Role Of Obesity Research Articles

Leflunomide alleviates obesity via activation of the TAK1-AMPK pathway and induction of lipophagy.

Lipophagy is a subset of selective autophagy that specifically degrades lipid droplets and plays an important role in obesity. Leflunomide treatment in rheumatoid arthritis (RA) patients has been associated with weight loss and decreased blood glucose levels, which cannot be attributed to its known side effects. Our prior studies showed that A77 1726, the active metabolite of leflunomide, acts as an inhibitor of S6K1 to sensitize the insulin receptor and control hyperglycemia. Whether the anti-obesity effect of leflunomide is mediated by targeting S6K1 and its underlying mechanisms remain unclear. Here, we report that A77 1726 induced LC3 lipidation and increased the formation of autophagosomes and lipoautolysosomes in 3T3-L1 adipocytes by activating TGF-β-activated kinase 1 (TAK1), AMP-activated kinase (AMPK), and Unc-51 like autophagy-activated kinase 1 (ULK1). A77 1726 reduced the content of lipid droplets in 3T3-L1 adipocytes, which was blocked by bafilomycin or by beclin-1 knockdown. Similar observations were made in murine adipocytes differentiated from S6K1-/- embryonic fibroblasts (MEFs). Leflunomide treatment restricted bodyweight gains in ob/ob mice and reduced the visceral fat deposit and the size of adipocytes. Leflunomide treatment induced autophagy in adipose and liver tissues and reduced hepatic lipid contents. Consistently, S6K1 knockout increased the levels of LC3 lipidation in the liver, muscle, and fat of S6K-/- mice. Leflunomide treatment and S6K1 deficiency both induced TAK1, AMPK, and ULK1 phosphorylation in these tissues. These observations collectively suggest that leflunomide controls obesity in part by activating AMPK and inducing lipophagy. Our study provides insights into the mechanisms of leflunomide-mediated anti-obesity activity.

Circulating Selenium Level Was Positively Related to Visceral Adiposity Index with a Non-linear Trend: a Nationwide Study of the General Population.

Selenium plays a role in obesity. However, whether circulating selenium levels are related to the visceral adiposity index (VAI), an indicator of obesity, is still unknown. Based on the National Health and Nutrition Examination Survey (NHANES) 2011-2018, data from 12,777 individuals aged ≥ 20 years were analyzed to clarify this question. In fully adjusted models of multivariate regression analysis, natural logarithm (Ln) selenium was positively related to Ln VAI (β = 0.41; 95% confidence interval [CI], 0.27, 0.55; P < 0.001). Compared with the lowest quartile of Ln selenium, the highest quartile was also positively associated with Ln VAI (β = 0.16; 95% CI, 0.11, 0.21; P < 0.001). Moreover, we found that this positive connection was non-linear. When Ln selenium was less than the inflection point, Ln selenium was positively related to Ln VAI (β = 0.41; 95% CI, 0.31, 0.52; P < 0.001). However, when Ln selenium was greater than or equal to the inflection point, Ln selenium was not significantly related to Ln VAI (β = -0.15; 95% CI, -0.56, 0.25; P = 0.455). In subgroup analysis, significant interactions were observed with age and sex (P for interaction < 0.05). Stronger interactions were observed among middle-aged participants (β = 0.65; 95% CI, 0.31, 0.98; P = 0.002) and males (β = 0.61; 95% CI, 0.43, 0.79; P < 0.001). Overall, circulating selenium levels were positively related to VAI, with a non-linear trend. Prospective studies and interventional experiments are necessary to verify the possible mechanisms.

A Comprehensive Review on the Role of Obesity in Functional Cognition (Part I): Epidemiology and Alternations in Brain Structure

