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Science Translational Medicine Nov 2023Obesity-associated inflammation is a systemic process that affects all metabolic organs. Prominent among these is adipose tissue, where cells of the innate and adaptive... (Review)
Review
Obesity-associated inflammation is a systemic process that affects all metabolic organs. Prominent among these is adipose tissue, where cells of the innate and adaptive immune system are markedly changed in obesity, implicating these cells in a range of processes linking immune memory to metabolic regulation. Furthermore, weight loss and weight cycling have unexpected effects on adipose tissue immune populations. Here, we review the current literature on the roles of various immune cells in lean and obese adipose tissue. Within this context, we discuss pharmacological and nonpharmacological approaches to obesity treatment and their impact on systemic inflammation.
Topics: Humans; Obesity; Adipose Tissue; Inflammation
PubMed: 37992150
DOI: 10.1126/scitranslmed.adf9382 -
Seminars in Cancer Biology Jul 2023Excess body weight is a global health problem due to sedentary lifestyle and unhealthy diet, affecting 2 billion population worldwide. Obesity is a major risk factor for... (Review)
Review
Excess body weight is a global health problem due to sedentary lifestyle and unhealthy diet, affecting 2 billion population worldwide. Obesity is a major risk factor for metabolic diseases. Notably, the metabolic risk of obesity largely depends on body weight distribution, of which visceral adipose tissues but not subcutaneous fats are closely associated with obesity comorbidities, including type 2 diabetes, non-alcoholic fatty liver disease, cardiovascular disease and certain types of cancer. Latest multi-omics and mechanistical studies reported the crucial involvement of genetic and epigenetic alterations, adipokines dysregulation, immunity changes, imbalance of white and brown adipose tissues, and gut microbial dysbiosis in mediating the pathogenic association between visceral adipose tissues and comorbidities. In this review, we explore the epidemiology of excess body weight and the up-to-date mechanism of how excess body weight and obesity lead to chronic complications. We also examine the utilization of visceral fat measurement as an accurate clinical parameter for risk assessment in healthy individuals and clinical outcome prediction in obese subjects. In addition, current approaches for the prevention and treatment of excess body weight and its related metabolic comorbidities are further discussed.
Topics: Humans; Diabetes Mellitus, Type 2; Obesity; Comorbidity; Risk Factors; Diet
PubMed: 36965839
DOI: 10.1016/j.semcancer.2023.03.008 -
Nutrients Dec 2023The literature on the connection between obesity, metabolic syndrome, and subclinical hypothyroidism is critically analyzed in this narrative review. These conditions... (Review)
Review
The literature on the connection between obesity, metabolic syndrome, and subclinical hypothyroidism is critically analyzed in this narrative review. These conditions are frequently observed among adult populations and various studies and meta-analyses have assessed their association. The prevalence of subclinical hypothyroidism in obese individuals is higher than in non-obese subjects and this trend is more pronounced in unhealthy obesity phenotypes. However, the diagnosis and treatment of subclinical hypothyroidism can be difficult in obese patients. Exaggerated body fat is linked to thyroid hypoechogenicity as evident through ultrasonography and euthyroid obese people have greater TSH, FT3, and FT3/FT4 ratios than non-obese individuals in a euthyroid condition. Moreover, a reduced expression of the TSH receptor and altered function of deiodinases has been found in the adipose tissue of obese patients. Current data do not support the necessity of a pharmacological correction of the isolated hyperthyrotropinemia in euthyroid obese patients because treatment with thyroid hormone does not significantly improve weight loss and the increase in serum TSH can be reversible after hypocaloric diet or bariatric surgery. On the other hand, obesity is linked to elevated leptin levels. Inflammation can raise the risk of Hashimoto thyroiditis, which increases the likelihood that obese patients will experience overt or subclinical hypothyroidism. Both metabolic syndrome and subclinical hypothyroidism are associated with atherosclerosis, liver and kidney disease. Hence, the association of these two illnesses may potentiate the adverse effects noted in each of them. Subclinical hypothyroidism should be identified in patients with obesity and treated with appropriate doses of L-thyroxine according to the lean body mass and body weight. Randomized controlled trials are necessary to verify whether treatment of thyroid deficiency could counteract the expected risks.
