Obesity-induced Inflammation Research Articles

Hyaluronic acid-graphene oxide quantum dots nanoconjugate as dual purpose drug delivery and therapeutic agent in meta-inflammation

Type 2 diabetes mellitus (T2DM) predominantly considered a metabolic disease is now being considered an inflammatory disease as well due to the involvement of meta-inflammation. Obesity-induced adipose tissue inflammation (ATI) is one of the earliest phenomena in the case of meta-inflammation, leading to the advent of insulin resistance (IR) and T2DM. The key events of ATI are orchestrated by macrophages, which aggravate the inflammatory state in the tissue upon activation, ultimately leading to systemic chronic low-grade inflammation and Non-Alcoholic Steatohepatitis (NASH) through the involvement of proinflammatory cytokines. The CD44 receptor on macrophages is overexpressed in ATI, NASH, and IR. Therefore, we developed a CD44 targeted Hyaluronic Acid functionalized Graphene Oxide Quantum Dots (GOQD-HA) nanocomposite for tissue-specific delivery of metformin. Metformin-loaded GOQD-HA (GOQD-HA-Met) successfully downregulated the expression of proinflammatory cytokines and restored antioxidant status at lower doses than free metformin in both palmitic acid-induced RAW264.7 cells and diet induced obese mice. Our study revealed that the GOQD-HA nanocarrier enhanced the efficacy of Metformin primarily by acting as a therapeutic agent apart from being a drug delivery platform. The therapeutic properties of GOQD-HA stem from both HA and GOQD having anti-inflammatory and antioxidant properties respectively. This study unravels the function of GOQD-HA as a targeted drug delivery option for metformin in meta-inflammation where the nanocarrier itself acts as a therapeutic agent.Graphical

Obesity-Related Knee Osteoarthritis-Current Concepts.

The knee is the joint most frequently involved in osteoarthritis and represents a significant contributor to patient morbidity and impaired functional status. Major risk factors include genetics, age, sex, mechanical load and obesity/metabolic syndrome. Recent studies highlighted the role of obesity and metabolic syndrome in the pathogenesis of knee osteoarthritis not simply through increased mechanical loading but the systemic effects of obesity-induced inflammation. The current concept of knee osteoarthritis is that of a 'whole joint disease', which highlights the involvement not only of articular cartilage but also the synovium, subchondral bone, ligaments and muscles. Obesity and metabolic syndrome are associated with higher levels of pro-inflammatory cytokines, increased production of adipokines with both protective and destructive effects on articular cartilage, an up-regulation of proteolytic enzymes such as matrix metalloproteinases and aggrecanases and an increase in free fatty acids and reactive oxygen species induced by dyslipidemia. These findings underscore that the adequate management of knee osteoarthritis needs to include an optimization of body weight and a beneficial mobility regimen. The possible introduction of pharmacological therapy targeting specific molecules involved in the pathogenesis of obesity-related osteoarthritis will likely also be considered in future therapeutic strategies, including personalized treatment approaches.

Bacillus coagulans T4 and Lactobacillus paracasei TD3 Ameliorate Skeletal Muscle Oxidative Stress and Inflammation in High-Fat Diet-Fed C57BL/6J Mice.

This study aims to investigate the effects of Bacillus coagulans T4 and Lactobacillus paracasei TD3 probiotics on skeletal muscle inflammation and oxidative stress in C57BL/6J mice fed a high-fat diet (HFD). Probiotics B. coagulans T4, and L. paracasei TD3 were administered to male C57BL/6J mice fed with HFD. The gene expression of macrophage infiltration markers, inflammatory cytokines, and oxidative stress indicators in the muscle tissue was investigated. Treatment with B. coagulans T4 and L. paracasei TD3 reduced macrophage infiltration, accompanied by a decrease in the expression of monocyte chemoattractant protein-1 (MCP-1) and an increase in the expression of interleukin (IL)-10. On the other hand, L. paracasei TD3 decreased malondialdehyde (MDA) while B. coagulans T4 decreased carbonyl and increased catalase activity. Treatment with probiotics B. coagulans T4 and L. paracasei TD3 partially ameliorated obesity-induced skeletal muscle inflammation in HFD-fed mice.