The condition of obesity, which is defined by an excessive amount of adipose tissue, is being increasingly acknowledged as having significant consequences for the structure and functioning of the brain. Numerous studies have demonstrated that obesity is linked to significant modifications in the structure of the brain, encompassing variations in the volume of gray matter, the integrity of white matter, and modifications in particular brain regions responsible for regulating appetite and cognitive control. For example, research employing neuroimaging methodologies such as magnetic resonance imaging has consistently indicated that individuals with obesity frequently display diminished gray matter volume in areas such as the prefrontal cortex, which is known to play a critical role in processes such as decision-making and impulse control. Furthermore, there have been observations of white matter abnormalities that impact the interconnection among brain regions responsible for hunger regulation and reward processing. These abnormalities may potentially play a role in the development of overeating tendencies and compromised self-control. The aforementioned alterations in structure are not solely connected to obesity, but are also correlated with cognitive deficits, namely in domains pertaining to memory, attention, and executive functioning. Gaining a comprehensive understanding of the complex correlation between obesity and brain structure is of utmost importance, as it provides valuable insights into the neurological foundations of cognitive impairments in individuals affected by obesity. Moreover, this knowledge serves as a basis for the creation of specific interventions aimed at alleviating the cognitive repercussions associated with this widespread public health issue.

A Comprehensive Review on the Role of Obesity in Functional Cognition (Part III): Risk Factors and Studying Challenges

Gaining a comprehensive understanding of the risk factors, devising efficacious therapies, and tackling the methodological obstacles inherent in investigating the cognitive consequences of obesity are imperative undertakings in both clinical and research contexts. The complex interaction between metabolic, inflammatory, and lifestyle factors highlights the necessity of adopting a holistic strategy to address cognitive impairments in patients with obesity. The resolution of methodological obstacles, including ethical concerns and the identification of suitable evaluation instruments, is crucial for the progression of our understanding in this domain and the enhancement of cognitive well-being among individuals impacted by obesity.

A Comprehensive Review on the Role of Obesity in Functional Cognition (Part II): Cognition Impairment and Underlying Mechanisms, and Development of Neurodegenerative Diseases

Obesity

Upregulation of hypothalamic TRPV4 via S100a4/AMPKα signaling pathway promotes the development of diet-induced obesity

Obesity is associated with abnormal regulation of energy metabolism in the hypothalamus. Transient receptor potential vanilloid 4 (TRPV4) is involved in regulating osmotic pressure, temperature and mechanical force transmission, but little is known about its role in obesity. Herein, the present study aimed to elucidate the effect of hypothalamic TRPV4 on high-fat diet-induced obesity (DIO) and evaluate its potential for regulating energy metabolism. Here we show that hypothalamic TRPV4 content is increased in DIO rats. Central administration of adeno-associated virus expressing TRPV4 in these animals remarkably increased body weight and fat mass by activating the S100a4/AMPKα signaling pathway, thereby promoting positive energy metabolism. Overexpressed hypothalamic TRPV4 impaired glucose tolerance, while promoting the accumulation of fat in liver cells, resulting in hepatic steatosis. In addition, the upregulation of hypothalamic TRPV4 reduces high-fat induced central inflammation. This study provides evidence that hypothalamic TRPV4 plays a significant role in regulating homeostasis. Hypothalamic TRPV4 emerges as a target for therapeutic intervention against obesity.

The role of obesity on autologous bone marrow transplant and post-transplant outcomes

Background/Aim: Autologous hematopoietic cell transplantation (AutoHCT), administered at high doses, has improved survival rates among patients with refractory or recurrent lymphoma and multiple myeloma (MM). However, inconsistencies in defining obesity, varying body weight ranges, and heterogeneous patient populations have been examined. Some researchers have hypothesized that significantly overweight patients face a higher risk of transplant-related complications. This study investigates the association between body mass index (BMI), obesity, and autologous peripheral stem cell mobilization. Methods: A retrospective evaluation of data from 180 patients who underwent peripheral stem cell mobilization at our clinic between 2014 and 2020 was conducted. Excluding patients under 18 years of age, the primary objective was to assess how BMI influences autologous transplant outcomes and mortality. This retrospective cohort study aimed to determine whether obesity constitutes an independent risk factor for autologous bone marrow transplantation. Results: Among the patients, the most prevalent diagnosis (47.2%) was MM, with notable differences in incidence rates across BMI categories (P=0.039). Obesity and overweight were associated with a higher incidence of MM (47.2%), whereas normal and underweight individuals had predominantly been diagnosed with DLBCL (44.2%). Significant differences in CD34 cell counts were observed among BMI groups (P=0.033). Overweight and obese individuals exhibited lower CD34 cell counts than underweight/normal groups (P=0.033). The treatment group showed significantly higher CD34 cell counts than the G-CSF alone group (P=0.046). Female gender (P=0.022), PLT engraftment (P=0.024), post-chemo-mobilization hospital-stay duration (P=0.019), and G-CSF count were identified as mortality risk factors (P=0.017). Conclusions: This investigation found no adverse correlation between mortality and weight among patients with various hematological malignancies undergoing AutoHCT. Obesity alone should not be a contraindication for proceeding with AutoHCT in clinically warranted hematological malignancy treatment, as no significant survival differences were observed among overweight, obese, and normal-weight individuals.