Topics: Adult; Humans; Obesity; Metabolic Syndrome; Diet, Reducing; Hypothyroidism; Thyrotropin
PubMed: 38201918
DOI: 10.3390/nu16010087 -
International Journal of Molecular... Feb 2024Obesity or excessive weight gain is identified as the most important and significant risk factor in the development and progression of type 2 diabetes mellitus (DM) in... (Review)
Review
Obesity or excessive weight gain is identified as the most important and significant risk factor in the development and progression of type 2 diabetes mellitus (DM) in all age groups. It has reached pandemic dimensions, making the treatment of obesity crucial in the prevention and management of type 2 DM worldwide. Multiple clinical studies have demonstrated that moderate and sustained weight loss can improve blood glucose levels, insulin action and reduce the need for diabetic medications. A combined approach of diet, exercise and lifestyle modifications can successfully reduce obesity and subsequently ameliorate the ill effects and deadly complications of DM. This approach also helps largely in the prevention, control and remission of DM. Obesity and DM are chronic diseases that are increasing globally, requiring new approaches to manage and prevent diabetes in obese individuals. Therefore, it is essential to understand the mechanistic link between the two and design a comprehensive approach to increase life expectancy and improve the quality of life in patients with type 2 DM and obesity. This literature review provides explicit information on the clinical definitions of obesity and type 2 DM, the incidence and prevalence of type 2 DM in obese individuals, the indispensable role of obesity in the pathophysiology of type 2 DM and their mechanistic link. It also discusses clinical studies and outlines the recent management approaches for the treatment of these associated conditions. Additionally, in vivo studies on obesity and type 2 DM are discussed here as they pave the way for more rigorous development of therapeutic approaches.
Topics: Humans; Diabetes Mellitus, Type 2; Quality of Life; Obesity; Risk Factors; Weight Loss
PubMed: 38339160
DOI: 10.3390/ijms25031882 -
Macrophage DCLK1 promotes obesity-induced cardiomyopathy via activating RIP2/TAK1 signaling pathway.Cell Death & Disease Jul 2023Obesity increases the risk for cardiovascular diseases and induces cardiomyopathy. Chronic inflammation plays a significant role in obesity-induced cardiomyopathy and...
Obesity increases the risk for cardiovascular diseases and induces cardiomyopathy. Chronic inflammation plays a significant role in obesity-induced cardiomyopathy and may provide new therapeutic targets for this disease. Doublecortin-like kinase 1 (DCLK1) is an important target for cancer therapy and the role of DCLK1 in obesity and cardiovascular diseases is unclear. Herein, we showed that DCLK1 was overexpressed in the cardiac tissue of obese mice and investigated the role of DCLK1 in obesity-induced cardiomyopathy. We generated DCLK1-deleted mice and showed that macrophage-specific DCLK1 knockout, rather than cardiomyocyte-specific DCLK1 knockout, prevented high-fat diet (HFD)-induced heart dysfunction, cardiac hypertrophy, and fibrosis. RNA sequencing analysis showed that DCLK1 deficiency exerted cardioprotective effects by suppressing RIP2/TAK1 activation and inflammatory responses in macrophages. Upon HFD/palmitate (PA) challenge, macrophage DCLK1 mediates RIP2/TAK1 phosphorylation and subsequent inflammatory cytokine release, which further promotes hypertrophy in cardiomyocytes and fibrogenesis in fibroblasts. Finally, a pharmacological inhibitor of DCLK1 significantly protects hearts in HFD-fed mice. Our study demonstrates a novel role and a pro-inflammatory mechanism of macrophage DCLK1 in obesity-induced cardiomyopathy and identifies DCLK1 as a new therapeutic target for the treatment of this disease. Upon HFD/PA challenge, DCLK1 induces RIP2/TAK1-mediated inflammatory response in macrophages, which subsequently promotes cardiac hypertrophy and fibrosis. Macrophage-specific DCLK1 deletion or pharmacological inhibition of DCLK1 protects hearts in HFD-fed mice.