UBE2M-mediated neddylation of TRIM21 regulates obesity-induced inflammation and metabolic disorders

Inflammation is closely associated with obesity and related metabolic disorders. However, its origin during obesity is largely unknown. Here, we report that ubiquitin-conjugating enzyme E2M (UBE2M) is critical to obesity-related inflammation induced by macrophages. In mice with UBE2M-deficient macrophages, obesity, insulin resistance, and hepatic steatosis induced by a high-fat diet are greatly alleviated, an effect related to the decreased proinflammatory activity of macrophages due to reduced IL-1β production. Mechanistically, UBE2M deficiency inhibits the neddylation of E3 ubiquitin ligase TRIM21 on K129/134, leading to reduced recruitment and ubiquitination-mediated degradation of E3 ubiquitin ligase VHL. Subsequently, VHL reduces HIF-1α-induced IL-1β production by degrading HIF-1α. Targeting macrophage TRIM21 with Trim21 antisense oligonucleotide-loaded red blood cell extracellular vesicles effectively inhibits obesity-induced inflammation and related metabolic disorders. Thus, our results demonstrate that macrophage UBE2M is essential for obesity-induced inflammation and that TRIM21 is a proof-of-concept target for treating obesity and associated metabolic diseases.

354-OR: Attenuation of Obesity-Induced Vascular Inflammation by microRNA-485 in Endothelial Cells

Obesity induced endothelial dysfunction contributes to the vascular inflammation. MicroRNAs (miRNAs) are implicated in the epigenetic regulation of inflammatory pathways. However, relevant miRNAs in the microvasculature, and their relation to chronic inflammation and metabolic dysfunction are poorly understood. Using micro-RNA Seq approach to profile microRNAs from the endothelial cells (ECs) of brown adipose tissue (BAT) of mice with diet-induced obesity (DIO), we identified microRNA- 485-5p (miR-485-5p) as one of the most differentially regulated miRNA. MiR-485-5p was rapidly induced in ECs in response to TNFα, highly enriched in the BAT vascular endothelium of mice with DIO, and was increased by 1.97 fold in human plasma samples with obesity. MiR-485-5p inhibition decreased TNF-α-induced NF-kB-responsive adhesion molecules VCAM-1 (32.6%) and ICAM-1 (34.7%) and phosphorylation of IKBα in ECs in vitro. Gain and loss-of-function studies revealed that neutralization of miR-485-5p potently inhibited leukocyte adhesion to EC monolayers by 20.8% while the overexpression had the opposite effects. Mechanistically, miR-485-5p inhibited the expression of its target gene PCF11 (~40.3%), a polyadenylation factor subunit, an effect that increased VCAM-1 (2.51 fold) and ICAM-1 (1.43 fold) expression as well as leukocyte adhesion to EC monolayers by 18.6% in vitro. Systemic neutralization of miR-485-5p in mice decreased leukocyte adhesion and rolling by 55.1% and 46.7% respectively by intravital microscopy. Finally, systemic delivery of LNA-anti-miR-485-5p inhibitor resulted in improved glucose and insulin tolerance and energy expenditure in mice with DIO while decreasing Ly6Chigh proinflammatory monocytes in blood as measured by FACS. Our findings indicate that miR-485-5p plays a key regulatory role in controlling vascular inflammation in diet-induced obesity, an effect that could be exploited for therapeutic intervention in obesity-induced chronic inflammation. Disclosure F.Bestepe: None. P.F.O'tierney-ginn: None. P.Alcaide: None. I.Z.Jaffe: None. B.Icli: None. R.Pal-ghosh: None. C.Fritsche: None. K.Lakhotiya: None. S.Smolgovsky: None. J.Weston: None. A.Stepanian: None. F.Alvarado: None. P.Catalano: None. Funding American Diabetes Association (1-16-JDF-046 to B.I.); National Institutes of Health (HL149999)

