Obesity-induced Type Research Articles

Type I Interferons Interfere with Liver Glucose Metabolism

The specific immunological components linking metabolic stresses to liver inflammation and systemic metabolic pathologies in obesity are not entirely known. A recent study (Ghazarian etal., 2017) reveals that obesity-induced type I interferon signaling drives the accumulation and activation of intrahepatic CD8+ Tcells, leading to systemic metabolic deterioration.

SUCNR1-mediated chemotaxis of macrophages aggravates obesity-induced inflammation and diabetes

Aims/hypothesisObesity induces macrophages to drive inflammation in adipose tissue, a crucial step towards the development of type 2 diabetes. The tricarboxylic acid (TCA) cycle intermediate succinate is released from cells under metabolic stress and has recently emerged as a metabolic signal induced by proinflammatory stimuli. We therefore investigated whether succinate receptor 1 (SUCNR1) could play a role in the development of adipose tissue inflammation and type 2 diabetes.MethodsSuccinate levels were determined in human plasma samples from individuals with type 2 diabetes and non-diabetic participants. Succinate release from adipose tissue explants was studied. Sucnr1−/− and wild-type (WT) littermate mice were fed a high-fat diet (HFD) or low-fat diet (LFD) for 16 weeks. Serum metabolic variables, adipose tissue inflammation, macrophage migration and glucose tolerance were determined.ResultsWe show that hypoxia and hyperglycaemia independently drive the release of succinate from mouse adipose tissue (17-fold and up to 18-fold, respectively) and that plasma levels of succinate were higher in participants with type 2 diabetes compared with non-diabetic individuals (+53%; p < 0.01). Sucnr1−/− mice had significantly reduced numbers of macrophages (0.56 ± 0.07 vs 0.92 ± 0.15 F4/80 cells/adipocytes, p < 0.05) and crown-like structures (0.06 ± 0.02 vs 0.14 ± 0.02, CLS/adipocytes p < 0.01) in adipose tissue and significantly improved glucose tolerance (p < 0.001) compared with WT mice fed an HFD, despite similarly increased body weights. Consistently, macrophages from Sucnr1−/− mice showed reduced chemotaxis towards medium collected from apoptotic and hypoxic adipocytes (−59%; p < 0.05).Conclusions/interpretationOur results reveal that activation of SUCNR1 in macrophages is important for both infiltration and inflammation of adipose tissue in obesity, and suggest that SUCNR1 is a promising therapeutic target in obesity-induced type 2 diabetes.Data availabilityThe dataset generated and analysed during the current study is available in GEO with the accession number GSE64104, www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE64104.

Parasites, nutrition, immune responses and biology of metabolic tissues.

Nutritional immunology, immunometabolism and identification of novel immunotherapeutic targets are areas of active investigation in parasitology. There is a well-documented crosstalk among immune cells and cells in metabolically active tissues that is important for homeostasis. The numbers and function of these cells are altered by obesity leading to inflammation. A variety of helminths spend some part of their life cycle in the gastrointestinal tract and even entirely enteral nematode infections exert beneficial effects on glucose and lipid metabolism. The foundation of this review is the ability of enteric nematode infections to improve obesity-induced type 2 diabetes and the metabolic syndrome, which are significant health issues in developed areas. It considers the impact of nutrition and specific nutritional deficiencies, which are occur in both undeveloped and developed areas, on the host's ability mount a protective immune response against parasitic nematodes. There are a number of proposed mechanisms by which parasitic nematodes can impact metabolism including effects gastrointestinal hormones, altering epithelial function and changing the number and/or phenotype of immune cells in metabolic tissues. Nematodes can also exert their beneficial effects through Th2 cytokines that activate the transcription factor STAT6, which upregulates genes that regulate glucose and lipid metabolism.