Topics: Mice; Animals; Doublecortin-Like Kinases; Cardiovascular Diseases; Cardiomyopathies; Myocytes, Cardiac; Obesity; Cardiomegaly; Signal Transduction; Protein Serine-Threonine Kinases; Palmitates; Macrophages; Fibrosis
PubMed: 37443105
DOI: 10.1038/s41419-023-05960-4 -
Nature Metabolism Feb 2024Mitochondrial dysfunction is a characteristic trait of human and rodent obesity, insulin resistance and fatty liver disease. Here we show that high-fat diet (HFD)...
Mitochondrial dysfunction is a characteristic trait of human and rodent obesity, insulin resistance and fatty liver disease. Here we show that high-fat diet (HFD) feeding causes mitochondrial fragmentation in inguinal white adipocytes from male mice, leading to reduced oxidative capacity by a process dependent on the small GTPase RalA. RalA expression and activity are increased in white adipocytes after HFD. Targeted deletion of RalA in white adipocytes prevents fragmentation of mitochondria and diminishes HFD-induced weight gain by increasing fatty acid oxidation. Mechanistically, RalA increases fission in adipocytes by reversing the inhibitory Ser637 phosphorylation of the fission protein Drp1, leading to more mitochondrial fragmentation. Adipose tissue expression of the human homolog of Drp1, DNM1L, is positively correlated with obesity and insulin resistance. Thus, chronic activation of RalA plays a key role in repressing energy expenditure in obese adipose tissue by shifting the balance of mitochondrial dynamics toward excessive fission, contributing to weight gain and metabolic dysfunction.
Topics: Animals; Humans; Male; Mice; Adipocytes, White; Adipose Tissue; Insulin Resistance; Obesity; Weight Gain; ral GTP-Binding Proteins
PubMed: 38286821
DOI: 10.1038/s42255-024-00978-0 -
Nature Communications Oct 2023Obesity is a risk factor for type 2 diabetes and cardiovascular disease. However, a substantial proportion of patients with these conditions have a seemingly normal body...
Obesity is a risk factor for type 2 diabetes and cardiovascular disease. However, a substantial proportion of patients with these conditions have a seemingly normal body mass index (BMI). Conversely, not all obese individuals present with metabolic disorders giving rise to the concept of "metabolically healthy obese". We use lipidomic-based models for BMI to calculate a metabolic BMI score (mBMI) as a measure of metabolic dysregulation associated with obesity. Using the difference between mBMI and BMI (mBMIΔ), we identify individuals with a similar BMI but differing in their metabolic health and disease risk profiles. Exercise and diet associate with mBMIΔ suggesting the ability to modify mBMI with lifestyle intervention. Our findings show that, the mBMI score captures information on metabolic dysregulation that is independent of the measured BMI and so provides an opportunity to assess metabolic health to identify "at risk" individuals for targeted intervention and monitoring.
