Obesity-related Diseases Research Articles

Adiposity, immunity, and inflammation: interrelationships in health and disease: a report from 24th Annual Harvard Nutrition Obesity Symposium, June 2023

The rapidly evolving field of immunometabolism explores how changes in local immune environments may affect key metabolic and cellular processes, including that of adipose tissue. Importantly, these changes may contribute to low-grade systemic inflammation. In turn, chronic low-grade inflammation affecting adipose tissue may exacerbate the outcome of metabolic diseases. Novel advances in our understanding of immunometabolic processes may critically lead to interventions to reduce disease severity and progression. An important example in this regard relates to obesity, which has a multifaceted effect on immunity, activating the proinflammatory pathways such as the inflammasome and disrupting cellular homeostasis. This multifaceted effect of obesity can be investigated through study of downstream conditions using cellular and systemic investigative techniques. To further explore this field, the National Institutes of Health P30 Nutrition Obesity Research Center at Harvard, in partnership with Harvard Medical School, assembled experts to present at its 24th Annual Symposium entitled “Adiposity, Immunity, and Inflammation: Interrelationships in Health and Disease” on 7 June, 2023. This manuscript seeks to synthesize and present key findings from the symposium, highlighting new research and novel disease-specific advances in the field. Better understanding the interaction between metabolism and immunity offers promising preventative and treatment therapies for obesity-related immunometabolic diseases.

Optimization of Phloretin-loaded Nanospanlastics for Targeting of FAS/SREBP1c/AMPK/ OB-Rb Signaling Pathway in HFD-induced Obesity.

Obese patients are at increased risk for CVD, which is the main cause of premature death and has been a major cause of disability and ill health in recent years. PTN, a natural dihydrochalcone flavonoid, has a variety of pharmacological characteristics. This article aimed to prepare PTN-NSLs to evaluate their anti-obesity activity. Morphology, Particle size, zeta potential, UV-vis, entrapment efficiency, FT-IR spectra, and an in vitro release study of PTN-NSLs were described. PTN-NSLs were also tested for their anti-obesity properties in obese rats. The LD50 of PTN-NSLs was calculated, as was the 1/20 LD50 prepared for the treatment of obese rats. Also, the level of glycemic, oxidative stress and inflammatory biomarkers were estimated in the obese rat's model. The synthesized PTN-NSLs were uniform, spherically shaped, and well dispersed with no aggregation noted, with a size range of 114.06 ± 8.35 nm. The measured zeta potential value of PTN-NSLs was -32.50.8 mv. Also, the UV spectra of PTN and PTN-NSLs have strong absorption at 225 and 285 nm. Also, the LD50 of PTN-NSLs was found to be 2750 mg/kg.b.w. Moreover, administrating obese rats with PTN-NSLs resulted in improved glycemic features as well as GSH, SOD, GPx, GR, IL10, TBARs, and IL-6 levels, as well as attenuated FAS, SREBP1c, AMPK, ACO, CPT1, and OB-Rb gene expression. Administration of PTN-NSLs significantly attenuated the levels of glycemic, oxidative stress, and inflammatory biomarkers. The biochemical and PCR findings are aided by histological investigations. Also, the present findings imply that PTN-NSLs might be a promising pharmacological tool for the treatment of obesity-related diseases.

GPX4 Over-expression Is Associated with Increased Senescence Burden and Metabolic Dysfunction