High BMI levels associate with reduced mRNA expression of IL10 and increased mRNA expression of iNOS (NOS2) in human frontal cortex

Several studies link increasing body mass index (BMI) to cognitive decline both as a consequence of obesity per se and as a sequela of obesity-induced type 2 diabetes. Obese individuals are prone to a chronic low-grade inflammation as the metabolically active visceral fat produces proinflammatory cytokines. Animal studies indicate that these cytokines can cross the blood–brain barrier. Such crossover could potentially affect the immune system in the brain by inducing gene expression of proinflammatory genes. The relationship between obesity and neuroinflammation in the human brain is currently unknown. Therefore we aim to examine the relationship between BMI and gene expression of central inflammatory markers in the human frontal cortex. Microarray data of 141 neurologically and psychiatrically healthy individuals were obtained through the BrainCloud database. A simple linear regression analysis was performed with BMI as variable on data on IL10, IL1β, IL6, PTGS2 (COX2) and NOS2 (iNOS). Increasing BMI is associated with a decrease in the mRNA expression of IL10 (P=0.014) and an increase in the expression of NOS2 (iNOS; P=0.040). Expressions of IL10 and NOS2 (iNOS) were negatively correlated (P<0.001). The expression of IL10 was mostly affected by individuals with BMI ⩾40. Multiple linear regression analyses with BMI, age, sex and race as variables were performed in order to identify potential confounders. In conclusion, increasing BMI could affect the IL10-mediated anti-inflammatory defense in the brain and induce iNOS-mediated inflammatory activity.

The Effects of Metformin on Obesity-Induced Dysfunctional Retinas.

PurposeThe purpose of this study was to determine the effects of metformin on dysfunctional retinas in obesity-induced type 2 diabetic mice.MethodsA high-fat diet (HFD)-induced diabetic mouse model (C57BL/6J) was used in this study. After 2 months of the HFD regimen, HFD mice were given daily metformin through oral gavage. Body weights, glucose tolerance, and retinal light responses were monitored regularly. Fluorescein angiography (FA) was used to assess changes in retinal vasculature. Ocular tissues (retina, vitreous, and lens) were harvested and analyzed for molecular changes as determined by immunofluorescent staining, Western blot analysis, and cytokine profiling.ResultsStarting 1 month after the diet regimen, mice fed the HFD had mildly compromised retinal light responses as measured by electroretinography (ERG), which worsened over time compared to that in the control. In HFD mice treated with metformin, systemic glucose levels reverted back to normal, and their weight gain slowed. Metformin reversed HFD-induced changes in phosphorylated protein kinase B (pAKT), extracellular signal-regulated kinase (pERK), and 5′AMP-activated protein kinase (pAMPK) in the retina. However, metformin treatments for 3 months did not restore the retinal light responses nor lessen the HFD-induced retinal neovascularization, even though it did reduce intraocular inflammation.ConclusionsAlthough metformin was able to reverse systemic changes induced by HFD, it was not able to restore HFD-caused retinal light responses or deter neovascularization.

A Hypothalamic Leptin-Glutamate Interaction in the Regulation of Sympathetic Nerve Activity.

Accumulated evidence indicates that obesity-induced type 2 diabetes (T2D) is associated with enhanced sympathetic activation. The present study was conducted to investigate the role for leptin-glutamate signaling within the hypothalamus in regulating sympathetic nerve activity. In anesthetized rats, microinjections of leptin (5 ng ~ 100 ng) into the arcuate nucleus (ARCN) and paraventricular nucleus (PVN) induced increases in renal sympathetic nerve activity (RSNA), blood pressure (BP), and heart rate (HR). Prior microinjections of NMDA receptor antagonist AP5 (16 pmol) into the ARCN or PVN reduced leptin-induced increases in RSNA, BP, and HR in both ARCN and PVN. Knockdown of a leptin receptor with siRNA inhibited NMDA-induced increases in RSNA, BP, and HR in the ARCN but not in the PVN. Confocal calcium imaging in the neuronal NG108 and astrocytic C6 cells demonstrated that preincubation with leptin induced an increase in intracellular calcium green fluorescence when the cells were challenged with glutamate. In high-fat diet and low-dose streptozotocin-induced T2D rats, we found that leptin receptor and NMDA NR1 receptor expressions in the ARCN and PVN were significantly increased. In conclusion, these studies provide evidence that within the hypothalamic nuclei, leptin-glutamate signaling regulates the sympathetic activation. This may contribute to the sympathoexcitation commonly observed in obesity-related T2D.

