This review summarizes the role of macrophages in adipose tissue remodeling, particularly focusing on the paracrine loop between adipocytes and macrophages.
The adipose tissue secretes a large number ...of bioactive substances, adipocytokines, which may be involved in a variety of physiologic and pathologic processes. Unbalanced production of pro‐ and anti‐inflammatory adipocytokines seen in visceral fat obesity contributes critically to the development of the metabolic syndrome. Evidence has accumulated indicating that obesity is associated with a state of chronic, low‐grade inflammation, suggesting that inflammation may be a potential mechanism, whereby obesity leads to insulin resistance. Indeed, obese adipose tissue is characterized by adipocyte hypertrophy, followed by increased angiogenesis, immune cell infiltration, extracellular matrix overproduction, and thus, increased production of proinflammatory adipocytokines during the progression of chronic inflammation. The dynamic change found in the adipose tissue can be referred to as “adipose tissue remodeling,” in which stromal cells change dramatically in number and cell type during the course of obesity. Among stromal cells, infiltration of macrophages in the adipose tissue precedes the development of insulin resistance in animal models, suggesting that they are crucial for obesity‐related adipose tissue inflammation. We have demonstrated that a paracrine loop involving saturated fatty acids and TNF‐α derived from adipocytes and macrophages, respectively, aggravates obesity‐induced adipose tissue inflammation. Notably, saturated fatty acids, which are released from hypertrophied adipocytes via the macrophage‐induced lipolysis, serve as a naturally occurring ligand for TLR4 complex, thereby activating macrophages. Understanding the molecular mechanism underlying adipose tissue remodeling may lead to the identification of novel, therapeutic strategies to prevent or treat obesity‐induced adipose tissue inflammation.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Obesity may be viewed as a chronic low-grade inflammatory disease as well as a metabolic disease. Indeed, unbalanced production of pro- and anti-inflammatory adipocytokines critically contributes to ...the obesity-induced insulin resistance. In addition to lipid-laden mature adipocytes, adipose tissue is composed of various stromal cells such as preadipocytes, endothelial cells, fibroblasts, and immune cells that may be involved in adipose tissue functions. Accumulating evidence has suggested that adipocytes and stromal cells in adipose tissue change dramatically in number and cell type during the course of obesity, which is referred to as “adipose tissue remodeling.” Among stromal cells, infiltration of macrophages in obese adipose tissue precedes the development of insulin resistance in animal models, suggesting that they are crucial for adipose tissue inflammation. We have provided evidence suggesting that a paracrine loop involving saturated fatty acids and tumor necrosis factor-α derived from adipocytes and macrophages, respectively, aggravates obesity-induced adipose tissue inflammation. On the other hand, storing excessive energy as triglyceride is also a fundamental function of adipose tissue. Recent evidence suggests that reduced lipid storage in obese adipose tissue contributes to ectopic lipid accumulation in non-adipose tissues such as the liver, skeletal muscle, and pancreas, where lipotoxicity impairs their metabolic functions. Notably, chronic inflammation is capable of inducing insulin resistance, lipolysis, and interstitial fibrosis in adipose tissue, all of which may reduce the lipid-storing function. Understanding the molecular mechanism underlying adipose tissue remodeling may lead to the identification of novel therapeutic strategies to prevent or treat obesity-induced adipose tissue inflammation.
Background
Although endoscopic ultrasound (EUS) is reported to be suitable for determining the layer from which subepithelial lesions (SELs) originate, it is difficult to distinguish gastrointestinal ...stromal tumor (GIST) from non-GIST using only EUS images. If artificial intelligence (AI) can be used for the diagnosis of SELs, it should provide several benefits, including objectivity, simplicity, and quickness. In this pilot study, we propose an AI diagnostic system for SELs and evaluate its efficacy.
Methods
Thirty sets each of EUS images with SELs ≥ 20 mm or < 20 mm were prepared for diagnosis by an EUS diagnostic system with AI (EUS-AI) and three EUS experts. The EUS-AI and EUS experts diagnosed the SELs using solely the EUS images. The concordance rates of the EUS-AI and EUS experts’ diagnoses were compared with the pathological findings of the SELs.