Chronic inflammation is a hallmark of obesity, diabetes, and cardiovascular disease (CVD), contributing to morbidity and mortality worldwide. Adipose tissue inflammation is commonly observed in obesity-related diseases and is considered a critical driver of metabolic dysfunction. Cellular senescence, a state of cell cycle arrest, accumulates in adipose tissues in obesity and contributes to tissue inflammation through the production of pro-inflammatory factors known as the SASP (senescence associated secretory phenotype). Novel therapeutics targeting senescent cells have been shown to improve metabolic function in obesity, although the underlying mechanisms of senescent cell accumulation and clearance are not well known. Here, we compared a genetically modified mouse model that overexpresses glutathione peroxidase 4 (GPX4), with wildtype (WT) littermate mice. GPX4 is an antioxidant, selenoenzyme, and a key regulator of ferroptosis, an iron-dependent form of regulated cell death. Previous in vitro studies have shown that activation of ferroptosis through inhibition of GPX4 is associated with a decrease in senescence burden, suggesting that ferroptosis may serve as a novel senolytic pathway. We hypothesized that overexpression of GPX4 in the transgenic (TG) mice will reduce ferroptosis, increase senescence burden, and impair metabolic function compared to WT mice. To determine the effects of ferroptosis on metabolic function, GPX4 WT and TG mice were fed either a 60% high fat diet (HFD) or normal chow (NC) ad libitum for 8-10 weeks. We found higher body, liver, and white adipose tissue (WAT) mass in GPX4 TG compared to WT mice fed NC and HFD (Interaction all p<0.0003, 0.0001, 0.0044, n=8-10/group). After HFD, T cell infiltration in the WAT was higher in GPX4 TG mice compared to WT (Interaction all p<0.0253), and both CD8 and CD4 were significantly different from NC controls, contributing to metabolic dysfunction in these animals (p=0.027,0.207, n=4/group). Mice fed HFD demonstrated increased glucose intolerance compared to NC controls (p=0.029, p=0.0216, n=8-12/group), however, the TG HFD mice were trending towards higher glucose intolerance compared to WT HFD (p=0.17). Compared to NC and HFD fed WT mice, there was increased gene expression for the senescence markers, p16 (all p<0.0041) and p21(all p<0.002), as well as increased expression of SASP factors, CXCL2 (all p<0.0055), TNFa (all p<0.0159), and PAI1 (all p<0.05, n=5-7/group) in the HFD fed TG mice, indicating increased senescence burden in the TG HFD mice. Malondialdehyde (MDA), a byproduct and marker of ferroptosis, was elevated in the HFD fed WT mice (p=0.0002) compared to all other groups, indicating increased ferroptosis. HFD fed TG mice also had increased expression of ferritin (all p<0.0079, n=5/group) compared to all other groups, suggesting resistance to ferroptosis that may contribute to the increased senescence burden in the TG HFD group. Together these data demonstrate that increases in cellular senescence and impairments in metabolic function after HFD are exacerbated by increased GPX4 expression, suggesting that GPX4 may be a novel target to decrease senescence and improve metabolic function through induction of the ferroptosis pathway. Funded in part by awards from National Institute of Health Awards R01 AG 060395, R01 AG048366, T32 HL139451-05, T32 HL007576, R01 AG077751, Nora Eccles Treadwell Foundation (NEFT), and Veteran's Affairs Merit Review Award I01 BX004492. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Metabolomic analysis reveals macrophage metabolic reprogramming and polarization under different nutritional cues

Background and aimsObesity-induced chronic inflammation and metabolic abnormalities are highly relevant to the functional dysregulation of macrophages, especially under obese conditions. Hyperglycemia and hyperlipidemia, central to obesity, directly alter macrophage activity. However, the impacts of different nutritional cues on the intricate metabolic networks in macrophages remain unclear. Materials and methodsIn this study, we employed metabolomic approaches to examine the metabolic responses of macrophages to high glucose, high fat and their coexistence, aiming to delineate the molecular mechanisms of nutritional factors on macrophage activation and obesity-related diseases from a metabolic perspective. ResultsOur findings revealed that different nutritional conditions could reprogram key metabolism in macrophages. Additionally, we identified a metabolite derived from macrophages, Long-Chain Phosphatidylcholine (LPC), which exerts beneficial effects on obese mice. It ameliorates the obesity phenotype and improves glucose metabolism profiles. This discovery suggests that LPC has a significant therapeutic potential in the context of obesity-induced metabolic dysfunctions. Our study unveils the metabolic phenotype of macrophages in high-fat and high-sugar environments and uncovers a macrophage-derived metabolite that significantly ameliorates the obesity phenotype. ConclusionThis finding reveals a potential dialogue mechanism between macrophages and adipocytes, shedding light on the complex interplay of immune and metabolic systems in obesity. This discovery not only enhances our understanding of obesity’s underlying mechanisms but also opens up new avenues for therapeutic interventions targeting macrophage-adipocyte interactions.

