Inhibitory Effects of Toll-Like Receptor 4, NLRP3 Inflammasome, and Interleukin-1β on White Adipocyte Browning

Adipose tissue expansion is accompanied by infiltration and accumulation of pro-inflammatory macrophages, which links obesity to pathologic conditions such as type 2 diabetes. However, little is known regarding the role of pro-inflammatory adipose tissue remodeling in the thermogenic activation of brown/beige fat. Here, we investigated the effect of pattern recognition receptors (PRR) activation in macrophages, especially the toll-like receptor 4 (TLR4) and Nod-like receptor 3 (NLRP3), on white adipocyte browning. We report that TLR4 activation by lipopolysaccharide repressed white adipocyte browning in response to β3-adrenergic receptor activation and caused ROS production and mitochondrial dysfunction, while genetic deletion of TLR4 protected mitochondrial function and thermogenesis. In addition, activation of NLRP3 inflammasome in macrophages attenuated UCP1 induction and mitochondrial respiration in cultures of primary adipocytes, while the absence of NLRP3 protected UCP1 in adipocytes. The effect of NLRP3 inflammasome activation on browning was mediated by IL-1β signaling, as blocking IL-1 receptor in adipocytes protected thermogenesis. We also report that IL-1β interferes with thermogenesis via oxidative stress stimulation and mitochondrial dysfunction as we observed a statistically significant increase in ROS production, decrease in SOD enzyme activity, and increase in mitochondrial depolarization in adipocytes treated with IL-1β. Collectively, we demonstrated that inflammatory response to obesity, such as TLR4 and NLRP3 inflammasome activation as well as IL-1β secretion, attenuates β3-adrenoreceptor-induced beige adipocyte formation via oxidative stress and mitochondrial dysfunction. Our findings provide insights into targeting innate inflammatory system for enhancement of the adaptive thermogenesis against obesity

Regulation of Obesity and Metabolic Complications by Gamma and Delta Tocotrienols

Tocotrienols (T3s) are a subclass of unsaturated vitamin E that have been extensively studied for their anti-proliferative, anti-oxidative and anti-inflammatory properties in numerous cancer studies. Recently, T3s have received increasing attention due to their previously unrecognized property to attenuate obesity and its associated metabolic complications. In this review, we comprehensively evaluated the recent published scientific literature about the influence of T3s on obesity, with a particular emphasis on the signaling pathways involved. T3s have been demonstrated in animal models or human subjects to reduce fat mass, body weight, plasma concentrations of free fatty acid, triglycerides and cholesterol, as well as to improve glucose and insulin tolerance. Their mechanisms of action in adipose tissue mainly include (1) modulation of fat cell adipogenesis and differentiation; (2) modulation of energy sensing; (3) induction of apoptosis in preadipocytes and (4) modulation of inflammation. Studies have also been conducted to investigate the effects of T3s on other targets, e.g., the immune system, liver, muscle, pancreas and bone. Since δT3 and γT3 are regarded as the most active isomers among T3s, their clinical relevance to reduce obesity should be investigated in human trials

Mechanisms by which conjugated linoleic acid causes human adipocyte delipidation

"Obesity is an important health issue, having risen to epidemic proportions in the U.S. Use of conjugated linoleic acid (CLA), positional and geometric isomers of linoleic acid, has received recent attention due to its potential health benefits including the reduction of fat mass in animals. However, the effectiveness and safety of CLA consumption in humans remains unclear. Our group previously reported that trans-10, cis-12 CLA impaired the conversion of preadipocytes into lipid-filled adipocytes (e.g., differentiation) and caused adipocyte delipidation that involved inflammatory cytokines in a human cell model. However, the isomer-specific mechanism for these events was unknown. Thus, this research examined mechanisms by which trans-10, cis-12 CLA induced adipocyte delipidation, inflammation, and insulin resistance in primary cultures of human adipocytes. Delipidation of adipocytes by trans-10, cis-12 CLA was accompanied by increased lipolysis and changes in the morphology of lipid droplets and the expression and localization of proteins regulating lipid droplet metabolism. This process involved the translational control of adipose differentiated related protein (ADRP) through activation of mTOR/p70S6K/S6 signaling and transcriptional control of perilipin A. Prior to these morphological changes, it was shown that trans-10, cis-12 CLA promoted nuclear factor κB (NFκB) and mitogen activated protein kinase (MAPK) activation and subsequent induction of interleukin (IL)-6 which were, at least in part, responsible for trans-10, cis-12 CLA-mediated suppression of peroxisome proliferator activated receptor gamma (PPAR)γ target gene expression and insulin sensitivity in human adipocytes. The essential role of NFκB on CLA-induced inflammation was confirmed by using RNA interference. Further studies were conducted examining the localization and characterization of the inflammatory response, including the type of cells involved, using lipopolysaccharide (LPS) as the inflammatory agent. It was demonstrated that LPS-induced, NFκB-dependent proinflammatory cytokine expression was predominantly from preadipocytes, which led to, at least in part, the suppression of PPAR activity and adipogenic gene expression and insulin sensitivity. Collectively, these data support the emerging concept that adipose tissue is a dynamic endocrine organ with the capacity to generate inflammatory signals that impact glucose and lipid metabolism. Furthermore, human preadipocytes have the capacity to generate these inflammatory signals induced by trans-10, cis-12 CLA and LPS, subsequently causing insulin resistance in neighboring adipocytes. These studies also revealed that NFκB- and MAPK-signaling mediate inflammation and insulin resistance induced by CLA and LPS. Thus, although the trans-10, cis-12 isomer of CLA may decrease the size and lipid content of human adipocytes, it may also cause insulin resistance, which is a hallmark of type 2 diabetes. "--Abstract from author supplied metadata