344-OR: Post-translational Modification of SHDA Regulating Macrophage Polarization and Inflammation in Obesity

The succinate dehydrogenase enzyme (SDH) catalyzes the oxidation of succinate into fumarate in the tricarboxylic acid cycle. Among the four subunits, SDHA and SDHB carry the catalytic activity. Mounting evidence implicates the link between the catalytic subunit SDHA expression and mitochondrial energy metabolism. However, the molecular mechanisms regulating SDH subunits stabilization in macrophages remain largely unknown. Here, we showed that AMPK, an energy sensor, could be a key regulator of SDHA ubiquitination through directly binding to sentrin-specific protease in adipose tissue macrophages, thus contributing to obesity-induced inflammation. Our study identified that SDHA expression was significantly downregulated in AMPKα siRNA RAW264.7 cells. Moreover, MG132 could significantly rescue AMPKα knockdown-induced SDHA degradation in cells, indicating that AMPK regulates SDHA stabilization via proteasomal degradation. However, AMPK protein interaction analyses by yeast two-hybrid showed that SDHA is not AMPK downstream target. Instead sentrin-specific protease was identified as a novel, putative AMPK substrate. To further clarify the potential interaction between AMPK, SDHA, and sentrin-specific protease, Co-IP experiment was included, and results indicated that AMPK directly binds with sentrin-specific protease instead of SDHA. As a desumoylating enzyme, SENP catalyzes hydrolysis peptide bond of SUMO. How the SUMOylation of SDHA impacts its ubiquitination still needs more investigations. In our scenario, we identified a new regulatory mechanism of SDHA stabilization, AMPKα-induced SUMOylation, that partially impacts the ubiquitination level of SDHA in activated macrophages. AMPKα-induced SUMOylation level change of SDHA is directly involved in the regulation of macrophage polarization, which may contribute to adipose inflammation. Disclosure R.Wu: None. H.Jiang: None.

The Influence of Antioxidants on Oxidative Stress-Induced Vascular Aging in Obesity.

Obesity is a worldwide trend that is growing in incidence very fast. Adipose tissue dysfunction caused by obesity is associated with the generation of oxidative stress. Obesity-induced oxidative stress and inflammation play a key role in the pathogenesis of vascular diseases. Vascular aging is one of the main pathogenesis mechanisms. The aim of this study is to review the effect of antioxidants on vascular aging caused by oxidative stress in obesity. In order to achieve this aim, this paper is designed to review obesity-caused adipose tissue remodeling, vascular aging generated by high levels of oxidative stress, and the effects of antioxidants on obesity, redox balance, and vascular aging. It seems that vascular diseases in obese individuals are complex networks of pathological mechanisms. In order to develop a proper therapeutic tool, first, there is a need for a better understanding of interactions between obesity, oxidative stress, and aging. Based on these interactions, this review suggests different lines of strategies that include change in lifestyle to prevent and control obesity, strategies for adipose tissue remodelling, oxidant-antioxidant balance, inflammation suppression, and strategies against vascular aging. Some antioxidants support different lines of these strategies, making them appropriate for complex conditions such as oxidative stress-induced vascular diseases in obese individuals.

Semaglutide ameliorates obesity-induced cardiac inflammation and oxidative stress mediated via reduction of neutrophil Cxcl2, S100a8, and S100a9 expression.