Murine model of obesity-induced type II diabetes by GADD34 (PPP1R15A) and other phosphatase 1 regulatory subunits deficiency.

Murine model of obesity-induced type II diabetes by GADD34 (PPP1R15A) and other phosphatase 1 regulatory subunits deficiency.

Stimulatory Effects of Cinnamon Extract (Cinnamomum cassia) during the Initiation Stage of 3T3-L1 Adipocyte Differentiation.

Cinnamon (Cinnamomum cassia) has an anti-diabetic effect by possibly increasing the lipid storage capacity of white adipocytes; however, this effect remains controversial. The aim of this study was to examine which stage of adipogenesis is critical for the stimulatory effect of cinnamon in adipogenesis using 3T3-L1 cells. Cells were treated with cinnamon extract during three different stages of adipogenesis. We found that genes related to adipogenesis and lipogenesis were enhanced when cinnamon extract was administered during the initiation stage of differentiation but not when administered during the preadipocyte and post stages of differentiation. At the same time, genes that were involved in the regulation of fatty acid oxidation were unexpectedly upregulated. Taken together, cinnamon may boost lipid storage in white adipocytes and increase the fatty acid oxidation capacity throughout the initiation stage of differentiation, which may be beneficial for the prevention of obesity-induced type II diabetes.

Successful in vitro fertilization and generation of transgenics in Black and Tan Brachyury (BTBR) mice.

The Black and Tan Brachyury (BTBR) mouse strain is a valuable model for the study of long-term complications from obesity-induced type 2 diabetes mellitus and autism spectrum disorder. Due to technical difficulties with assisted reproduction, genetically modified animals on this background have previously been generated through extensive backcrossing, which is expensive and time-consuming. We successfully generated two separate transgenic mouse lines after direct zygote microinjection into this background strain. Additionally, we developed in vitro fertilization (IVF) methods for the BTBR mouse. We found low rates of fertilization and implantation in this strain, and identified the BTBR oocyte as the primary culprit of low success with BTBR IVF. We achieved an increase in live born pups from 5.9 to 35.6 % with IVF in the BTBR strain by use of BTBR females at a younger age (18-25days), collection of oocytes 15-17h after superovulation, and the use of supplemented fertilization media. This method eliminates the need for time consuming assisted embryo manipulations that are otherwise required for success with BTBR oocytes. This advancement provides an exciting opportunity to directly generate BTBR transgenics and gene-edited mice using both traditional and emerging genomic editing techniques, such as CRISPR/Cas9. These methods also allow effective colony preservation and rederivation with these strains. To our knowledge, this is the first report describing embryo manipulations in BTBR mice.

Hepatic mitochondrial oxidative phosphorylation is normal in obese patients with and without type 2 diabetes.

Hepatic insulin resistance in patients with obesity or type 2 diabetes has been suggested to result from hepatic mitochondrial dysfunction. High-resolution respirometry (HRR) can be used to assess oxidative phosphorylation by measuring the mitochondrial oxygen consumption rate in the individual complexes of the mitochondria. By using HRR, the present study demonstrates no difference in hepatic mitochondrial oxidative phosphorylation among subjects with obesity with or without type 2 diabetes and non-obese controls. Furthermore, the amount of mitochondria, assessed by the citrate synthase activity, is not different between the three groups. Together the present findings indicate that hepatic mitochondrial oxidative phosphorylation capacity is not impaired in patients with obesity or type 2 diabetes. Obese patients with type 2 diabetes (T2DM) and without type 2 diabetes (OB) are characterized by high hepatic lipid content and hepatic insulin resistance. This may be linked to impaired hepatic mitochondrial oxidative phosphorylation (OXPHOS) capacity. The aim of the present study was to investigate and compare hepatic mitochondrial OXPHOS capacity in T2DM, OB and non-obese controls (CON). Seventeen obese patients (nine OB and eight T2DM) and six CON patients had perioperative liver biopsies taken. Samples were divided into three parts to measure (1) complex I, II and IV linked respiration, (2) citrate synthase (CS) activity and (3) lipid droplet (LD) size and area (% of total tissue area filled by LDs). State 3 respiration of complex I, II and IV and the CS activity did not differ in OB, T2DM and CON. LD size was significantly higher in T2DM compared with CON, and LD area tended (P=0.10) to be higher in T2DM and OB compared with CON. The present findings indicate that hepatic OXPHOS capacity is not different in patients with markedly different weight and glycaemic control. Furthermore, the results do not support impaired hepatic mitochondrial respiratory capacity playing a major role in the development of obesity-induced type 2 diabetes.