Alpha-Linolenic Acid-Enriched Butter Promotes Fatty Acid Remodeling and Thermogenic Activation in the Brown Adipose Tissue

Supplementation with n-3 long-chain (LC) polyunsaturated fatty acids (PUFA) is known to promote thermogenesis via the activation of brown adipose tissue (BAT). Agricultural products that are biofortified with α-linolenic acid (ALA), the precursor of n-3 LC PUFA, have been launched to the market, but their impact on BAT function is unknown. This study aimed to evaluate the effects of ALA-biofortified butter on lipid metabolism and thermogenic functions in the BAT. C57BL/6 mice were fed a high-fat diet containing ALA-biofortified butter (n3Bu, 45% calorie from fat) for ten weeks in comparison with the isocaloric high-fat diets prepared from conventional butter or margarine. The intake of n3Bu significantly reduced the whitening of BAT and increased the thermogenesis in response to acute-cold treatment. Also, n3Bu supplementation is linked with the remodeling of BAT by promoting bioconversion into n-3 LC PUFA, FA elongation and desaturation, and mitochondrial biogenesis. Taken together, our results support that ALA-biofortified butter is a novel source of n-3 PUFA, which potentiates the BAT thermogenic function

Muscadine Grape (\u3ci\u3eVitis rotundifolia\u3c/i\u3e) and Wine Phytochemicals Prevented Obesity-Associated Metabolic Complications in C57BL/6J Mice

The objective of this study was to determine the effects of muscadine grape or wine (cv. Noble) phytochemicals on obesity and associated metabolic complications. Muscadine grape or wine phytochemicals were extracted using Amberlite FPX66 resin. Male C57BL/6J mice were given a low-fat diet (LF, 10% kcal fat), high-fat diet (HF, 60% kcal fat), HF + 0.4% muscadine grape phytochemicals (HF+MGP), or HF + 0.4% muscadine wine phytochemicals (HF+MWP) for 15 weeks. At 7 weeks, mice fed HF+MGP had significantly decreased body weights by 12% compared to HF controls. Dietary MGP or MWP supplementation reduced plasma content of free fatty acids, triglycerides, and cholesterol in obese mice. Inflammation was alleviated, and activity of glutathione peroxidase was enhanced. Consumption of MGP or MWP improved insulin sensitivity and glucose control in mice. Thus, consumption of muscadine grape and wine phytochemicals in the diet may help to prevent obesity-related metabolic complications

Nutrigenomic Functions of PPARs in Obesogenic Environments

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that mediate the effects of several nutrients or drugs through transcriptional regulation of their target genes in obesogenic environments.This review consists of three parts. First, we summarize current knowledge regarding the role of PPARs in governing the development of white and brown/beige adipocytes from uncommitted progenitor cells. Next, we discuss the interactions of dietary bioactive molecules, such as fatty acids and phytochemicals, with PPARs for the modulation of PPAR-dependent transcriptional activities and metabolic consequences. Lastly, the effects of PPAR polymorphism on obesity and metabolic outcomes are discussed. In this review, we aim to highlight the critical role of PPARs in the modulation of adiposity and subsequent metabolic adaptation in response to dietary challenges and genetic modifications. Understanding the changes in obesogenic environments as a consequence of PPARs/nutrient interactions may help expand the field of individualized nutrition to prevent obesity and obesity-associated metabolic comorbidities

Immunomodulatory Role of Urolithin A on Metabolic Diseases

Urolithin A (UroA) is a gut metabolite produced from ellagic acid-containing foods such as pomegranates, berries, and walnuts. UroA is of growing interest due to its therapeutic potential for various metabolic diseases based on immunomodulatory properties. Recent advances in UroA research suggest that UroA administration attenuates inflammation in various tissues, including the brain, adipose, heart, and liver tissues, leading to the potential delay or prevention of the onset of Alzheimer’s disease, type 2 diabetes mellitus, and non-alcoholic fatty liver disease. In this review, we focus on recent updates of the anti-inflammatory function of UroA and summarize the potential mechanisms by which UroA may help attenuate the onset of diseases in a tissue-specific manner. Therefore, this review aims to shed new insights into UroA as a potent anti-inflammatory molecule to prevent immunometabolic diseases, either by dietary intervention with ellagic acid-rich food or by UroA administration as a new pharmaceutical drug