Obesity, which is driven by inflammation and oxidative stress, is a risk factor for cardiovascular disease. Semaglutide, a glucagon-like peptide-1 receptor agonist, is an antidiabetic drug with major effects on weight loss. In this study, single-cell transcriptomics was used to examine non-cardiomyocytes to uncover the mechanism of obesity-induced myocardial damage and the cardioprotective impact of semaglutide. We constructed obese mouse models and measured Tumor Necrosis Factor-α (TNF-α), Interleukin-6 (IL-6), Reactive Oxygen Species (ROS), and Malonic dialdehyde (MDA) levels in serum and heart tissue to determine the levels of inflammation and oxidative stress in obesity and the effect of semaglutide on these levels. Then, utilizing single-cell transcriptomes to screen for key cell populations and differentially expressed genes (DEGs), we assessed the effects of obesity and semaglutide on non-cardiac cells. Finally, a DEG localization analysis was performed to explore DEGs as well as cell types associated with inflammation and oxidative stress. Semaglutide reduced increased TNF-α, IL-6, ROS, and MDA levels in serum and cardiac tissues in obese mouse. Several genes are closely associated with inflammation and oxidative stress. Chemokine (C-X-C motif) ligand 2 (Cxcl2), S100 calcium binding protein A8 (S100a8), and S100 calcium binding protein A9 (S100a9), which were elevated in obesity but decreased following semaglutide treatment, were also expressed particularly in neutrophils. Finally, by decreasing neutrophil Cxcl2, S100a8, and S100a9 expressions, semaglutide may help to reduce cardiac inflammation and oxidative stress. Semaglutide significantly reduced body weight in obese mice as well as exerted anti-inflammatory and antioxidant effects possibly by inhibiting the expression of S100a8, S100a9, and Cxcl2 in neutrophils. These discoveries are expected to reveal new molecular mechanisms underlying obesity-related heart damage and semaglutide's cardioprotective properties.

The Preventive Mechanisms of Bioactive Food Compounds against Obesity-Induced Inflammation.

Dietary patterns are promising strategies for preventing and treating obesity and its coexisting inflammatory processes. Bioactive food compounds have received considerable attention due to their actions against obesity-induced inflammation, with limited harmful side effects. They are perceived as food ingredients or dietary supplements other than those necessary to meet basic human nutritional needs and are responsible for positive changes in the state of health. These include polyphenols, unsaturated fatty acids, and probiotics. Although the exact mechanisms of bioactive food compounds' action are still poorly understood, studies have indicated that they involve the modulation of the secretion of proinflammatory cytokines, adipokines, and hormones; regulate gene expression in adipose tissue; and modify the signaling pathways responsible for the inflammatory response. Targeting the consumption and/or supplementation of foods with anti-inflammatory potential may represent a new approach to obesity-induced inflammation treatment. Nevertheless, more studies are needed to evaluate strategies for bioactive food compound intake, especially times and doses. Moreover, worldwide education about the advantages of bioactive food compound consumption is warranted to limit the consequences of unhealthy dietary patterns. This work presents a review and synthesis of recent data on the preventive mechanisms of bioactive food compounds in the context of obesity-induced inflammation.

From Obesity-Induced Low-Grade Inflammation to Lipotoxicity and Mitochondrial Dysfunction: Altered Multi-Crosstalk between Adipose Tissue and Metabolically Active Organs.

Obesity is a major risk factor for several metabolic diseases, including type 2 diabetes, hyperlipidemia, cardiovascular diseases, and brain disorders. Growing evidence suggests the importance of inter-organ metabolic communication for the progression of obesity and the subsequent onset of related disorders. This review provides a broad overview of the pathophysiological processes that from adipose tissue dysfunction leading to altered multi-tissue crosstalk relevant to regulating energy homeostasis and the etiology of obesity. First, a comprehensive description of the role of adipose tissue was reported. Then, attention was turned toward the unhealthy expansion of adipose tissue, low-grade inflammatory state, metabolic inflexibility, and mitochondrial dysfunction as root causes of systemic metabolic alterations. In addition, a short spot was devoted to iron deficiency in obese conditions and the role of the hepcidin-ferroportin relationship in the management of this issue. Finally, different classes of bioactive food components were described with a perspective to enhance their potential preventive and therapeutic use against obesity-related diseases.

Allium macrostemon whole extract ameliorates obesity-induced inflammation and endoplasmic reticulum stress in adipose tissue of high-fat diet-fed C57BL/6N mice.