High fat diet-induced TGF-β/Gbb signaling provokes insulin resistance through the tribbles expression.

Hyperglycemia, hyperlipidemia, and insulin resistance are hallmarks of obesity-induced type 2 diabetes, which is often caused by a high-fat diet (HFD). However, the molecular mechanisms underlying HFD-induced insulin resistance have not been elucidated in detail. In this study, we established a Drosophila model to investigate the molecular mechanisms of HFD-induced diabetes. HFD model flies recapitulate mammalian diabetic phenotypes including elevated triglyceride and circulating glucose levels, as well as insulin resistance. Expression of glass bottom boat (gbb), a Drosophila homolog of mammalian transforming growth factor-β (TGF-β), is elevated under HFD conditions. Furthermore, overexpression of gbb in the fat body produced obese and insulin-resistant phenotypes similar to those of HFD-fed flies, whereas inhibition of Gbb signaling significantly ameliorated HFD-induced metabolic phenotypes. We also discovered that tribbles, a negative regulator of AKT, is a target gene of Gbb signaling in the fat body. Overexpression of tribbles in flies in the fat body phenocopied the metabolic defects associated with HFD conditions or Gbb overexpression, whereas tribbles knockdown rescued these metabolic phenotypes. These results indicate that HFD-induced TGF-β/Gbb signaling provokes insulin resistance by increasing tribbles expression.

LXRα improves myocardial glucose tolerance and reduces cardiac hypertrophy in a mouse model of obesity-induced type 2 diabetes

Aims/hypothesisDiabetic cardiomyopathy is a myocardial disease triggered by impaired insulin signalling, increased fatty acid uptake and diminished glucose utilisation. Liver X receptors (LXRs) are key transcriptional regulators of metabolic homeostasis. However, their effect in the diabetic heart is largely unknown.MethodsWe cloned murine Lxrα (also known as Nr1h3) behind the α-myosin heavy chain (αMhc; also known as Myh6) promoter to create transgenic (Lxrα-Tg) mice and transgene-negative littermates (wild-type [WT]). A mouse model of type 2 diabetes was induced by a high-fat diet (HFD, 60% energy from fat) over 16 weeks and compared with a low-fat diet (10% energy from fat). A mouse model of type 1 diabetes was induced via streptozotocin injection over 12 weeks.ResultsHFD manifested comparable increases in body weight, plasma triacylglycerol and insulin resistance per OGTT in Lxrα-Tg and WT mice. HFD significantly increased left ventricular weight by 21% in WT hearts, but only by 5% in Lxrα-Tg. To elucidate metabolic effects in the heart, microPET (positron emission tomography) imaging revealed that cardiac glucose uptake was increased by 1.4-fold in WT mice on an HFD, but further augmented by 1.7-fold in Lxrα-Tg hearts, in part through 5′ adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and restoration of glucose transporter 4 (GLUT4). By contrast, streptozotocin-induced ablation of insulin signalling diminished cardiac glucose uptake levels and caused cardiac dysfunction, indicating that insulin may be important in LXRα-mediated glucose uptake. Chromatin immunoprecipitation assays identified natriuretic peptides, atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), as potential direct targets of cardiac LXRα overexpression.Conclusions/interpretationCardiac-specific LXRα overexpression ameliorates the progression of HFD-induced left ventricular hypertrophy in association with increased glucose reliance and natriuretic peptide signalling during the early phase of diabetic cardiomyopathy. These findings implicate a potential protective role for LXR in targeting metabolic disturbances underlying diabetes.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-015-3827-x) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Combination of bofutsushosan (Kampo medicine) and voluntary exercise improves insulin sensitivity in Otsuka Long-Evans Tokushima fatty rats

