inflammation. Our data demonstrate that adipocyte ATF3 is a gatekeeper in counteracting MASH development under physiological and pathological conditions.

Insulin receptor signalling in PDGFRβ-expressing cells influences systemic metabolism and negatively impacts lipid storage

Pericytes are vascular mural cells that support the microvasculature; their dysfunction contributes to diabetic retinopathy and has been linked to obesity in humans. To explore the role of pericyte insulin signalling on systemic metabolism we utilised male mice from our previously described PIR−/− (PIRKO) mouse line which has insulin receptor (Insr) knockout in PDGFRβ-expressing cells. These animals exhibit systemic insulin resistance from as early as 8-weeks of age, despite no change in body weight or activity level, and show altered body composition and hepatosteatosis. When challenged with high fat diet, PIR−/− remain insulin resistant but are protected from weight gain with reduced adipose tissue expansion across all depots and altered adipose morphology. Exhibiting parallels with the metabolically-obese-normal-weight (MONW) human phenotype, the PIR−/− line underlines the importance of pericyte biology in the development of both diabetes and obesity and establishes the angiopoietin (Ang)/Tie signalling pathway as a focus for future research.

Periodontitis and Diabetes Differentially Affect Inflammation in Obesity

Periodontitis (PD) potentiates systemic inflammatory diseases and fuels a feed-forward loop of pathogenic inflammation in obesity and type 2 diabetes (T2D). Published work in this area often conflates obesity with obesity-associated T2D; thus, it remains unclear whether PD similarly affects the inflammatory profiles of these 2 distinct systemic diseases. We collected peripheral blood mononuclear cells (PBMCs) from cross-sectionally recruited subjects to estimate the ability of PD to affect cytokine production in human obesity and/or T2D. We analyzed 2 major sources of systemic inflammation: T cells and myeloid cells. Bioplex quantitated cytokines secreted by PBMCs stimulated with T cell– or myeloid-targeting activators, and we combinatorially analyzed outcomes using partial least squares discriminant analysis. Our data show that PD significantly shifts peripheral T cell– and myeloid-generated inflammation in obesity. PD also changed myeloid- but not T cell–generated inflammation in T2D. T2D changed inflammation in samples from subjects with PD, and PD changed inflammation in samples from subjects with T2D, consistent with the bidirectional relationship of inflammation between these 2 conditions. PBMCs from T2D subjects with stage IV PD produced lower amounts of T cell and myeloid cytokines compared with PBMCs from T2D subjects with stage II to III PD. We conclude that PD and T2D affect systemic inflammation through overlapping but nonidentical mechanisms in obesity, indicating that characterizing both oral and metabolic status (beyond obesity) is critical for identifying mechanisms linking PD to systemic diseases such as obesity and T2D. The finding that stage IV PD cells generate fewer cytokines in T2D provides an explanation for the paradoxical findings that the immune system can appear activated or suppressed in PD, given that many studies do not report PD stage. Finally, our data indicate that a focus on multiple cellular sources of cytokines will be imperative to clinically address the systemic effects of PD in people with obesity.

8066 Compensatory Signatures of Islet Cells That Protect Obese Humans From Diabetes

Abstract Disclosure: H. Kim: None. Y. Li: None. H. Zhu: None. K. El Jellas: None. N. Shukla: None. Z. Ren: None. K. Fukuda: None. M. Chen: None. R. Kulkarni: Advisory Board Member; Self; Novo Nordisk, Inversago, Biomea, REDD. The increasing prevalence of obesity and type 2 diabetes (T2D) continues to be a major global socioeconomic burden. Healthy humans adapt to metabolic stress by increasing their functional β-cell mass. Failure of this process, called decompensation, potentially triggers the development of T2D in many but not all obese humans. Furthermore, the molecular mechanism(s) underlying the ability of heterogeneous human β-cells to compensate and protect obese humans from developing T2D remain elusive. Here we report unique gene signatures of β-cell subtypes and their molecular interactions with islet stellate cells during successful compensation in human obesity. Using a single-nucleus multiomics approach, we profiled gene expression and chromatin accessibility of 160,954 islet nuclei from non-diabetic lean, overweight, obese, or T2D human donors. We identified multiple β-cell subtypes and their unique sets of genes, biological pathways, and transcription factors associated with compensation. The genome-wide association studies corroborated the compensatory genes identified in the subsets, showing significant associations with metabolic phenotypes in humans. Unbiased cell-cycle gene and ligand-receptor analyses of islet cell types revealed that activated stellate cells proliferate and interact with the β-cell subtypes that involves the extracellular matrix-integrin protein complex in non-diabetic obesity. These results highlight the physiological roles of islet stellate cells in regulating β-cell compensation and point to therapeutic opportunities in precision medicine to protect obese humans from developing T2D. Presentation: 6/3/2024