Obesity is a major risk factor for metabolic syndrome and a serious health concern worldwide. Various strategies exist to treat and prevent obesity, including dietary approaches using bioactive ingredients from natural sources. This study aimed to investigate the anti-obesity effect of whole-plant Allium macrostemon (also called as long-stamen chive) extract (AME) as a potential new functional food. C57BL/6N mice were divided into three groups and fed either a control diet (CD), high-fat diet (HFD), or HFD with AME treatment (200 mg/kg BW daily) for 9 weeks. The mice in the CD and HFD groups were treated with vehicle control. AME supplementation reduced HFD-induced body weight gain, fat mass, and adipocyte size. AME suppressed peroxisome proliferator-activated receptor γ and fatty acid synthase mRNA expression, indicating reduced adipogenesis and lipogenesis in adipose tissue. In addition, AME lowered inflammation in adipose tissue, as demonstrated by the lower number of crown-like structures, mRNA, and/or protein expression of macrophage filtration markers, as well as pro-inflammatory cytokines, including F4/80 and IL-6. Endoplasmic reticulum stress was also alleviated by AME administration in adipose tissue. Several phenolic acids known to have anti-obesity effects, including ellagic acid, protocatechuic acid, and catechin, have been identified in AME. By suppressing adipose tissue expansion and inflammation, AME is a potential functional food for the prevention and/or treatment of obesity and its complications.

Apocynin alleviates weight gain and obesity-induced adipose tissue inflammation in high-fat diet-fed C57BL/6 mice.

Obesity involves chronic low-grade inflammation within adipose tissue. Apocynin (APO) is a therapeutic agent for the treatment of inflammatory diseases. Therefore, the present study aimed to investigate whether APO can reduce weight gain and obesity-induced adipose tissue inflammation. C57BL/6 mice were administered APO or orlistat (Orli) as a positive control with a high-fat diet (HFD) for 12 weeks. Lipopolysaccharide-stimulated 3T3-L1 adipocytes were used for the in vitro study. Our results showed a significantly lower white adipose tissue (WAT) mass index in 10 mg/kg APO-treated mice than in 20 mg/kg Orli-treated mice. Moreover, the protein expression of adipose triglyceride lipase, fatty acid synthase, sterol regulatory element-binding transcription factor 1, and peroxisome proliferator-activated receptor γ was reversed in the WAT of 10 mg/kg APO-treated mice. Furthermore, APO reduced the expression of the macrophage marker F4/80, decreased the mRNA levels of tumor necrosis factor-α and monocyte chemoattractant protein-1, and increased the mRNA levels of interleukin-10 in WAT. APO decreased the phosphorylation of c-Jun N-terminal kinase, extracellular signal-regulated kinase, and p65 in vivo and in vitro. Notably, APO had a stronger effect on the amelioration of adipose tissue inflammation than Orli did. Our findings lay the foundation for research on the use of APO as an agent to ameliorate weight gain and obesity-induced inflammatory diseases.

Rapid adipose tissue expansion induces proliferation of memory adipose tissue T cells

Abstract Obesity is recognized as a pro-inflammatory state featuring immune dysregulation and metabolic disease. Obesity-induced inflammation is observed in the adipose tissue of humans and mice. Adipose tissue T cells (ATTs) are dynamically shifted from Th2 cells in the lean state to an influx of CD8 +and Th1 T cells that promote adipose tissue inflammation in the obese state. Knowing this, many gaps remain in our understanding of ATT generation, maintenance, expansion, and regulation in adipose tissue. Specifically, it is unknown if naïve T cells are recruited to and stimulated within adipose tissue or if resident memory ATTs, which are abundant in the lean state, are stimulated during the initiation of the obese state. We hypothesized that memory ATTs respond to the early fat expansion elicited upon obesity induction. To test this, we used a short-term DIO male mouse model and assessed ATT proliferation during high-fat diet (HFD) feeding. Mice on HFD gained significantly more total body, epidydimal white adipose tissue (eWAT), and inguinal WAT (iWAT) weight compared to normal diet mice. We observed no increase in frequency or proliferation of naïve ATTs with HFD. Conversely, we observed significant proliferation of memory ATTs with 1 week of HFD in the eWAT, iWAT and omental WAT. This proliferation was restored to normal diet levels by 2 weeks of HFD. These data suggest that memory ATTs uniquely and intensely respond to signals present during HFD-induced rapid adipose tissue expansion. Ongoing studies seek to determine if there are sex differences by examining ATT dynamics in female mice. Further, we seek to determine which signal(s) drive memory ATT proliferation to identify targets to suppress ATT initiation of obesity-associated inflammation. Supported by grants from NIH (K12 GM111725, R01 DK090262).