Clock and Bmal1 inhibit expression of Sglt1 in mouse Kidneys and glucose reabsorption

Aberrantly elevated sodium/glucose cotransporter 1 (Sglt1) expression and increased glucose reabsorption contribute to obesity or lean-associated metabolic complications, however, the precise mechanisms underlying the high expression of Sglt1 and increased glucose absorption are unclear. Clock (circadian locomotor output cycles kaput protein) is known as the master clock gene; Bmal1 (basic helix-loop-helix arnt like 1) is a known heterodimer of Clock that is a critical regulator of circadian metabolism and has the potential for regulating obesity-related diseases. We examined whether circadian clock genes involving Clock/Bmal1 and the orphan nuclear receptor Shp (the small heterodimer partner) regulate the expression of Sglt1 to maintain glucose reabsorption and glucose homeostasis. Renal Sglt1 levels were increased in Clock-mutant or Bmal1-knockout (KO) mice and were decreased by activation of Bmal1 in an SHP-dependent manner. Mechanistically, the transactivation of Sglt1 by HNF1α (hepatic nuclear factor 1 alpha) was inhibited by SHP. In wild-type mice fed a western diet, activation of Shp by Nobiletin reduced Sglt1 levels and improved glucose reabsorption and glucose handling, but these beneficial effects were not seen in Clock−mutant and Bmal1 KO mice. These results demonstrate that normal inhibition of Sglt1 by Clock/Bmal1-SHP is defective in obesity, resulting in increased Sglt1 levels, glucose reabsorption, and renal steatosis. This Clock/Bmal1-SHP-Sglt1 pathway may present novel targets for treating obesity. This work was supported in part by National Institutes of Health (NIH) grant R56 HL137912 and American Heart Association Scientist Development Grant 2300158 and Grant-in-Aid 16GRNT30960027 to XP; by U.S. NIH grants DK121490, HL137202, HL158054 and HD094778, and VA Merit Award BX004113 to MMH; and NIH grants R01DK112042, R01HL142814, RF1AG061296, the UAB/UCSD O’Brien Center of Acute Kidney Injury NIH-P30DK079337, and the Department of Veterans Affairs to V Vallon. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The Effect of Weight Cycling on Myelopoiesis

Abstract Inflammation is a hallmark of obesity and is associated with many complications, with myeloid cells being major culprits. Weight loss improves obesity-related comorbidities, however, subsequent weight regain, known as weight cycling (WC), has been linked to worsening of obesity-related diseases. Therefore, it is critical to understand how WC impacts inflammation. We hypothesize that mice undergoing WC will have greater myeloid cell production with heightened inflammatory capacity. To test this hypothesis, we characterized immune cell populations in bone marrow (BM) and blood using multi-parametric flow cytometry in mice undergoing acute and long-term WC compared to non-WC mice. Our results indicate WC increases the frequency of inflammatory Ly6Chi monocytes and lowers pro-resolving Ly6Clo monocytes in the BM. Additionally, WC increases circulating monocytes. The increase in monocytes are coupled with expansion of their bone marrow progenitors, suggesting that WC heightens myelopoiesis. We will further examine inflammatory capacity by stimulating bone marrow derived macrophages with lipopolysaccharide and measuring cytokine secretion. Furthermore, hematopoietic progenitor differentiation will be tested through colony forming assays. Combined RNA/ATAC-seq will be used to understand the transcriptomic and epigenetic changes occurring in progenitors with WC. This study will provide novel insight into how WC worsens disease, and the basic mechanisms regulating myelopoiesis.

Unveiling the Potential of Natural Compounds: A Comprehensive Review on Adipose Thermogenesis Modulation.

The process of adipocyte browning has recently emerged as a novel therapeutic target for combating obesity and obesity-related diseases. Non-shivering thermogenesis is the process of biological heat production in mammals and is primarily mediated via brown adipose tissue (BAT). The recruitment and activation of BAT can be induced through chemical drugs and nutrients, with subsequent beneficial health effects through the utilization of carbohydrates and fats to generate heat to maintain body temperature. However, since potent drugs may show adverse side effects, nutritional or natural substances could be safe and effective as potential adipocyte browning agents. This review aims to provide an extensive overview of the natural food compounds that have been shown to activate brown adipocytes in humans, animals, and in cultured cells. In addition, some key genetic and molecular targets and the mechanisms of action of these natural compounds reported to have therapeutic potential to combat obesity are discussed.

