Adipose Tissue Infiltration Research Articles

Relationship between epicardial adipose tissue and ventricular fibrillation in Brugada syndrome by cardiac computed tomography analysis

Abstract Background Fibrofatty changes in the myocardium of the right ventricular (RV) to right ventricular outflow tract (RVOT) in patients with Brugada syndrome (BrS) may contribute to ventricular conduction delay and ultimately in the development of ventricular fibrillation (VF). In patients with atrial fibrillation (AF), inflammatory infiltration of epicardial adipose tissue (EAT) into the atrial muscle, along with reduced quantity and quality of EAT, has been demonstrated to be associated with the development of AF. We hypothesized that EAT in the RVOT from the RV in patients with BrS may lead to organic abnormalities in the ventricular muscle, resulting in VF. Purpose The purpose of this study was to evaluate the quantity and quality of EAT in patients with BrS using cardiac computed tomography (CT) and to determine the relationship with the occurrence of VF. Methods We retrospectively evaluated 61 of 82 patients with BrS regularly followed in our outpatient clinic from January 2000 to December 2023, who underwent cardiac CT scans. Patients were divided into two groups: those with VF events during follow-up (VF event group) and those without events (VF non-event group). Patient background, various parameters, volume of epicardial adipose tissue (EAT), and CT values from cardiac CT scans were compared between the two groups. EAT volume and CT values were measured for the entire heart and four specific regions: right ventricle (RV-EAT), right ventricular outflow tract (RVOT) to pulmonary artery bifurcation (RVOT-EAT), left ventricle (LV-EAT), and the left coronary artery main trunk circumference (LV summit-EAT) were measured for four specific sites. Results Median age at first diagnosis of BrS was 43 years, 98% were male patients, 41 patients (71%) had symptomatic BrS, and 18 patients (31%) had a family history. During a median follow-up of 72 months (30-136 months), 22 patients (38%) had VF events, including 2 arrhythmic sudden deaths. The median time from diagnosis to the first VF event was 14.3 months (4.3-24.5 months). The VF event group had more overall EAT volume (98.3 cm3 [range: 77.4 to 120.3 cm3] vs. 70.1 cm3 [range: 53.8 to 98.0 cm3], P=0.02) and significantly more RV-EAT volume (18.4 cm3 [range: 11.5 to 28.0 cm3] vs. 11.0 cm3 [range: 7.9 to 18.3 cm3], P=0.008). The CT value of RV-EAT was significantly lower in the VF event group (-83.1±6.1 vs -78.0±6.2, P=0.003), although the RV-EAT/LV-EAT density ratio was not different between the two groups (1.01±0.05 vs 0.99±0.07, P=0.14). On the other hand, the density ratio of RVOT-EAT/LV-EAT was significantly lower in the VF event group (0.95±0.08 vs. 1.00±0.08, P=0.03). Conclusions EAT analysis via CT in patients with BrS revealed that those experiencing VF events during follow-up tended to exhibit greater RV-EAT volume, lower CT values of RV-EAT, and higher CT values of RVOT-EAT density. These findings suggest EAT involvement in VF occurrence in patients with BrS.

Obesity cardiomyopathy could contribute to sudden cardiac death: a Japanese epidemiological morphological study

BackgroundWe aimed to clarify the existence and pathological features of obesity cardiomyopathy (OCM) in Japan using our series of autopsy cases.MethodsIn this retrospective autopsy study, OCM was defined as cardiac hypertrophy (≥ 400 g in men, ≥ 320 g in women) of unknown aetiology in individuals with obesity (body mass index [BMI] ≥ 25 kg/m2 according to the Japanese definition of obesity). We compared cases of OCM with those with obesity without cardiac hypertrophy (OB) and normal weight without cardiac hypertrophy (normal control). Macroscopically, heart weight and cardiac parameters, including epicardial adipose tissue, were measured. Fibrosis, cardiomyocyte diameter, and adipose tissue infiltration were analysed microscopically.ResultsOf the 294 cases, we identified 19 cases of OCM (6.5%) and compared them with the OB and normal control groups. Patients with OCM were slightly younger than non-OCM patients (p = 0.081). The median heart weight was significantly heavier in OCM cases than in OB cases (435 g, interquartile range [IQR] 408–515 g vs. 360 g, IQR 341–385 g). Macroscopically, OCM hearts had a “globoid” appearance with a thickened right ventricular outflow tract. Some OCM cases showed focal interstitial fibrosis in the left ventricle. Approximately half the OCM cases were diagnosed with sudden cardiac death (SCD), with significant differences.ConclusionsThe prevalence of OCM may be higher than expected in Japan, and this may be a specific pathological finding. Given that approximately half the cases of OCM were due to SCD, OCM may cause SCD, emphasizing the need to recognise and diagnose OCM.