Erythritol aggravates gut inflammation and anxiety-like behavioral disorders induced by acute dextran sulfate sodium administration in mice.

Erythritol is a widely used sugar substitute in food and beverages with beneficial and detrimental roles in obesity and cardiovascular diseases, respectively; however, its influence on inflammatory bowel disease (IBD) and related behavioral disorders is not well understood. Here, we found that erythritol exacerbated gut inflammation by promoting macrophage infiltration and inducing M1 macrophage polarization, thus increasing gut leakage during colitis triggered by acute dextran sulfate sodium (DSS) treatment. Increased gut permeability can cause neuroinflammation and anxiety-like behavioral disorders. In conclusion, our results revealed a negative role for erythritol in gut inflammation and anxiety-like behavioral disorders induced by erythritol administration in a mouse model of acute colitis, suggesting that erythritol intake control may be necessary for IBD treatment.

Stable Binding of Full-Length Chemerin Is Driven by Negative Charges in the CMKLR1 N Terminus.

The adipokine chemerin is the endogenous ligand of the chemokine-like receptor 1 (CMKLR1), a member of the family of G protein-coupled receptors (GPCRs). This protein ligand plays an important role in obesity and inflammatory processes. Stable receptor-ligand interactions are highly relevant for its different physiological effects such as the migration of immune cells towards sites of inflammation. Here, we demonstrate that negative charges in the CMKLR1 N terminus are involved in the formation of strong contacts with a specific positively charged patch at the surface of full-length chemerin, which is absent in the short nonapeptide agonist chemerin-9, thus explaining its reduced affinity. Using receptor chimera of G protein-coupled receptor 1 (GPR1) and CMKLR1, we were able to identify the residues of this interaction and its relevance for stable full-length chemerin binding. This could help to develop more potent ligands for the treatment of inflammation-related diseases.

Effect modifications of BMI transition and trajectory in the associations of adverse childhood experiences with new-onset dementia and its subtypes in older US adults

BackgroundAdverse childhood experiences (ACEs) and dementia are associated and comorbid with obesity. However, according to emerging research, the role of obesity in the association between ACEs and dementia seems controversial.AimsThis...

Fibroblast growth factor 21 in metabolic syndrome.

Metabolic syndrome is a complex metabolic disorder that often clinically manifests as obesity, insulin resistance/diabetes, hyperlipidemia, and hypertension. With the development of social and economic systems, the incidence of metabolic syndrome is increasing, bringing a heavy medical burden. However, there is still a lack of effective prevention and treatment strategies. Fibroblast growth factor 21 (FGF21) is a member of the human FGF superfamily and is a key protein involved in the maintenance of metabolic homeostasis, including reducing fat mass and lowering hyperglycemia, insulin resistance and dyslipidemia. Here, we review the current regulatory mechanisms of FGF21, summarize its role in obesity, diabetes, hyperlipidemia, and hypertension, and discuss the possibility of FGF21 as a potential target for the treatment of metabolic syndrome.

Reactive oxygen species: role in obesity and mitochondrial energy efficiency.

Changes correlating with increasing obesity include insulin resistance, hyperlipidaemia, hyperinsulinaemia, highly processed food and environmental toxins including plastics and air pollution. The relationship between the appearance of each of these potential causes and the onset of obesity is unknown. The cause(s) must precede obesity, the consequence, and temporally relate to its rising incidence. Macronutrients such as carbohydrates or fats are unlikely to cause obesity since these have long been constituents of human diets. Furthermore, food consumption and body weight have been well-regulated in most humans and other species until recent times. Thus, attention must focus on changes that have occurred in the last half-century and the relationship between such changes and specific populations that are impacted. The hypothesis presented here is that substances that have entered our bodies recently cause obesity by generating false and misleading information about energy status. We propose that this misinformation is caused by changes in the oxidation-reduction (redox) potential of metabolites that circulate and communicate to organs throughout the body. Examples are provided of food additives that generate reactive oxygen species and impact redox state, thereby, eliciting inappropriate tissue-specific functional changes, including insulin secretion. Reversal requires identification, neutralization, or removal of these compounds. This article is part of a discussion meeting issue 'Causes of obesity: theories, conjectures and evidence (Part I)'.