Topics: Humans; Diabetes Mellitus, Type 2; Body Mass Index; Obesity; Risk Factors; Cardiovascular Diseases; Metabolic Syndrome
PubMed: 37805498
DOI: 10.1038/s41467-023-41963-7 -
Nature Metabolism Feb 2024Obesity is a major public health crisis. Multi-specific peptides have emerged as promising therapeutic strategies for clinical weight loss. Glucagon-like peptide-1... (Randomized Controlled Trial)
Randomized Controlled Trial
Obesity is a major public health crisis. Multi-specific peptides have emerged as promising therapeutic strategies for clinical weight loss. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are endogenous incretins that regulate weight through their receptors (R). AMG 133 (maridebart cafraglutide) is a bispecific molecule engineered by conjugating a fully human monoclonal anti-human GIPR antagonist antibody to two GLP-1 analogue agonist peptides using amino acid linkers. Here, we confirm the GIPR antagonist and GLP-1R agonist activities in cell-based systems and report the ability of AMG 133 to reduce body weight and improve metabolic markers in male obese mice and cynomolgus monkeys. In a phase 1, randomized, double-blind, placebo-controlled clinical study in participants with obesity ( NCT04478708 ), AMG 133 had an acceptable safety and tolerability profile along with pronounced dose-dependent weight loss. In the multiple ascending dose cohorts, weight loss was maintained for up to 150 days after the last dose. These findings support continued clinical evaluation of AMG 133.
Topics: Animals; Humans; Male; Mice; Glucagon-Like Peptide 1; Obesity; Peptides; Weight Loss; Glucagon-Like Peptide-1 Receptor
PubMed: 38316982
DOI: 10.1038/s42255-023-00966-w -
European Journal of Preventive... Jun 2024Obesity has risen to epidemic levels worldwide over the past few decades and has become a huge global health burden owing to its direct contribution to the development... (Review)
Review
Obesity has risen to epidemic levels worldwide over the past few decades and has become a huge global health burden owing to its direct contribution to the development of some of the most prevalent chronic diseases including diabetes, hypertension, hyperlipidaemia, and other cardiovascular diseases. Obesity is a disease of positive energy balance resulting from complex interactions between abnormal neurohumoral responses and an individual's socioeconomic, environmental, behavioural, and genetic factors leading to a state of chronic inflammation. Understanding the complex nature of the disease is crucial in determining the best approach to combat its rising numbers. Despite recent advancements in pharmacological therapy for the treatment of obesity, reversing weight gain and maintaining weight loss is challenging due to the relapsing nature of the disease. Prevention, therefore, remains the key which needs to start in utero and continued throughout life. This review summarizes the role obesity plays in the pathophysiology of various cardiovascular diseases both by directly affecting endothelial and myocyte function and indirectly by enhancing major cardiovascular risk factors like diabetes, hypertension, and hyperlipidaemia. We highlight the importance of a holistic approach needed to prevent and treat this debilitating disease. Particularly, we analyse the effects of plant-based diet, regular exercise, and non-exercise activity thermogenesis on obesity and overall cardiorespiratory fitness. Moreover, we discuss the significance of individualizing obesity management with a multimodal approach including lifestyle modifications, pharmacotherapy, and bariatric surgery to tackle this chronic disease.
Topics: Humans; Obesity; Cardiovascular Diseases; Risk Reduction Behavior; Risk Factors; Heart Disease Risk Factors; Risk Assessment
PubMed: 38243826
DOI: 10.1093/eurjpc/zwae025 -
Ugeskrift For Laeger Nov 2023The impact of diet on psoriasis is not well studied but it is of interest to many patients. A hypocaloric diet with corresponding weight loss can reduce psoriasis... (Review)
Review
The impact of diet on psoriasis is not well studied but it is of interest to many patients. A hypocaloric diet with corresponding weight loss can reduce psoriasis severity in overweight or obese patients and should be considered an important supplement to conventional therapy, as argued in this review. Gluten-free diet might improve severity of psoriasis in patients with coeliac disease or merely presence of coeliac-specific antibodies. Mediterranean diet might also be beneficial. Overall, studies do not support a beneficial effect of micronutrient supplements (i.e., vitamin D, selenium, vitamin B12) in patients with normal serum levels.
Topics: Humans; Diet, Reducing; Obesity; Diet; Vitamins; Psoriasis; Dietary Supplements; Celiac Disease
PubMed: 38018738
DOI: No ID Found