Distinct PD-1 hiCD4+ T helper cell populations promote CD11c+ T-bet+ B cell expansion in liver and spleen during obesity.

Abstract Obesity is associated with increased deposition of fat in ectopic tissues, such as within the liver and visceral adipose depots, including the omentum and mesentery. Increased visceral fat is an accompanying feature of the metabolic syndrome and is associated with increased end-organ damage in NAFLD. Emerging evidence implicates intrahepatic B cells in the progression of NAFLD, and increased number of proinflammatory B cells have been found in the steatotic livers of HFD-fed mice. Our preliminary studies demonstrate accumulation of inflammatory T-bet+ CD11c+ B cells in the subcutaneous adipose tissue of obese humans and perigonadal adipose tissue of mice on HFD. We now extend those findings into other sites of ectopic fat deposition to determine the obesity-related changes in T-bet+ B cell frequencies in the liver, omenta, and MAT. Flow cytometry identified increased frequencies of T-bet+ B cells in the spleen and livers, but not visceral adipose, of HFD mice. Furthermore, HFD-associated expansion of T-bet+ B cells in the spleen and liver correlated with a rise of T FHand T PHfrequencies, respectively. Future studies will determine the mechanism of tissue-specific T and B cell interactions associated with obesity-induced chronic inflammation. B.T.E. is supported by the NIH award (K12GM111726). T.H. is supported by a postdoctoral fellowship from the Swedish Research Council. This study was supported by NIH R01 AI32798-01A1 and the Voelcker Fund Young Investigator Awards (E.A.L).

Neutrophil peptidylarginine deiminase 4 plays a systemic role in obesity-induced chronic inflammation in mice

Abstract Obesity is an increasing problem in our current society. In morbidly obese patients, the level of circulating neutrophil extracellular traps (NETs) was found to be higher than in lean control subjects. Essential in this process of NET formation is the activation of the enzyme peptidylarginine deiminase 4 (PAD4). We aimed to understand how NETs contribute to the detrimental effects associated with a prolonged state of (morbid) obesity. Therefore, an animal model was adopted in which wild type (WT) and neutrophil specific PAD4 deficient (Ne-PAD4 −/−) mice on a C57BL6/J background were fed a high fat containing diet (HFD – 60kcal% fat) for a period of 10 weeks. Neutrophil activation status, evaluated through the formation of NETs in response to calcium ionophore ionomycin (4 μM) stimulation, was initially reduced after 3 days of HFD feeding. At later timepoints (5- and 10-weeks), neutrophils isolated from HFD-fed mice showed increased levels of NET formation in response to ionomycin stimulation in comparison to neutrophils from control diet-fed mice. Ne-PAD4 −/−mice on the HFD gained less weight than WT mice, which had a constant gain of body weight over the 10-week experimental period. Finally, after 10-weeks of high fat intake, cardiac function was evaluated in WT and Ne-PAD4 −/−mice by echocardiography. Interestingly, in WT mice diastolic function (early passive vs late active filling, E/A ratio) decreased as compared to baseline values, while Ne-PAD4 −/−mice kept E/A ratios comparable to baseline levels. Here, we demonstrate the importance of systemic NET release under metabolic challenge, and how this can contribute to cardiac deterioration at a young age due to obesity-induced alteration in the innate immune system.

Molecular Mechanisms of Obesity-Induced Development of Insulin Resistance and Promotion of Amyloid-β Accumulation: Dietary Therapy Using Weak Organic Acids via Improvement of Lowered Interstitial Fluid pH.