The Evaluation of Physiopathological and Immunological Exercise Effects During Pandemic and Pathogenicity on Coronavirus COVID-19 (with Considerations and Instructions of Doing Related Physical Activity)

Context: The 2019 coronavirus disease (COVID-19), also commonly known as the coronavirus, is an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The virus is associated with several challenges, including an increased sedentary lifestyle, obesity, and elevated inflammatory factors and related diseases. Evidence Acquisition: In conducting this research, we utilized the latest articles from prestigious domestic and foreign journals indexed in databases such as PubMed, Google Scholar, and ScienceDirect. Results: There are various hypotheses regarding the intensity of exercise and its impact on infection rates. Moderate-intensity exercise is believed to enhance immune function and reduce mortality, whereas high-intensity and stressful exercise may have the opposite effect. When exposed to infection, high-intensity exercise can suppress the immune system, whereas moderate-intensity exercise may reduce inflammation. Conclusions: Therefore, given that exercise affects the strength and anti-inflammatory mechanisms of the immune system, it plays a crucial role in reducing complications for patients. Consequently, it can be concluded that exercise strengthens the immune system, reduces inflammation, and creates favorable physiological and immunological conditions to aid athletes in overcoming the virus.

Estimation of the Impact of Abdominal Adipose Tissue (Subcutaneous and Visceral) on the Occurrence of Carbohydrate and Lipid Metabolism Disorders in Patients with Obesity-A Pilot Study.

Obesity represents a significant global public health concern. The excessive accumulation of abdominal adipose tissue is often implicated in the development of metabolic complications associated with obesity. Our study aimed to investigate the impact of particular deposits of abdominal adipose tissue on the occurrence of carbohydrate and lipid metabolism complications. We established cut-off points for visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and the VAT/SAT ratio at which selected metabolic complications of obesity-related diseases (disorders of carbohydrate and/or lipid metabolism) occur. We conducted an observational study involving 91 subjects with first- and second-degree obesity, accounting for gender differences. Anthropometric measurements were taken, body composition analysis (BIA) was conducted, and biochemical determinations were made. Our findings suggest that commonly used parameters for assessing early metabolic risk, such as BMI or waist circumference, may overlook the significant factor of body fat distribution, as well as gender differences. Both visceral and subcutaneous adipose tissue were found to be important in estimating metabolic risk. We identified the cut-off points in women in terms of their elevated fasting glucose levels and the presence of insulin resistance (HOMA-IR: homeostasis model assessment of insulin resistance) based on SAT, VAT, and the VAT/SAT ratio. In men, cut-off points were determined for the presence of insulin resistance (HOMA-IR) based on VAT and the VAT/SAT ratio. However, the results regarding lipid disorders were inconclusive, necessitating further investigation of a larger population.

Association between visceral adipose tissue and total testosterone among the United States male adults: a cross-sectional study.

Visceral adipose tissue (VAT) is regarded as an important risk factor for obesity-related diseases. The results of the association between VAT and total testosterone (TT) are controversial and whether this association is nonlinear is still unknown. 3971 male participants who were aged 20-59 years from the National Health and Nutrition Examination Surveys 2011-2016 were included. VAT area was measured by dual-energy x-ray absorptiometry. TT in serum was assessed utilizing the isotope dilution liquid chromatography-tandem mass spectrometry technique. Linear regression models assessed the associations between VAT area and TT. A restricted cubic spline model was employed to investigate nonlinear relationships. A two-piecewise linear regression model was applied to determine the threshold effect. Subgroup analyses were conducted. The weighted methods were utilized in all analyses. VAT area was inversely associated with TT in the crude and adjusted models. In the fully adjusted model, VAT area was associated with TT (β = -0.59, 95% confidence interval [CI] = -0.74, -0.43) and compared to the first tertile of VAT area, the second and the third tertile had a lower TT level, the β and 95% CI = -65.49 (-83.72, -47.25) and -97.57 (-121.86, -73.27) respectively. We found these inverse associations were nonlinear. The cutoff point of the VAT area was 126 cm2. When the VAT area was <126 cm2, VAT area was significantly associated with a lower TT level (β = -1.55, 95% CI = -1.93 to -1.17, p < 0.0001). However, when the VAT area was ≥126 cm2, this association was less apparent (β = -0.26, 95% CI = -0.52 to 0.01, p = 0.06). No significant interactions among different ages (<50 or ≥50 years), marital, and physical activity status were found. These findings underscore the potential for VAT area as a modifiable indicator for improving testosterone deficiency.