Results
The accuracy, sensitivity, and specificity for SELs < 20 mm were 86.3, 86.3, and 62.5%, respectively for the EUS-AI, and 73.3, 68.2, and 87.5%, respectively, for the EUS experts. In contrast, accuracy, sensitivity, and specificity for SELs ≥ 20 mm were 90.0, 91.7, and 83.3%, respectively, for the EUS-AI, and 53.3, 50.0, and 83.3%, respectively, for the EUS experts. The area under the curve for the diagnostic yield of the EUS-AI for SELs ≥ 20 mm (0.965) was significantly higher than that (0.684) of the EUS experts (
P
= 0.007).
Conclusion
EUS-AI had a good diagnostic yield for SELs ≥ 20 mm. EUS-AI has potential as a good option for the diagnosis of SELs.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Rising prevalence of childhood obesity and type 2 diabetes mellitus (T2DM) is an emerging public health issue.
To investigate the association of maternal hyperglycemia exposure during pregnancy with ...obesity and abnormal glucose tolerance in offspring, and the age at occurrence.
We searched MEDLINE and EMBASE for observational studies on obesity and diabetes in offspring of diabetic mothers (gestational diabetes mellitus (GDM), type 1 diabetes mellitus (T1DM) and T2DM), and those on non-diabetic mothers. We performed fixed effect meta-analysis for all studies except when heterogeneity was detected. The quality of studies was evaluated using the Risk of Bias Assessment Tool for Nonrandomized Studies (RoBANS).
Twenty observational studies were included involving a total of 26,509 children. Offspring of GDM mother had higher BMI z-score in childhood (pooled MD: 0.14, 95%CI: 0.04-0.24, seven studies, 21,691children, low quality of evidence). Offspring of T1DM mothers had higher BMI z-score from prepubertal to adolescent (pooled MD: 0.35, 95% CI: 0.13-0.58, three studies, 844 children, low quality of evidence) compared with control. After adjustment for maternal pre-pregnancy BMI, this association remained in offspring of T1DM, but disappeared in those of GDM mothers. Offspring of GDM mother had higher 2-hour plasma glucose from prepubertal to early adulthood (pooled MD: 0.43 mmol/L, 95% CI: 0.18-0.69, five studies, 890 children), while those of T1DM mothers had higher rate of T2DM in 2-5 years old to early adulthood (pooled odds ratio OR, 6.10: 95% CI: 1.23-30.37, two studies, 448 children, very low quality of evidence) compared with control. As there was only one study with offspring of T2DM mothers, evidence is sparse.
Only observational studies were included, with a few adequately adjusted for covariables.
Exposure to maternal hyperglycemia was associated with offspring obesity and abnormal glucose tolerance especially in offspring of T1DM mothers, but the evidence relies on observational studies with low quality of evidence only.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Biologics against tumor necrosis factor-α (TNF) and the p40 subunit of interleukin (IL)-12 and IL-23 are increasingly used in inflammatory bowel disease (IBD) treatment. However, ...information on response prediction to these agents is limited. Thus, we aimed to identify factors for IBD treatment response prediction.
Methods
We conducted a retrospective study in 33 IBD subjects for anti-TNF and a prospective study of 23 IBD and 11 non-IBD subjects for ustekinumab (UST). Mucosal biopsy specimens were obtained before treatment with biologics. The expression of 18 immune-related genes encoding representative cytokines and transcription factors was analyzed by quantitative polymerase chain reaction.
Results
There was no difference between the treatment-resistant and -sensitive groups with regard to clinical characteristics. A higher expression of oncostatin M (OSM) and its receptor OSMR in the intestinal mucosa was most strongly associated with anti-TNF resistance, whereas lower IL23A expression was most strongly associated with UST resistance. In addition to the absolute expression levels of genes, concordant or discordant expression patterns of particular gene sets were associated with treatment sensitivity and resistance.