Insulin resistance is one of the etiologies of type 2 diabetes mellitus (T2DM) and has been suggested to contribute to the development of Alzheimer's disease by promoting amyloid-β accumulation. Various causes of insulin resistance have been suggested; however, mechanisms of insulin resistance development remain to be elucidated in many respects. Elucidating the mechanisms underlying the development of insulin resistance is one of the key factors in developing methods to prevent the onset of T2DM and Alzheimer's disease. It has been suggested that the body pH environment plays an important role in the control of cellular functions by regulating the action of hormones including insulin and the activity of enzymes and neurons, thereby maintaining homeostatic conditions of the body. This review introduces: (1) Mitochondrial dysfunction through oxidative stress caused by obesity-induced inflammation. (2) Decreased pH of interstitial fluid due to mitochondrial dysfunction. (3) Development of insulin resistance due to diminution of insulin affinity to its receptor caused by the lowered interstitial fluid pH. (4) Accelerated accumulation of amyloid-β due to elevated activities of β- and γ-secretases caused by the lowered interstitial fluid pH. (5) Diet therapies for improving insulin resistance with weak organic acids that act as bases in the body to raise the pH of lowered interstitial fluid and food factors that promote absorption of weak organic acids in the gut.

Adipose tissue macrophages as potential targets for obesity and metabolic diseases.

Macrophage infiltration into adipose tissue is a key pathological factor inducing adipose tissue dysfunction and contributing to obesity-induced inflammation and metabolic disorders. In this review, we aim to present the most recent research on macrophage heterogeneity in adipose tissue, with a focus on the molecular targets applied to macrophages as potential therapeutics for metabolic diseases. We begin by discussing the recruitment of macrophages and their roles in adipose tissue. While resident adipose tissue macrophages display an anti-inflammatory phenotype and promote the development of metabolically favorable beige adipose tissue, an increase in pro-inflammatory macrophages in adipose tissue has negative effects on adipose tissue function, including inhibition of adipogenesis, promotion of inflammation, insulin resistance, and fibrosis. Then, we presented the identities of the newly discovered adipose tissue macrophage subtypes (e.g. metabolically activated macrophages, CD9+ macrophages, lipid-associated macrophages, DARC+ macrophages, and MFehi macrophages), the majority of which are located in crown-like structures within adipose tissue during obesity. Finally, we discussed macrophage-targeting strategies to ameliorate obesity-related inflammation and metabolic abnormalities, with a focus on transcriptional factors such as PPARγ, KLF4, NFATc3, and HoxA5, which promote macrophage anti-inflammatory M2 polarization, as well as TLR4/NF-κB-mediated inflammatory pathways that activate pro-inflammatory M1 macrophages. In addition, a number of intracellular metabolic pathways closely associated with glucose metabolism, oxidative stress, nutrient sensing, and circadian clock regulation were examined. Understanding the complexities of macrophage plasticity and functionality may open up new avenues for the development of macrophage-based treatments for obesity and other metabolic diseases.

Casein Hydrolysate Alleviates Adipose Chronic Inflammation in High Fat-Diet Induced Obese C57BL/6J Mice through MAPK Pathway.

Obesity-induced adipose chronic inflammation is closely related to the development of insulin resistance and T2DM. Tripeptides l-valyl-l-prolyl-l-proline (VPP) and l-isoleucyl-l-prolyl-L-proline (IPP) derived from bovine casein have been reported to prevent inflammatory changes and mitigate insulin resistance in adipocytes. In this study, we aimed to investigate the influence of casein hydrolysates (CH) containing VPP and IPP on a high fat diet (HFD)-induced obese mice and cytokine TNF-α-induced adipocytes. Our data showed that CH alleviated chronic inflammation both in vivo and in vitro. 4% CH suppressed HFD-induced systemic inflammatory factors, hypertrophic white adipocytes, and macrophage infiltration. More importantly, CH was able to improve adipocyte dysfunction induced by TNF-α by increasing the expression of CCAAT/enhancer binding protein α (C/EBP-α) rather than peroxisome proliferator-activated receptor γ (PPAR-γ). Furthermore, CH also dose-dependently suppressed mitogen-activated protein kinase (MAPK)-c-Jun N-terminal kinase (JNK) phosphorylation and enhanced the phosphorylation of Erk 1/2, but not nuclear factor-kappa B (NF-κB) p65 phosphorylation, in TNF-α-induced 3T3-L1 cells. These results indicated that CH could ameliorate adipose chronic inflammation through the MAPK pathway. Altogether, our findings suggested that 4% CH supplementation for 6 weeks exerted a protective role in preventing obesity-related inflammation and adipose dysfunction.