Laparoscopic sleeve gastrectomy for premenstrual syndrome symptoms in patients with obesity.

Premenstrual syndrome (PMS) is a pathological condition characterized by a series of abnormal physical, psychological, and behavioral symptoms. We evaluated the effectiveness of laparoscopic sleeve gastrectomy (LSG) in the treatment of patients with obesity and PMS. In this case-control study, 131 patients with obesity (BMI ≥ 27.5kg/cm2) diagnosed with moderate-to-severe PMS from March 2018 to March 2022 were prospectively selected to undergo LSG or not at their own discretion. Participants self-reported their PMS severity using the Premenstrual Syndrome Screening Tool. Among them, 68 patients chose LSG surgery, and 63 control group patients were followed up without surgery. Data were recorded at baseline and at 3months post-treatment. We used a multivariate analysis to assess the improvement in PMS symptoms and associated factors. Of the 131 patients with obesity and PMS, the improvement rate of PMS in the LSG group was 57.35% (n = 39), while the improvement rate of PMS in the control group was 25.40% (n = 16). Furthermore, our study revealed that surgery is an independent factor affecting the improvement of patients with PMS. Additionally, there was a correlation between alcohol use, T2DM and obesity-related metabolic diseases, and BMI with PMS. The changes in BMI, testosterone, and estradiol(E2) levels may also contribute to the improvement of patients with obesity and PMS. LSG can improve the management of obesity in patients with PMS to some extent. Changes in BMI, testosterone, and E2 may be indicative of improvement in patients with obesity and PMS.

Mechanistic insights into the role of USP14 in adipose tissue macrophage recruitment and insulin resistance in obesity

Diet-induced obesity can cause metabolic syndromes. The critical link in disease progression is adipose tissue macrophage (ATM) recruitment, which drives low-level inflammation, triggering adipocyte dysfunction. It is unclear whether ubiquitin-specific proteinase 14 (USP14) affects metabolic disorders by mediating adipose tissue inflammation. In the present study, we showed that USP14 is highly expressed in ATMs of obese human patients and diet-induced obese mice. Mouse USP14 overexpression aggravated obesity-related insulin resistance by increasing the levels of pro-inflammatory ATMs, leading to adipose tissue inflammation, excessive lipid accumulation, and hepatic steatosis. In contrast, USP14 knockdown in adipose tissues alleviated the phenotypes induced by a high-fat diet. Co-culture experiments showed that USP14 deficiency in macrophages led to decreased adipocyte lipid deposition and enhanced insulin sensitivity, suggesting that USP14 plays an important role in ATMs. Mechanistically, USP14 interacted with TNF receptor-associated 6, preventing K48-linked ubiquitination as well as proteasome degradation, leading to increased pro-inflammatory polarization of macrophages. In contrast, the pharmacological inhibition of USP14 significantly ameliorated diet-induced hyperlipidemia and insulin resistance in mice. Our results demonstrated that macrophage USP14 restriction constitutes a key constraint on the pro-inflammatory M1 phenotype, thereby inhibiting obesity-related metabolic diseases.

A population-based prospective study on obesity-related non-communicable diseases in northern Iran: rationale, study design, and baseline analysis.

