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PPARs-Orchestrated Metabolic Homeostasis in the Adipose Tissue.
Sun, C, Mao, S, Chen, S, Zhang, W, Liu, C
International journal of molecular sciences. 2021;(16)
Abstract
It has been more than three decades since peroxisome proliferator-activated receptors (PPARs) were first discovered. Many investigations have revealed the central regulators of PPARs in lipid and glucose homeostasis in response to different nutrient conditions. PPARs have attracted much attention due to their ability to improve metabolic syndromes, and they have also been proposed as classical drug targets for the treatment of hyperlipidemia and type 2 diabetes (T2D) mellitus. In parallel, adipose tissue is known to play a unique role in the pathogenesis of insulin resistance and metabolic syndromes due to its ability to "safely" store lipids and secrete cytokines that regulate whole-body metabolism. Adipose tissue relies on a complex and subtle network of transcription factors to maintain its normal physiological function, by coordinating various molecular events, among which PPARs play distinctive and indispensable roles in adipocyte differentiation, lipid metabolism, adipokine secretion, and insulin sensitivity. In this review, we discuss the characteristics of PPARs with special emphasis on the roles of the different isotypes in adipocyte biology.
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Gut-adipose tissue crosstalk: A bridge to novel therapeutic targets in metabolic syndrome?
Rosendo-Silva, D, Matafome, P
Obesity reviews : an official journal of the International Association for the Study of Obesity. 2021;(2):e13130
Abstract
The gut is one of the main endocrine organs in our body, producing hormones acknowledged to play determinant roles in controlling appetite, energy balance and glucose homeostasis. One of the targets of such hormones is the adipose tissue, a major energetic reservoir, which governs overall metabolism through the secretion of adipokines. Disturbances either in nutrient and metabolic sensing and consequent miscommunication between these organs constitute a key driver to the metabolic complications clustered in metabolic syndrome. Thus, it is essential to understand how the disruption of this crosstalk might trigger adipose tissue dysfunction, a strong characteristic of obesity and insulin resistance. The beneficial effects of metabolic surgery in the amelioration of glucose homeostasis and body weight reduction allowed to understand the potential of gut signals modulation as a treatment for metabolic syndrome-related obesity and type 2 diabetes. In this review, we cover the effects of gut hormones in the modulation of adipose tissue metabolic and endocrine functions, as well as their impact in tissue plasticity. Furthermore, we discuss how the modulation of gut secretome, either through surgical procedures or pharmacological approaches, might improve adipose tissue function in obesity and metabolic syndrome.
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3.
The burden of metabolic syndrome on osteoarthritic joints.
Dickson, BM, Roelofs, AJ, Rochford, JJ, Wilson, HM, De Bari, C
Arthritis research & therapy. 2019;(1):289
Abstract
BACKGROUND The prevalence of osteoarthritis (OA) increases with obesity, with up to two thirds of the elderly obese population affected by OA of the knee. The metabolic syndrome (MetS), frequently associated with central obesity and characterised by elevated waist circumference, raised fasting plasma glucose concentration, raised triglycerides, reduced high-density lipoproteins, and/or hypertension, is implicated in the pathogenesis of OA. This narrative review discusses the mechanisms involved in the influence of MetS on OA, with a focus on the effects on macrophages and chondrocytes. MAIN TEXT A skewing of macrophages towards a pro-inflammatory M1 phenotype within synovial and adipose tissues is thought to play a role in OA pathogenesis. The metabolic perturbations typical of MetS are important drivers of pro-inflammatory macrophage polarisation and activity. This is mediated via alterations in the levels and activities of the cellular nutrient sensors 5' adenosine monophosphate-activated protein kinase (AMPK) and mammalian target of rapamycin complex 1 (mTORC1), intracellular accumulation of metabolic intermediates such as succinate and citrate, and increases in free fatty acids (FFAs) and hyperglycaemia-induced advanced glycation end-products (AGEs) that bind to receptors on the macrophage surface. Altered levels of adipokines, including leptin and adiponectin, further influence macrophage polarisation. The metabolic alterations in MetS also affect the cartilage through direct effects on chondrocytes by stimulating the production of pro-inflammatory and catabolic factors and possibly by suppressing autophagy and promoting cellular senescence. CONCLUSIONS The influence of MetS on OA pathogenesis involves a wide range of metabolic alterations that directly affect macrophages and chondrocytes. The relative burden of intra-articular versus systemic adipose tissue in the MetS-associated OA remains to be clarified. Understanding how altered metabolism interacts with joints affected by OA is crucial for the development of further strategies for treating this debilitating condition, such as supplementing existing therapies with metformin and utilising ω-3 fatty acid derivatives to restore imbalances in ω-3 and ω-6 fatty acids.