Antioxidant, anti-inflammatory, and anticancer function of Engleromyces goetzei Henn aqueous extract on human intestinal Caco-2 cells treated with t-BHP.

High body mass index (high BMI, obesity) is a serious public health problem, and "obesity-induced oxidative stress, inflammation, and cancer" have become modern epidemic diseases. We carried out this study to explore a functional beverage that may protect against obesity-induced diseases. The Engleromyces goetzei Henn herbal tea is such a candidate. For this study, we carried out LC-MS analysis of E.goetzei Henn aqueous extract (EgH-AE); then used the Caco-2 cell line for the model cells and treated the cells with t-BHP to form an oxidative stress system. An MTT assay was used for testing the biocompatibility and cytoprotective effects; reactive oxygen species and malondialdehyde determination was used for evaluating the antioxidative stress effect; TNF-α and IL-1β were used for observing the anti-inflammatory effect, and 8-OHdG for monitoring anticancer activity. The results of this study demonstrate that the EgH-AE has very good biocompatibility with the Caco-2 cell line and has good cytoprotective, antioxidant, anti-inflammatory, and anticancer properties. It is clear that EgH-AE, a kind of ancient herbal tea, may be used to develop a functional beverage that can be given to people with a high BMI to protect against obesity-induced diseases.

LncRNA SNHG14/miR-497a-5p/BACE1 axis modulates obesity-induced adipocyte inflammation and endoplasmic reticulum stress.

Obesity is a metabolic disease with excess weight. LncRNA SNHG14 is abnormally expressed in numerous diseases. This research aimed to enucleate the lncRNA SNHG14 role in obesity. Adipocytes were treated with free fatty acid (FFA) to establish an in vitro model for obesity. Mice were fed a high-fat diet to construct an in vivo model. Gene levels were determined using quantitative real-time PCR (RT-PCR).The protein level was checked by western blot. The lncRNA SNHG14 role in obesity was assessed using western blot and enzyme-linked immunosorbent assay. The mechanism was estimated by Starbase, dual-luciferase reporter gene assay, and RNA pull-down. LncRNA SNHG14 function in obesity was estimated using mouse xenograft models, RT-PCR, western blot, and enzyme-linked immunosorbent assay. LncRNA SNHG14 and BACE1 levels were increased, but the miR-497a-5p level was decreased in FFA-induced adipocytes. Interference with lncRNA SNHG14 reduced endoplasmic reticulum (ER) stress-related molecules GRP78 and CHOP expressions in FFA-induced adipocytes, and decreased IL-1β, IL-6, and TNF-α expressions, indicating that lncRNA SNHG14 knockdown mitigated FFA-induced ER stress and inflammation in adipocytes. Mechanistically, lncRNA SNHG14 combined with miR-497a-5p, and miR-497a-5p targeted BACE1. Meanwhile, lncRNA SNHG14 knockdown reduced levels of GRP78, CHOP, IL-1β, IL-6, and TNF-α, while cotransfection with anti-miR-497a-5p or pcDNA-BACE1 abolished these trends. Rescue assays illustrated that lncRNA SNHG14 knockdown relieved FFA-induced adipocyte ER stress and inflammation through miR-497a-5p/BACE1. Meanwhile, lncRNA SNHG14 knockdown restrained adipose inflammation and ER stress caused by obesity in vivo. LncRNA SNHG14 mediated obesity-induced adipose inflammation and ER stress through miR-497a-5p/BACE1.