Conclusions
The association of anti-TNF resistance and mucosal OSM and OSMR expression was consistent with the results of a previous study in a European cohort. Our observation that IBD subjects with higher mucosal IL23A expression were more likely to achieve remission by UST has not been previously reported. The response to biologics may thus be predicted in IBD patients through the analysis of mucosal gene expression levels and patterns.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Understanding the genetic factors of diabetes is essential for addressing the global increase in type 2 diabetes. HNF1A mutations cause a monogenic form of diabetes called maturity-onset diabetes of ...the young (MODY), and HNF1A single-nucleotide polymorphisms are associated with the development of type 2 diabetes. Numerous studies have been conducted, mainly using genetically modified mice, to explore the molecular basis for the development of diabetes caused by HNF1A mutations, and to reveal the roles of HNF1A in multiple organs, including insulin secretion from pancreatic beta cells, lipid metabolism and protein synthesis in the liver, and urinary glucose reabsorption in the kidneys. Recent studies using human stem cells that mimic MODY have provided new insights into beta cell dysfunction. In this article, we discuss the involvement of HNF1A in beta cell dysfunction by reviewing previous studies using genetically modified mice and recent findings in human stem cell-derived beta cells.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Type 2 diabetes mellitus (T2DM) is associated with a high incidence of non-alcoholic fatty liver disease (NAFLD) related to obesity and insulin resistance. Currently, medical interventions for NAFLD ...have focused on diet control and exercise to reduce body weight, and there is a requirement for effective pharmacological therapies. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are oral antidiabetic drugs that promote the urinary excretion of glucose by blocking its reabsorption in renal proximal tubules. SGLT2 inhibitors lower blood glucose independent of insulin action and are expected to reduce body weight because of urinary calorie loss. Here we show that an SGLT2 inhibitor ipragliflozin improves hepatic steatosis in high-fat diet-induced and leptin-deficient (ob/ob) obese mice irrespective of body weight reduction. In the obese mice, ipragliflozin-induced hyperphagia occurred to increase energy intake, attenuating body weight reduction with increased epididymal fat mass. There is an inverse correlation between weights of liver and epididymal fat in ipragliflozin-treated obese mice, suggesting that ipragliflozin treatment promotes normotopic fat accumulation in the epididymal fat and prevents ectopic fat accumulation in the liver. Despite increased adiposity, ipragliflozin ameliorates obesity-associated inflammation and insulin resistance in epididymal fat. Clinically, ipragliflozin improves liver dysfunction in patients with T2DM irrespective of body weight reduction. These findings provide new insight into the effects of SGLT2 inhibitors on energy homeostasis and fat accumulation and indicate their potential therapeutic efficacy in T2DM-associated hepatic steatosis.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Several clinical studies have shown the beneficial effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on diabetic nephropathy. The underlying mechanisms are not fully understood. We found ...that administration of canagliflozin at a low dose (0.01 mg/kg/day) did not affect either blood glucose levels or glycosuria, but it improved albuminuria and mesangial expansion in db/db mice to a similar extent as at a high dose (3.0 mg/kg/day) that lowered blood glucose levels. This indicated the existence of a tubular SGLT2-independent reno-protective mechanism. Here we focused on the potential role of SGLT2 in mesangial cells (MCs). Western blot analysis revealed the expression of SGLT2 in cultured mouse MCs. Exposure of MCs to high glucose levels for 72 h significantly increased the expression of SGLT2. Canagliflozin or ipragliflozin (both 100 nM) treatment inhibited glucose consumption in the medium under high-glucose conditions but not under normal-glucose conditions. Furthermore, canagliflozin inhibited high-glucose-induced activation of the protein kinase C (PKC)-NAD(P)H oxidase pathway and increases in reactive oxygen species (ROS) production. Thus, the inhibition of mesangial SGLT2 may cause an inhibition of PKC activation and ROS overproduction in diabetic nephropathy, and this may at least in part account for the reno-protective effect of SGLT2 inhibitors.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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