Aim Previous studies have shown that the traditional Kampo medicine bofutsushosan (BTS) has an anti-obesity effect. In the current study, we investigated the effects of BTS and voluntary exercise, and their combination on insulin sensitivity in Otsuka Long-Evans Tokushima fatty (OLETF) rats. Methods Male OLETF rats aged 16 weeks were divided into four groups: standard powdered diet (C); powdered diet containing BTS (BTS); access to a running wheel for voluntary running exercise and standard diet (EX); and combined BTS and EX (BTS + EX). After 7 weeks, euglycemic clamp (insulin infusion rate: 3.0 mU/kg/min) was performed in awake rats and the insulin-signaling pathway in skeletal muscle was evaluated. Results At 23 weeks of age, C, BTS, EX and BTS + EX rats showed an average of 656, 582, 459 and 417 g and had epididymal fat mass of 2.99, 2.36, 1.09 and 0.66 g/100 g bodyweight respectively. Glucose infusion rate (GIR) during euglycemic clamp was significantly higher in BTS and EX rats than in C rats. In addition, GIR in BTS + EX rats was significantly higher than in C, BTS and EX rats. The total content of skeletal muscle insulin receptor β-subunit and insulin receptor substrate-1 protein was significantly increased in EX and BTS + EX rats compared with C rats. Conclusion Combination of BTS and EX could be considered beneficial for the prevention and treatment of obesity-induced type 2 diabetes mellitus.

KPNβ1 promotes palmitate-induced insulin resistance via NF-κB signaling in hepatocytes.

It has been intensively studied that inflammation contributes to the insulin resistance development in obesity-induced type 2 diabetes mellitus (T2DM). In this study, we assessed the effect of karyopherin β1 (KPNβ1) in hepatic insulin resistance and the underlying mechanisms using high-fat diet (HFD) fed mice and palmitate (PA)-stimulated hepatocytes (HepG2). KPNβ1 expression is increased in the HFD fed mice liver. PA upregulated KPNβ1 expression in HepG2 cells in a time-dependent manner. PA also increased pro-inflammatory cytokines expression, including tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), and interleukin 1β (IL-1β). KPNβ1 knockdown reversed PA-induced pro-inflammatory cytokines expression and insulin-stimulated glucose uptake in HepG2 cells. In addition, KPNβ1 knockdown reduced intracellular lipid accumulation. Mechanistically, KPNβ1 transports nuclear factor kB (NF-κB) p65 from the cytoplasm to the nucleus to increase pro-inflammatory genes expression. In summary, KPNβ1 acts as a positive regulator in the NF-κB pathway to enhance palmitate-induced inflammation response and insulin resistance in HepG2 cells.

Accelerated healing in NONcNZO10/LtJ type 2 diabetic mice by FGF-1.

The development of novel therapies to treat chronic diabetic ulcers depends upon appropriate animal models for early stage investigation. The NONcNZO10/LtJ mouse is a new polygenic strain developed to more realistically model human metabolic syndrome and obesity-induced type 2 diabetes; however, detailed wound healing properties have not been reported. Herein, we describe a quantitative wound healing study in the NONcNZO10/LtJ mouse using a splinted excisional wound. The rate of wound healing is compared to various controls, and is also quantified in response to topical administration of normal and mutant fibroblast growth factor-1 (FGF-1). Quantitation of reepithelialization shows that the diabetic condition in the NONcNZO10/LtJ mouse is concomitant with a decreased rate of dermal healing. Furthermore, topical administration of a FGF-1/heparin formulation effectively accelerates reepithelialization. A similar acceleration can also be achieved by a stabilized mutant form of FGF-1 formulated in the absence of heparin. Such accelerated rates of healing are not associated with any abnormal histology in the healed wounds. The results identify the NONcNZO10/LtJ mouse as a useful model of impaired wound healing in type 2 diabetes, and further, identify engineered forms of FGF-1 as a potential “second-generation” therapeutic to promote diabetic dermal wound healing.