Iran is facing an epidemiological transition with the increasing burden of non-communicable diseases, such as obesity-related disorders and cardiovascular diseases (CVDs). We conducted a population-based prospective study to assess the prevalence and incidence rates of CVDs and obesity-related metabolic disorders and to evaluate the predictive ability of various CVD risk assessment tools in an Iranian population. We enrolled 5,799 participants in Amol, a city in northern Iran, in 2009-2010 and carried out the first repeated measurement (RM) after seven years (2016-2017). For all participants, demographic, anthropometric, laboratory, hepatobiliary imaging, and electrocardiography data have been collected in the enrollment and the RM. After enrollment, all participants have been and will be followed up annually for 20 years, both actively and passively. We adopted a multidisciplinary approach to overcome barriers to participation and achieved a 7-year follow-up success rate of 93.0% with an active follow-up of 5,394 participants aged 18-90 years. In the RM, about 64.0% of men and 81.2% of women were obese or overweight. In 2017, about 16.2% and 5.2% of men had moderate or severe non-alcoholic fatty liver disease, while women had a significantly higher prevalence of metabolic syndrome (35.9%), and type 2 diabetes mellitus (20.9%) than men. Of 160 deceased participants, 69 cases (43.1%) died due to CVDs over seven years. The most prevalent obesity-related chronic disease in the study was metabolic syndrome. Across the enrollment and RM phases, women exhibited a higher prevalence of obesity-related metabolic disorders. Focusing on obesity-related metabolic disorders in a population not represented previously and a multidisciplinary approach for enrolling and following up were the strengths of this study. The study outcomes offer an evidence base for future research and inform policies regarding non-communicable diseases in northern Iran.

Risk factors for bariatric surgery in patients over 65years of age-a multicenter retrospective cohort study.

Societies are aging, life expectancy is increasing, and as a result, the percentage of elderly people in the population is constantly increasing. When qualifying patients over 65years of age for bariatric surgery, the benefits and risks should be carefully assessed. Weighing risk factors against each other to improve the quality of life and better control of obesity-related diseases. The study aimed to determine risk factors for bariatric surgery among patients over 65years of age. A multicenter, retrospective analysis of patients undergoing laparoscopic bariatric procedures from 2008 to 2022. The patients were divided into two groups: complicated (C) and uncomplicated (UC). Uni- and multivariate logistic regression analysis was performed to obtain significant, independent risk factors. There were 20 (7.0%) patients in C group and 264 (93.0%) patients in UC group. The most common complication was intraperitoneal bleeding (8, 2.8). There was no postoperative mortality. The mean follow-up was 47.5months. In a multivariate logistic regression analysis, length of stay and %EWL significantly corresponded to general complications (OR 1.173, OR 1.020). A higher weight loss before surgery lowered the risk for hemorrhagic events after surgery (OR 0.889). A longer length of stay corresponded to leak after surgery (OR 1.175). Bariatric and metabolic surgery appears to be a safe method of obesity treatment in patients over 65years of age. The most common complication was intraperitoneal bleeding. A prolonged hospital stay may increase the risk of leakage, while a higher weight loss before the surgery may lower the risk of bleeding.

The molecular mechanism of macrophage-adipocyte crosstalk in maintaining energy homeostasis.

Interactions between macrophages and adipocytes in adipose tissue are critical for the regulation of energy metabolism and obesity. Macrophage polarization induced by cold or other stimulations can drive metabolic reprogramming of adipocytes, browning, and thermogenesis. Accordingly, investigating the roles of macrophages and adipocytes in the maintenance of energy homeostasis is critical for the development of novel therapeutic approaches specifically targeting macrophages in metabolic disorders such as obesity. Current review outlines macrophage polarization not only regulates the release of central nervous system and inflammatory factors, but controls mitochondrial function, and other factor that induce metabolic reprogramming of adipocytes and maintain energy homeostasis. We also emphasized on how the adipocytes conversely motivate the polarization of macrophage. Exploring the interactions between adipocytes and macrophages may provide new therapeutic strategies for the management of obesity-related metabolic diseases.

The causal impact of gut microbiota on circulating adipokine concentrations: a two-sample Mendelian randomization study.