Effects of tunable, 3D-bioprinted hydrogels on human brown adipocyte behavior and metabolic function

Obesity and its related health complications cause billions of dollars in healthcare costs annually in the United States, and there are yet to be safe and long-lasting anti-obesity approaches. Using brown adipose tissue (BAT) is a promising approach, as it uses fats for energy expenditure. However, the effect of the microenvironment on human thermogenic brown adipogenesis and how to generate clinically relevant sized and functioning BAT are still unknown. In our current study, we evaluated the effects of endothelial growth medium exposure on brown adipogenesis of human brown adipose progenitors (BAP). We found that pre-exposing BAP to angiogenic factors promoted brown adipogenic differentiation and metabolic activity. We further 3D bioprinted brown and white adipose progenitors within hydrogel-based bioink with controllable physicochemical properties and evaluated the cell responses in 3D bioprinted environments. We used soft, stiff, and stiff-porous constructs to encapsulate the cells. All three types had high cell viability and allowed for varying levels of function for both white and brown adipocytes. We found that the soft hydrogel constructs promoted white adipogenesis, while the stiff-porous hydrogel constructs improved both white and brown adipogenesis and were the optimal condition for promoting brown adipogenesis. Consistently, stiff-porous hydrogel constructs showed higher metabolic activities than stiff hydrogel constructs, as assessed by 2-deoxy glucose uptake (2-DOG) and oxygen consumption rate (OCR). These findings show that the physicochemical environments affect the brown adipogenesis and metabolic function, and further tuning will be able to optimize their functions. Our results also demonstrate that 3D bioprinting of brown adipose tissues with clinically relevant size and metabolic activity has the potential to be a viable option in the treatment of obesity and type 2 diabetes

Urolithin A, a Gut Metabolite, Improves Insulin Sensitivity through Augmentation of Mitochondrial Function and Biogenesis

Objective: Urolithin A (UroA) is a major metabolite of ellagic acid produced following microbial catabolism in the gut. Emerging evidence has suggested that UroA modulates energy metabolism in various cells. However, UroA’s physiological functions related to obesity and insulin resistance remain unclear. Methods: Male mice were intraperitoneally administrated either UroA or dimethyl sulfoxide (vehicle) along with a high-fat diet for 12 weeks. Insulin sensitivity was evaluated via glucose and insulin tolerance tests and acute insulin signaling. The effects of UroA on hepatic triglyceride accumulation, adipocyte size, mitochondrial DNA content, and proinflammatory gene expressions were determined. The impact of UroA on macrophage polarization and mitochondrial respiration were assessed in bone marrow–derived macrophages. Results: Administration of UroA (1) improved systemic insulin sensitivity, (2) attenuated triglyceride accumulation and elevated mitochondrial biogenesis in the liver, (3) reduced adipocyte hypertrophy and macrophage infiltration into the adipose tissue, and (4) altered M1/M2 polarization in peritoneal macrophages. In addition, UroA favored macrophage M2 polarization and mitochondrial respiration in bone marrow–derived macrophages. Conclusions: UroA plays a direct role in improving systemic insulin sensitivity independent of its parental compounds. This work supports UroA’s role in the metabolic benefits of ellagic acid–rich foods and highlights the significance of its microbial transformation in the gut

Polyphenolic fractions isolated from red raspberry whole fruit, pulp, and seed differentially alter the gut microbiota of mice with diet-induced obesity

Polyphenol extracts from red raspberry (RR) whole fruit or pulp, but not seed, attenuate high-fat (HF) diet-induced obesity in mice. Because host metabolism is linked to the microbiota, we investigated the effects of polyphenols from RR fruit, pulp, and seed on the microbiome. RR polyphenols significantly decreased the abundance of specific taxa that were increased during HF feeding relative to a low-fat diet, including Ruminococcus and an unclassified genus from Clostridiales. Compared to a HF diet, pulp and seed polyphenols increased Roseburia abundance and decreased levels of an unclassified genus from Mogibacteriaceae. RR seed polyphenols uniquely increased Bifidobacterium compared to a HF diet. The most notable taxon driving differential abundance among all diets was an unclassified genus from Coriobacteriaceae. Importantly, host metabolic markers improved by pulp polyphenols were strongly correlated with select microbiome features, indicating that specific gut bacteria may be involved in RR polyphenol catabolism and/or mediating health benefits