Treatment of Obese Insulin-Resistant Mice With an Allosteric MAPKAPK2/3 Inhibitor Lowers Blood Glucose and Improves Insulin Sensitivity.

The prevalence of obesity-induced type 2 diabetes (T2D) is increasing worldwide, and new treatment strategies are needed. We recently discovered that obesity activates a previously unknown pathway that promotes both excessive hepatic glucose production (HGP) and defective insulin signaling in hepatocytes, leading to exacerbation of hyperglycemia and insulin resistance in obesity. At the hub of this new pathway is a kinase cascade involving calcium/calmodulin-dependent protein kinase II (CaMKII), p38α mitogen-activated protein kinase (MAPK), and MAPKAPK2/3 (MK2/3). Genetic-based inhibition of these kinases improves metabolism in obese mice. Here, we report that treatment of obese insulin-resistant mice with an allosteric MK2/3 inhibitor, compound (cmpd) 28, ameliorates glucose homeostasis by suppressing excessive HGP and enhancing insulin signaling. The metabolic improvement seen with cmpd 28 is additive with the leading T2D drug, metformin, but it is not additive with dominant-negative MK2, suggesting an on-target mechanism of action. Allosteric MK2/3 inhibitors represent a potentially new approach to T2D that is highly mechanism based, has links to human T2D, and is predicted to avoid certain adverse effects seen with current T2D drugs.

Glucose Modulation of Vagal Sensory Signaling is Compromised in a Mouse Model of Type 2 Diabetes

Studies in both humans and animal models have demonstrated that vagal control of the upper gastrointestinal (GI) tract is compromised by hyperglycemia and diabetes; the mechanism by which this maladaptation occurs has not been investigated fully. The aim of the present study was to investigate whether disrupted glucose sensing within vagal neurocircuits precedes, and may even contribute to, the development of glycemic dysregulation. The NONcNZO10/LtJ (NON) mouse is a congenic strain developed to mimic human obesity-induced Type 2 diabetes and metabolic syndrome. After being weaned onto a 10-11% fat diet, male NON mice develop Type 2 diabetes spontaneously. To measure the ability of glucose to modulate glutamate release from the central terminals of vagal afferents, whole cell patch clamp recordings were made from second order nucleus of the tractus solitarius (NTS) neurons in thin brainstem slices. The table below summarizes the effects of glucose on mEPSC frequency in control and in NON mice before (prediabetes), during the transition towards (transition) and after the development of diabetes expressed as a percentage of the frequency in control (5mM) extracellular glucose. Glucose Control (n=5) Pre-diabetes (n=3) Transition (n=3) Diabetes (n=4) 1mM 66.5±3.3%* 82±21.3% 110±4% 100±7% 5mM 100±0% 100±0% 100±0% 100±0% 10mM 157±15.9%* 119±4% 93±6% 101±6% 20mM 180±17.9%* 125±9%* 94±3% 96±10% These results suggest that the ability of extracellular glucose to modulate vagal afferent signaling is compromised even prior to the development of diabetes. Since the NON mouse strain mimics human obesity-induced Type 2 diabetes, it may provide an excellent model in which to investigate the pathophysiology of dysregulated vago-vagal reflex control of the gastrointestinal tract.