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Ghrelin forms in the modulation of energy balance and metabolism.
Gortan Cappellari, G, Barazzoni, R
Eating and weight disorders : EWD. 2019;(6):997-1013
Abstract
Ghrelin is a gastric hormone circulating in acylated (AG) and unacylated (UnAG) forms. This narrative review aims at presenting current emerging knowledge on the impact of ghrelin forms on energy balance and metabolism. AG represents ~ 10% of total plasma ghrelin, has an appetite-stimulating effect and is the only form for which a receptor has been identified. Moreover, other metabolic AG-induced effects have been reported, including the modulation of glucose homeostasis with stimulation of liver gluconeogenesis, the increase of fat mass and the improvement of skeletal muscle mitochondrial function. On the other hand, UnAG has no orexigenic effects, however recent reports have shown that it is directly involved in the modulation of skeletal muscle energy metabolism by improving a cluster of interlinked functions including mitochondrial redox activities, tissue inflammation and insulin signalling and action. These findings are in agreement with human studies which show that UnAG circulating levels are positively associated with insulin sensitivity both in metabolic syndrome patients and in a large cohort from the general population. Moreover, ghrelin acylation is regulated by a nutrient sensor mechanism, specifically set on fatty acids availability. These recent findings consistently point towards a novel independent role of UnAG as a regulator of muscle metabolic pathways maintaining energy status and tissue anabolism. While a specific receptor for UnAG still needs to be identified, recent evidence strongly supports the hypothesis that the modulation of ghrelin-related molecular pathways, including those involved in its acylation, may be a potential novel target in the treatment of metabolic derangements in disease states characterized by metabolic and nutritional complications.Level of evidence Level V, narrative review.
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Fructose, Glucocorticoids and Adipose Tissue: Implications for the Metabolic Syndrome.
Legeza, B, Marcolongo, P, Gamberucci, A, Varga, V, Bánhegyi, G, Benedetti, A, Odermatt, A
Nutrients. 2017;(5)
Abstract
The modern Western society lifestyle is characterized by a hyperenergetic, high sugar containing food intake. Sugar intake increased dramatically during the last few decades, due to the excessive consumption of high-sugar drinks and high-fructose corn syrup. Current evidence suggests that high fructose intake when combined with overeating and adiposity promotes adverse metabolic health effects including dyslipidemia, insulin resistance, type II diabetes, and inflammation. Similarly, elevated glucocorticoid levels, especially the enhanced generation of active glucocorticoids in the adipose tissue due to increased 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) activity, have been associated with metabolic diseases. Moreover, recent evidence suggests that fructose stimulates the 11β-HSD1-mediated glucocorticoid activation by enhancing the availability of its cofactor NADPH. In adipocytes, fructose was found to stimulate 11β-HSD1 expression and activity, thereby promoting the adipogenic effects of glucocorticoids. This article aims to highlight the interconnections between overwhelmed fructose metabolism, intracellular glucocorticoid activation in adipose tissue, and their metabolic effects on the progression of the metabolic syndrome.
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Metabolic disorders in polycystic ovary syndrome.
Wikiera, B, Zubkiewicz-Kucharska, A, Nocoń-Bohusz, J, Noczyńska, A
Pediatric endocrinology, diabetes, and metabolism. 2017;(4):204-208
Abstract
Polycystic ovary syndrome (PCOS) is a complex disease. Depending on the used criteria the prevalence of PCOS ranges from 6 to 20%. It is necessary to exclude diseases leading to androgen excess. The participation of genetic and environmental factors is considered in the etiology of PCOS development. The highest rate of incidence of PCOS is assessed in girls who were born SGA and developed premature adrenarche later in life.The free androgen index (FAI) is concerned as the most sensitive marker of hyperandrogenaemia in PCOS although insulin resistance, anti-Müllerian hormone (AMH),and deficiency of vitamin D may intensify metabolic disturbances. The ultrasound criteria used in adolescent patients prefer the estimation of the ovarian volume or the ratio of ovarian stroma to total ovary, rather than the number of ovarian follicles. PCOS is connected with different metabolic disorders. Post-binding defect in signal transduction is responsible for insulin resistance. This defect results from an impaired activity of the kinase receptor. Moreover, the adipose tissue of PCOS women differs substantially from the tissue of the others according to morphology and function. The adipocytes produce lower amounts of adiponectin, which is an insulin-sensitizing agent. Dyspidemia with high triglycerides and low high density lipoprotein cholesterol concentrations is frequently noticed. Cardio-metabolic risk factors, insulin resistance, and endothelial dysfunction accompany PCOS from the very beginning. Oxidative stress plays a role as a link among systemic inflammation and dysfunction of endothelial cells and abnormal thecal cell action. The treatment efforts in PCOS depend on the patient's main problems. Modification of diet and lifestyle is the most important recommended advice to each woman independent of age and weight.