Association between plasma and dietary trace elements and obesity in a rural Chinese population.

Trace elements may play an important role in obesity. This study aimed to assess the plasma and dietary intake levels of four trace elements, Mn, Cu, Zn and Se in a rural Chinese population, and analyse the relationship between trace elements and obesity. A cross-sectional study involving 2587 participants was conducted. Logistic regression models were used to analyse the association between trace elements and obesity; restricted cubic spline (RCS) models were used to assess the dose-response relationship between trace elements and obesity; the weighted quantile sum (WQS) model was used to examine the potential interaction of four plasma trace elements on obesity. Logistic regression analysis showed that plasma Se concentrations in the fourth quartile (Q4) exhibited a lower risk of developing obesity than the first quartile (Q1) (central obesity: OR = 0·634, P = 0·002; general obesity: OR = 0·525, P = 0·005). Plasma Zn concentration in the third quartile (Q3) showed a lower risk of developing obesity in general obesity compared with the first quartile (Q1) (OR = 0·625, P = 0·036). In general obesity, the risk of morbidity was 1·727 and 1·923 times higher for the second and third (Q2, Q3) quartiles of dietary Mn intake than for Q1, respectively. RCS indicated an inverse U-shaped correlation between plasma Se and obesity. WQS revealed the combined effects of four trace elements were negatively associated with central obesity. Plasma Zn and Se were negatively associated with obesity, and dietary Mn was positively associated with obesity. The combined action of the four plasma trace elements had a negative effect on obesity.

Mental Health and Cognitive Development in Symptomatic Children and Adolescents Scoring High on Habitual Snoring: Role of Obesity and Allergy.

Obstructive sleep apnea can have a negative impact on children's and adolescents' neurocognitive abilities and hinder their academic and adaptive progress in academic, social, and/or behavioral dimensions. In this retrospective cross-sectional study, we investigated the influence of body weight conditions and allergy status on long-term mental health, cognitive development, and quality of life in children and adolescents who snored. The study sample included 47 subjects (age range 4.1 to 15.3 years) who exhibited high levels of snoring and underwent home-based polysomnography between 2015 and 2019. Follow-up assessments (3 years on average between baseline and follow-up) entailed phone interviews with the subject's parents/caregivers who completed three validated questionnaires investigating sleep, quality of life, and parental ratings. We found a correlation between age at diagnosis and being retrospectively overweight and high levels of snoring. In addition to a higher risk of developing emotional symptoms (8.2% increase in retrospective overweight status for each unit increase in the emotional score at follow-up) and oppositional behavior (9% increase in retrospective overweight status for each unit of oppositional T points at follow-up), we also noted reduced long-term social symptoms (11% decrease in retrospective overweight status for each unit increase in the social score at follow-up) and cognitive symptoms (10.6% decrease in retrospective overweight status for each unit increase in the cognitive score at follow-up), as well as a 6.1% increase in retrospective allergy status for each unit increase in academic performance at follow-up. Snoring can have negative impacts on mental health and cognitive development in the long term. Early detection and intervention for neuropsychological disorders is important in children and adolescents who score high on snoring. In the long term, the effects of snoring on neuropsychological disorders may vary based on previous body weight and allergy status.

Lower adiponectin is associated with higher anthropometry and insulin resistance but not with low cardiorespiratory fitness in adolescents.