Evidence from previous experimental and observational research demonstrates that the gut microbiota is related to circulating adipokine concentrations. Nevertheless, the debate as to whether gut microbiome composition causally influences circulating adipokine concentrations remains unresolved. This study aimed to take an essential step in elucidating this issue. We used two-sample Mendelian randomization (MR) to causally analyze genetic variation statistics for gut microbiota and four adipokines (including adiponectin, leptin, soluble leptin receptor [sOB-R], and plasminogen activator inhibitor-1 [PAI-1]) from large-scale genome-wide association studies (GWAS) datasets. A range of sensitivity analyses was also conducted to assess the stability and reliability of the results. The composite results of the MR and sensitivity analyses revealed 22 significant causal associations. In particular, there is a suggestive causality between the family Clostridiaceae1 (IVW: β = 0.063, P = 0.034), the genus Butyrivibrio (IVW: β = 0.029, P = 0.031), and the family Alcaligenaceae (IVW: β=-0.070, P = 0.014) and adiponectin. Stronger causal effects with leptin were found for the genus Enterorhabdus (IVW: β=-0.073, P = 0.038) and the genus Lachnospiraceae (NK4A136 group) (IVW: β=-0.076, P = 0.01). Eight candidate bacterial groups were found to be associated with sOB-R, with the phylum Firmicutes (IVW: β = 0.235, P = 0.03) and the order Clostridiales (IVW: β = 0.267, P = 0.028) being of more interest. In addition, the genus Roseburia (IVW: β = 0.953, P = 0.022) and the order Lactobacillales (IVW: β=-0.806, P = 0.042) were suggestive of an association with PAI-1. This study reveals a causal relationship between the gut microbiota and circulating adipokines and may help to offer novel insights into the prevention of abnormal concentrations of circulating adipokines and obesity-related diseases.

Five percent weight loss is a significant 1-year predictor and an optimal 5-year cut-off for reducing the number of obesity-related cardiovascular disease risk components: the Japan Obesity and Metabolic Syndrome Study.

This study aimed to identify the amount of weight loss needed in patients with obesity to improve metabolic syndrome (MetS), a risk factor for cardiovascular disease (CVD), over a long period of time. A total of 576 patients with obesity were enrolled in this study. Effects of continuous physician-supervised weight loss on the cumulative MetS components excluding abdominal circumference (defined as obesity-related CVD risk score) were investigated during a 5-year follow-up period. The extent of weight loss required to reduce the obesity-related CVD risk components was assessed using receiver operating characteristic (ROC) curve analyses. Of the 576 participants, 266 completed 5-year follow-up, with 39.1% and 24.1% of them achieving ≥5.0% and ≥7.5% weight loss at the 5-year follow-up, respectively. The area under the ROC curve for reducing the obesity-related CVD risk components was 0.719 [0.662-0.777] at 1 year and 0.694 [0.613-0.775] at 5 years. The optimal cut-off value for weight loss was 5.0% (0.66 sensitivity and 0.69 specificity) and the value with 0.80 specificity was 7.5% (0.45 sensitivity) at 5 years. Greater reductions in weight were associated with greater improvements in the obesity-related CVD risk score at all follow-up periods (P-trend <0.001). Obesity-related CVD risk score was significantly improved by 5.0-7.5% and ≥7.5% weight loss at 1 year (P = 0.029 and P < 0.001, respectively) and ≥7.5% weight loss at 5 years (P = 0.034). A weight loss of ≥5.0% at 1 year and ≥7.5% at 5 years could reduce the number of obesity-related CVD risk components in patients with obesity.

Deciphering adipose development: Function, differentiation and regulation.

The overdevelopment of adipose tissues, accompanied by excess lipid accumulation and energy storage, leads to adipose deposition and obesity. With the increasing incidence of obesity in recent years, obesity is becoming a major risk factor for human health, causing various relevant diseases (including hypertension, diabetes, osteoarthritis and cancers). Therefore, it is of significance to antagonize obesity to reduce the risk of obesity-related diseases. Excess lipid accumulation in adipose tissues is mediated by adipocyte hypertrophy (expansion of pre-existing adipocytes) or hyperplasia (increase of newly-formed adipocytes). It is necessary to prevent excessive accumulation of adipose tissues by controlling adipose development. Adipogenesis is exquisitely regulated by many factors in vivo and in vitro, including hormones, cytokines, gender and dietary components. The present review has concluded a comprehensive understanding of adipose development including its origin, classification, distribution, function, differentiation and molecular mechanisms underlying adipogenesis, which may provide potential therapeutic strategies for harnessing obesity without impairing adipose tissue function.