9325 Obesity Alters Pomc And Kisspeptin Neuron Crosstalk Leading To Lower Luteinizing Hormone

Abstract Disclosure: P. Villa: None. R. Ruggiero-Ruff: None. B. Jamieson: None. R. Campbell: None. D. Coss: None. Obesity is a significant public health concern due to its high prevalence and numerous comorbidities. It is associated with hypogonadism in males, characterized by low testosterone and sperm number. Previous studies determined that these stem from dysregulation of hypothalamic circuitry that regulates reproduction, by unknown mechanisms, since studies are confounded by chronic nature of this condition that leads to synaptic changes and alterations in neuron responsiveness to stimuli. Herein, we used mice fed chronic high-fat diet, that mimics human obesity, to determine mechanisms of impairment at the level of the hypothalamus, in particular gonadotropin-releasing hormone (GnRH) neurons that regulate luteinizing hormone levels (LH), which in turn regulates testosterone synthesis. Consistent with obese humans, we demonstrated lower LH, and lower pulse frequency of LH secretion, but unchanged pituitary responsiveness to GnRH. Pulse frequency of LH is regulated by pulsatile GnRH secretion, which is controlled by kisspeptin. Peripheral and central kisspeptin injections, and DREADD-mediated activation of kisspeptin neurons, demonstrated that kisspeptin neurons were suppressed in obese mice. Thus, we investigated regulators of kisspeptin secretion. We determined that LH response to NMDA was lower in obese mice, corresponding to fewer glutamate receptors in kisspeptin neurons, which may be critical for kisspeptin synchronization. Given that kisspeptin neurons also interact with POMC neurons, which regulate satiety and are particularly affected by obesity, we examined their crosstalk, and determined that LH response to either DREADD-mediated activation of POMC neurons or central injection of αMSH, a product of POMC, is abolished in obese mice. This was accompanied by diminished levels of αMSH receptor, MC4R, in kisspeptin neurons. The reason may be that chronically higher activity of POMC neurons in response to obesity, downregulates αMSH receptors on target neurons, including kisspeptin. This may lead to suppression of kisspeptin neurons, and their inability to regulate pulsatile secretion of GnRH. Together, our studies determined that obesity leads to downregulation of receptors that regulate kisspeptin neurons, which is associated with lower LH pulse frequency, leading to lower LH and hypogonadism. Presentation: 6/2/2024

Senescent Podocytes in Human Obesity Release Urinary Extracellular Vesicles (uEVs)

Senescent Podocytes in Human Obesity Release Urinary Extracellular Vesicles (uEVs)

Dysregulated Renal Microcirculation in Human Obesity Detected by Urinary Extracellular Vesicles (uEVs)

Dysregulated Renal Microcirculation in Human Obesity Detected by Urinary Extracellular Vesicles (uEVs)

The endocannabinoid system in appetite regulation and treatment of obesity.

The endocannabinoid system (ECS) is a complex cell-signaling system that is responsible for maintaining homeostasis by modulating various regulatory reactions in response to internal and environmental changes. The influence of ECS on appetite regulation has been a subject of much recent research, however, the full extent of its impact remains unknown. Current evidence links human obesity to ECS activation, increased endocannabinoid levels in both central and peripheral tissues, along with cannabinoid receptor type 1 (CBR1) up-regulation. These findings imply the potential pharmacological use of the ECS in the treatment of obesity. Here, we present various pathophysiological processes in obesity involving the ECS, highlighting different pharmacological options for modulating endocannabinoid activity to treat obesity. However, the potential of those pharmacological possibilities remains under investigation and requires further research.

O político da linguagem em Special, de Lizzo: uma análise semântico-enunciativa

This descriptive-interpretative study analyzes the functioning of the political aspect of language in the translation of the composition Special, interpreted by Lizzo. It is based on the framework of the Historical Semantics of Enunciation (Guimarães, 2002, 2006, 2007b, 2018). Through the description of the enunciative space and the argumentative orientation, it was found that the political aspect is manifested throughout the enunciation, by the establishment of discursive memories related to racism, fatphobia, media, social exclusion, self-acceptance and Lizzo’s own history/path. These statements intertwine, retracing and re-signifying, transversely, the possibilities of constructed meanings. The political meaning is evidenced by the struggle and constant effort of the Speaker to define her space in the world, as well as the space of the minoritized groups (fat people, black people, and women) that she represents through self-affirmations, which challenge the established hierarchy and other exclusionary representations.