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7.
Macrophage functions in lean and obese adipose tissue.
Thomas, D, Apovian, C
Metabolism: clinical and experimental. 2017;:120-143
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Abstract
Interactions between macrophages and adipocytes influence both metabolism and inflammation. Obesity-induced changes to macrophages and adipocytes lead to chronic inflammation and insulin resistance. This paper reviews the various functions of macrophages in lean and obese adipose tissue and how obesity alters adipose tissue macrophage phenotypes. Metabolic disease and insulin resistance shift the balance between numerous pro- and anti-inflammatory regulators of macrophages and create a feed-forward loop of increasing inflammatory macrophage activation and worsening adipocyte dysfunction. This ultimately leads to adipose tissue fibrosis and diabetes. The molecular mechanisms underlying these processes have therapeutic implications for obesity, metabolic syndrome, and diabetes.
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Specific metabolic characteristics of women with former gestational diabetes: the importance of adipose tissue.
Vejrazkova, D, Vankova, M, Lukasova, P, Vcelak, J, Cirmanova, V, Haluzik, M, Bendlova, B
Physiological research. 2017;(Suppl 3):S349-S356
Abstract
Women with a positive history of gestational diabetes mellitus (GDM) face a higher risk of developing type 2 diabetes mellitus (T2DM) and metabolic syndrome later in life. The higher risk of these metabolic complications is closely associated with adipose tissue. In this review, the importance of adipose tissue is discussed in relation to GDM, focusing on both the quantity of fat deposits and the metabolic activity of adipose tissue in particular periods of life: neonatal age, childhood, adolescence, and pregnancy followed by nursing. Preventive measures based on body composition and lifestyle habits with special attention to the beneficial effects of breastfeeding are also discussed.
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Hydrogen Sulfide in the Adipose Tissue-Physiology, Pathology and a Target for Pharmacotherapy.
Bełtowski, J, Jamroz-Wiśniewska, A
Molecules (Basel, Switzerland). 2016;(1)
Abstract
Hydrogen sulfide (H₂S) is synthesized in the adipose tissue mainly by cystathionine γ-lyase (CSE). Several studies have demonstrated that H₂S is involved in adipogenesis, that is the differentiation of preadipocytes to adipocytes, most likely by inhibiting phosphodiesterases and increasing cyclic AMP concentration. The effect of H₂S on adipose tissue insulin sensitivity and glucose uptake is controversial. Some studies suggest that H₂S inhibits insulin-induced glucose uptake and that excess of H₂S contributes to adipose tissue insulin resistance in metabolic syndrome. In contrast, other studies have demonstrated that H₂S stimulates glucose uptake and its deficiency contributes to insulin resistance. Similarly, the effect of H₂S on adipose tissue lipolysis is controversial. H₂S produced by perivascular adipose tissue decreases vascular tone by activating ATP-sensitive and/or voltage-gated potassium channels in smooth muscle cells. Experimental obesity induced by high calorie diet has a time dependent effect on H₂S in perivascular adipose tissue; short and long-term obesity increase and decrease H₂S production, respectively. Hyperglycemia has been consistently demonstrated to suppress CSE-H₂S pathway in various adipose tissue depots. Finally, H₂S deficiency may contribute to adipose tissue inflammation associated with obesity/metabolic syndrome.
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Adipose tissue as an immunological organ.
Grant, RW, Dixit, VD
Obesity (Silver Spring, Md.). 2015;(3):512-8
Abstract
OBJECTIVE This review will focus on the immunological aspects of adipose tissue and its potential role in development of chronic inflammation that instigates obesity-associated comorbidities. METHODS The review used PubMed searches of current literature to examine adipose tissue leukocytosis. RESULTS AND CONCLUSIONS The adipose tissue of obese subjects becomes inflamed and contributes to the development of insulin resistance, type 2 diabetes, and metabolic syndrome. Numerous immune cells including B cells, T cells, macrophages, and neutrophils have been identified in adipose tissue, and obesity influences both the quantity and the nature of immune cell subtypes, which emerges as an active immunological organ capable of modifying whole-body metabolism through paracrine and endocrine mechanisms. Adipose tissue is a large immunologically active organ during obesity and displays hallmarks of both and innate and adaptive immune response. Despite the presence of hematopoietic lineage cells in adipose tissue, it is unclear whether the adipose compartment has a direct role in immune surveillance or host defense. Understanding the interactions between leukocytes and adipocytes may reveal the clinically relevant pathways that control adipose tissue inflammation and is likely to reveal mechanisms by which obesity contributes to increased susceptibility to both metabolic and certain infectious diseases.