The aim of this study was to analyze the relationship between adiposity, cardiometabolic risk and cardiorespiratory fitness (CRF) according to different groups of adiponectin concentration. 255 adolescents of both sexes, aged 11-17years old, participated. Anthropometric and biochemical parameters such as body mass, height, abdominal circumference (AC), waist circumference (WC), fat mass, fat-free mass, total cholesterol (TC), high-density lipoprotein (HDL-c), low-density lipoprotein (LDL-c), triglycerides (TG), glucose, insulin, adiponectin, blood pressure, peak oxygen consumption (VO2peak) were measured. Body mass index (BMI), z-score BMI (BMI-z), triponderal mass index (TMI), waist-to-height ratio (WHtR), homeostasis model to assessment insulin resistance (HOMA-IR), and quantitative insulin sensitivity check index (QUICKI) were calculated. Adiponectin was categorized: low adiponectin concentration (LAC ≤ 5.18µg/mL-1), intermediate (IAC = 5.18 and 7.63µg/mL-1) and high (HAC ≥ 7.63µg/ml-1). LAC showed higher BMI, BMI-z and TMI than the other groups (p < 0.05) and higher AC, WC and WHtR that the HAC (p < 0.05). IAC showed lower values of TC, LDL-c and TG, and the LAC presented the highest values of insulin, HOMA-IR and QUICKI (p < 0.05) to the IAC and HAC. HAC presented the lower VO2peak than the other groups (p < 0.01). BMI, TMI, glucose, insulin, HOMA-IR showed inverse, and QUICKI a direct and weak correlation with adiponectin (p < 0.05). No significant association was found between adiponectin and VO2peak (p > 0.05). The LAC group had higher means in the anthropometric variables and the worst results related to insulin resistance and sensitivity. Thus, adiponectin may play an important role in obesity and reduced concentration may be a factor in the development of obesity-associated morbidities.

1623-P: Identification of Gut Microbes That Prevents Metabolic Syndrome in Healthy Japanese Adults

Gut microbiota is an important driver of metabolic status. Recent studies have demonstrated that dysbiosis precedes the development of metabolic disorders. However, the bacterial species associated with metabolic syndrome and their physiological role in obesity and glucose metabolism have not been fully elucidated. In this study, we performed 16S rRNA sequencing analysis on fecal samples from 49 metabolically healthy volunteers, a detailed lifestyle questionnaire survey including diet, and an analysis on metabolic parameters. We also examined the metabolic effects of some microbes by transplantation into HFD-fed mice. The average age, BMI and HbA1c were 43.5±9.0, 23.9±3.9 and 5.5±0.3, respectively. A clear correlation was observed between lifestyle and metabolic parameters. Analysis of fecal microbial structure divided the participants into three enterotypes according to their predominant phylogenic pattern; 1) Prevotella copri group, 2) Bacteroides group, and 3) others. Enterotype 1 had higher random blood glucose (BG), and lower HDL-C, while enterotype 2 had lower random BG, BMI, and waist circumference. Eleven bacterial species were identified as being positively or negatively correlated with metabolic parameters. Relative abundances of the Family Fusobacteriaceae and Prevotella stercorea were positively correlated with BMI, fasting BG, and visceral fat mass. In contrast, the Family Rikenellaceae and Bacteroides uniformis (Bu) negatively correlated with metabolic parameters. Transplantation of Alistipes indistinctus (Ali), a major bacterium of the Family Rikenellaceae, or Bu into HFD-fed C57BL/6J mice suppressed body weight gain, improved glucose tolerance and histological findings without altering food intake. In summary, our results suggest that microbial community structure can be altered by lifestyle even in good health. Moreover, maintaining microbial species such as Ali and Bu may contribute to the prevention of metabolic disorders in Japanese adults. Disclosure H. Honoki: None. S. Fujisaka: None. Y. Watanabe: None. M. Oku: None. Y. Kondo: None. A. Nishimura: None. T. Kado: None. M. Bilal: None. A. Enkaku: None. A. Takikawa: None. D. Chujo: None. Y. Morinaga: None. K. Tobe: Other Relationship; MSD K.K., Novo Nordisk Pharma Ltd., Takeda Pharmaceutical Company Limited, Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, Suntory Global Corporation, Ltd.,, Taiho Pharmaceutical Co. Ltd., Japan Diabetes Foundation, Japan Association for Diabetes Education and Care. Funding Japan Society for the Promotion of Science (20K10318); Japan Association for Diabetes Education and Care

Associations between body mass index and all-cause mortality: A systematic review and meta-analysis.