Waist-to-height ratio is independently associated with chronic kidney disease in overweight type 2 diabetic patients

Objective: Chronic kidney disease (CKD) is one of the most serious complications in obesity-induced type 2 diabetes mellitus (T2DM). Body mass index (BMI), waist-to-hip ratio (WHR), waist circumference (WC) and waist-to-height ratio (WHtR) are recognised as sensitive obesity measures. We aimed to investigate the association of BMI, WC, WHR and WHtR with CKD prevalence in overweight T2DM patients. Design, Subjects and Methods: We obtained 125 overweight T2DM patients coming for their in-patient annual visit. Metabolic profiles and anthropometric indices were measured and calculated. Urine albumin excretion (UAE) was determined as the mean of 24-h urine from two consecutive days. Serum creatinine was measured from fasting blood sample in order to calculate the estimated glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration formula. Patients were divided into two groups according to CKD prevalence. Results: Thirty-six (28.8%) patients met diagnostic criteria for CKD. The WHtR and WC were higher in the group with CKD. WHtR correlated positively with UAE (r = 0.828, p < 0.001) and negatively with eGFR (r = −0.262, p = 0.015). No significant correlation was observed with WC in relation to UAE (p = 0.335) nor eGFR (p = 0.121). WHtR yielded the significant and great OR in association with nephropathy after adjustment for all confounding risk factors. Conclusion: WHtR might be of a greater importance in association to CKD compared to other anthropometric parameters that indicate central obesity. Whether it is a best measure of central obesity and its exact role in CKD pathology is yet to be investigated.

Pathological changes in hepatocytes of mice with obesity-induced type 2 diabetes by monosodium glutamate

Type 2 diabetes caused by chronic obesity is a major lifestyle-related disease. The present study aimed to determine the pathological changes in hepatocytes in chronic obesity. To develop our type 2 diabetes mouse model, we induced chronic obesity to mice by monosodium glutamate. By overeating, the mice significantly increased their body weight compared with age-matched healthy animals. To analyze the pathological changes in hepatocytes of chronic obesity before preclinical stage of type 2 diabetes, the mice were analyzed by hematoxylin-eosin staining of tissue sections at 15 w of age. In these mice, we observed eosin-negative accumulations of hepatocytes around central veins in the hepatic lobule. By Oil-Red O staining, the eosin-negative granules were identified in the lipid droplets. We then ascertained whether these lipid droplets of hepatocytes in the obese mice could be modified by diet. After 24 h of diet restriction, the lipid droplets of hepatocytes in the obese mice were swollen. Furthermore, after 48 h of the diet restriction, the lipid droplets continued swelling and the autophagy-like structures that were found in the healthy mice under the same condition in the obese mice were not observed. These results suggest that the obese mice might have delayed energy metabolism, which might have influenced the mechanisms of hepatocytes. These findings provide new insight into the functional changes in chronic obesity-induced type 2 diabetes and it is possible that the pathological feature make a contribution to promise the target of pharmacological therapy.

T Cell–Derived IL-22 Amplifies IL-1β–Driven Inflammation in Human Adipose Tissue: Relevance to Obesity and Type 2 Diabetes

Proinflammatory cytokines are critically involved in the alteration of adipose tissue biology leading to deterioration of glucose homeostasis in obesity. Here we show a pronounced proinflammatory signature of adipose tissue macrophages in type 2 diabetic obese patients, mainly driven by increased NLRP3-dependent interleukin (IL)-1β production. IL-1β release increased with glycemic deterioration and decreased after gastric bypass surgery. A specific enrichment of IL-17- and IL-22-producing CD4(+) T cells was found in adipose tissue of type 2 diabetic obese patients. Coculture experiments identified the effect of macrophage-derived IL-1β to promote IL-22 and IL-17 production by human adipose tissue CD4(+) T cells. Reciprocally, adipose tissue macrophages express IL-17 and IL-22 receptors, making them sensitive to IL-17 and IL-22. IL-22 increased IL-1β release by inducing pro-IL-1β transcription through activation of C-Jun pathways in macrophages. In sum, these human data identified IL-1β and the T-cell cytokine IL-22 as key players of a paracrine inflammatory pathway previously unidentified in adipose tissue, with a pathological relevance to obesity-induced type 2 diabetes. These results provide an additional rationale for targeting IL-1β in obesity-linked type 2 diabetes and may have important implications for the conception of novel combined anti-IL-1β and anti-IL-22 immunotherapy in human obesity.