Abstract P193: Sex Moderates Diet Quality Differences in Integrated Collaborative Care for Comorbid Obesity and Depression: Post-Hoc Analysis of the Research Aimed at Improving Both Mood and Weight Randomized Clinical Trial

Background: High-quality diets, such as the Dietary Approaches to Stop Hypertension (DASH), are associated with lower risk for obesity and obesity-related chronic diseases. It is unclear whether diet quality improves aside from reduced calories in evidence-based behavioral weight loss interventions. Objective: Leveraging data from the Research Aimed at Improving Both Mood and Weight (RAINBOW) randomized trial, the objective of this post hoc analysis is to investigate (1) whether the study intervention was associated with improved diet quality in adults with comorbid obesity and depression, compared to usual care; and (2) whether the associations were modified by sex. Methods: Participants completed 24-hour dietary recalls at baseline, 6, 12, 18, and 24 months. Dietary outcomes included the DASH score as the composite measure of diet quality and its components. Between-group differences in dietary outcomes were examined among 409 participants and by sex, using repeated-measures mixed-effects linear models. Results: Changes in DASH scores did not differ between the intervention and usual care control groups through 24 months in both women and men. Compared with controls, men in the intervention group had significantly decreased nut, seed, and legume intake at 6 (mean difference, -1.1; 95% CI, -1.9, -0.3 servings/day; P=0.01) and 12 months (-1.0; -2.0, -0.0 servings/day; P=0.048). Compared with controls, women in the intervention group had significantly decreased fruit and vegetable intake at 18 (-1.8; -2.9, -0.6 servings/day; P=0.002) and 24 months (-1.1; -2.2, -0.1 servings/day; P=0.03), and whole grain intake at 24 months (-0.5; -0.9, -0.1 servings/day; P=0.03), but increased percent calories from fat at 24 months (3.6; 0.6, 6.5; P=0.02). Conclusions: Diet quality not only did not improve in an effective behavioral weight loss intervention but deteriorated in women, in particular. These post-hoc findings warrant confirmation and may suggest that behavior change techniques targeting diet quality that are tailored to women and men need to be an explicit focus of behavioral weight loss interventions aside from caloric reductions.

Abstract P341: Physical Activity and Dual Energy X-ray Absorptiometry Measured Body Composition in Global Multi-Ethnic Cohorts

Background: Obesity is an important risk factor for the development of heart disease, and unfortunately rates of obesity have been growing worldwide. Obesity is often defined by body mass index (BMI) ≥30kg/m 2 , however, BMI cannot distinguish between fat or lean mass nor differences in fat distribution. Dual energy x-ray absorptiometry (DXA) provides more detailed measurements of body composition, but research assessing the association between physical activity and detailed body composition measures in diverse populations is lacking. This study therefore examined associations between physical activity and DXA-derived measures of adiposity in Chinese, Malay, Indian and White European adults from two large-scale prospective cohort studies. Methods: From 2006-2010, adults from the general population were recruited to both The Malaysian Cohort (TMC) study (N=119 555) and the UK Biobank (N=502 487). Physical activity was self-reported by questionnaire at baseline assessment and approximately 5-yearly resurveys in both cohorts. Between 2020-2023, 5489 participants underwent a DXA scan in TMC; while between 2014-2023, 60 280 participants had DXA scans in UK Biobank. Analyses excluded participants with missing data and prior diseases that may impact body composition. Multivariable linear regression (adjusted for demographic and lifestyle confounders) was used to examine associations between physical activity and body composition measures across ethnic groups, and estimates were corrected for regression dilution bias by using estimates of ‘usual physical activity’ derived from repeat measurements. Results: After exclusions, 1723 Chinese, 1245 Malay and 609 Indian participants were included in the TMC analyses and 56 758 White Europeans in the UK Biobank (mean age 57.1 years, 41.2% male in TMC and 54.7 years, 47.7% male in UK). In TMC, physical activity was not associated with BMI, however it was inversely associated with DXA adiposity measures and positively associated with lean mass. Comparing the highest quintile of physical activity to the lowest, total fat mass was 0.7 kg lower (95%CI: -1.1- -0.3) and total lean mass was 0.6 kg higher (0.3-0.9). There was no evidence of effect modification by ethnicity in TMC, but results in White Europeans were stronger: total fat mass was 3.9 kg lower (-4.1- -3.6) and lean mass was 1.2 kg higher (1.1-1.4) comparing the highest to lowest quintiles of physical activity. Interpretation: This is the first large-scale study to examine associations between physical activity and DXA-derived measures of body composition in multi-ethnic cohorts from Malaysia and the UK. The findings support physical activity interventions to reduce obesity-related disease across diverse populations and highlight the value of using detailed body composition measures.