Fasting insulin and c-reactive protein confound the association between mortality and body mass index. An increase in fat mass may mediate the associations between hyperinsulinemia, hyperinflammation, and mortality. The objective of this study was to describe the "average" associations between body mass index and the risk of mortality and to explore how adjusting for fasting insulin and markers of inflammation might modify the association of BMI with mortality. MEDLINE and EMBASE were searched for studies published in 2020. Studies with adult participants where BMI and vital status was assessed were included. BMI was required to be categorized into groups or parametrized as non-first order polynomials or splines. All-cause mortality was regressed against mean BMI squared within seven broad clinical populations. Study was modeled as a random intercept. β coefficients and 95% confidence intervals are reported along with estimates of mortality risk by BMIs of 20, 30, and 40 kg/m2 . Bubble plots with regression lines are drawn, showing the associations between mortality and BMI. Splines results were summarized. There were 154 included studies with 6,685,979 participants. Only five (3.2%) studies adjusted for a marker of inflammation, and no studies adjusted for fasting insulin. There were significant associations between higher BMIs and lower mortality risk in cardiovascular (unadjusted β -0.829 [95% CI -1.313, -0.345] and adjusted β -0.746 [95% CI -1.471, -0.021]), Covid-19 (unadjusted β -0.333 [95% CI -0.650, -0.015]), critically ill (adjusted β -0.550 [95% CI -1.091, -0.010]), and surgical (unadjusted β -0.415 [95% CI -0.824, -0.006]) populations. The associations for general, cancer, and non-communicable disease populations were not significant. Heterogeneity was very large (I2 ≥ 97%). The role of obesity as a driver of excess mortality should be critically re-examined, in parallel with increased efforts to determine the harms of hyperinsulinemia and chronic inflammation.

Effects of multi-organ crosstalk on the physiology and pathology of adipose tissue.

In previous studies, adipocytes were found to play an important role in regulating whole-body nutrition and energy balance, and are also important in energy metabolism, hormone secretion, and immune regulation. Different adipocytes have different contributions to the body, with white adipocytes primarily storing energy and brown adipocytes producing heat. Recently discovered beige adipocytes, which have characteristics in between white and brown adipocytes, also have the potential to produce heat. Adipocytes interact with other cells in the microenvironment to promote blood vessel growth and immune and neural network interactions. Adipose tissue plays an important role in obesity, metabolic syndrome, and type 2 diabetes. Dysfunction in adipose tissue endocrine and immune regulation can cause and promote the occurrence and development of related diseases. Adipose tissue can also secrete multiple cytokines, which can interact with organs; however, previous studies have not comprehensively summarized the interaction between adipose tissue and other organs. This article reviews the effect of multi-organ crosstalk on the physiology and pathology of adipose tissue, including interactions between the central nervous system, heart, liver, skeletal muscle, and intestines, as well as the mechanisms of adipose tissue in the development of various diseases and its role in disease treatment. It emphasizes the importance of a deeper understanding of these mechanisms for the prevention and treatment of related diseases. Determining these mechanisms has enormous potential for identifying new targets for treating diabetes, metabolic disorders, and cardiovascular diseases.

Plant-Derived Nutraceuticals Involved in Body Weight Control by Modulating Gene Expression.

Obesity is the most prevalent health problem in the Western world, with pathological body weight gain associated with numerous co-morbidities that can be the main cause of death. There are several factors that can contribute to the development of obesity, such as diet, sedentary lifestyle, and genetic make-up. Genetic predispositions play an important role in obesity, but genetic variations alone cannot fully explain the explosion of obesity, which is why studies have turned to epigenetics. The latest scientific evidence suggests that both genetics and environmental factors contribute to the rise in obesity. Certain variables, such as diet and exercise, have the ability to alter gene expression without affecting the DNA sequence, a phenomenon known as epigenetics. Epigenetic changes are reversible, and reversibility makes these changes attractive targets for therapeutic interventions. While anti-obesity drugs have been proposed to this end in recent decades, their numerous side effects make them not very attractive. On the other hand, the use of nutraceuticals for weight loss is increasing, and studies have shown that some of these products, such as resveratrol, curcumin, epigallocatechin-3-gallate, ginger, capsaicin, and caffeine, can alter gene expression, restoring the normal epigenetic profile and aiding weight loss.

The role of obesity, nutrition, and physical activity on tinnitus: A narrative review

The role of obesity, nutrition, and physical activity on tinnitus: A narrative review