An Unusual Skin Finding in a Rare Case of Goltz Syndrome

Abstract Introduction/Objective Goltz Syndrome (Focal Dermal Hypoplasia) is a rare X linked dominant genetic disorder with various dermatologic, musculoskeletal and neurologic manifestations, secondary to a mutation in the PORCN gene. Skin findings include telangiectasias, raspberry-like papillomas (angiofibroma like lesions), nodular fat herniation, xerosis and photosensitivity. Lesions are bilateral, and asymmetrically distribututed along the lines of Blasco. The adipocytic lesions can be diagnosed via a skin biopsy showing adipose tissue in the superficial epidermis and dermis or via molecular techniques showing a mutation in the PORCN gene. Here we report a case of Goltz Syndrome with unique dermal findings. Methods/Case Report A male infant presented at birth with mild diffuse xerosis, large hypopigmented and depigmented atrophic patches and plaques and multiple pink yellow red exophyitic soft papules distributed asymetrically across the body along the lines of Blascho. Additionally the patient had clinodactly, widely spaced nipples, extra pads of fat in the toes and philtrum and fingernails with longitudal ridges and lateral nail plate deviation. A diagnosis of Goltz syndrome was made via molecular analysis that showed mosiacism at C.502G>A (p.Gly168Arg) in the PORCN gene. The patient had a very superficial 2-3 mm erosion at the intersection between the scrotum and perineum. At 18 months, this had grown to finger like projections and eventually grew into multiple tan red exophytic warty papillomatous telangactatic like lesions measuring 3.0 x 0.8 cm that were painful and bled easily. A biopsy of this lesion showed focal mild epidermal hyperplasia and elongation of the rete ridges with wide spread diffuse vascular proliferation with multiple ectactic vessels along with mild dermal and perivascular inflammatory infiltrates. Also noted was infiltration of mature adipose tissue in the superficial epidermis and dermis. We preformed elastin and trichrome stains to identify if this lesion was reactive in nature or de novo. Our results showed retained elastin staining with a negative trichrome eluding to a denovo process. Additionally GLUT1 was negative, ruling out an infantile hemangioma. The above findings in this lesion do not represent any previously described dermatologic entity. Results (if a Case Study enter NA) NA Conclusion This is a rare and unique dermatologic finding of a case of Goltz sydrome, which itself is a rare disorder. In our literature review, this is the only case of Goltz Syndrome thusfar to have presented with this unique skin lesion.

Subcutaneous Sweet Syndrome With Vasculitis Features: Case Report and Review.

Subcutaneous Sweet Syndrome (SSS) is a rare variant of Sweet Syndrome characterized by neutrophilic infiltration of subcutaneous adipose tissue without vasculitis. The presence of vasculitis in SSS is uncommon and poses diagnostic challenges. A 38-year-old female presented with a one-year history of recurrent painful erythematous nodules on her limbs and face. Physical examination revealed asymmetrical erythematous patches and tender subcutaneous nodules with central necrotic eschars on the lower limbs. Laboratory tests were unremarkable except for a mildly elevated erythrocyte sedimentation rate. Histopathological analysis showed significant neutrophilic infiltration within the adipose lobules and vascular walls, along with extravasation of red blood cells, indicating vasculitis. The patient responded promptly to systemic corticosteroids; however, symptoms recurred upon tapering, necessitating ongoing steroid therapy. This case underscores the rare occurrence of vasculitis in SSS, expanding the histopathological spectrum of the disease. Literature review suggests that vasculitis in SSS may result from neutrophil-mediated vascular damage rather than immune complex deposition. The recurrent symptoms upon steroid tapering highlight the therapeutic challenges in managing SSS with vasculitis. Recognition of vasculitis in SSS is crucial for accurate diagnosis and effective management. Further research is warranted to elucidate the pathogenesis and develop targeted treatment strategies for SSS with vasculitis.

A Rare Case with KMT2D: BCOR Fusion Alteration Sarcoma in A 14-Year-Old-Female

Abstract Introduction/Objective Tumors with BCL6-correpresor gene (BCOR) alteration are a heterogeneous group of undifferentiated sarcomas, occurring in various age groups and anatomic sites, characterized by spindle and round cell phenotype and diffuse immunoreactivity for BCOR. With widespread genomic testing, these alterations are now associated with different histologies. These sarcomas show a striking male predominance and occur in children/ adolescents. Methods/Case Report The Patient was a 14 years-old female presented after an accident with RLQ abdominal pain. Her pan-CT showed a 9.0 x 5.5 x 4.0 cm omental mass with free pelvic fluid in the anterior and upper pelvis. Results (if a Case Study enter NA) Microscopic examination showed lobulated spindle cell tumor with myxoid areas, extensive necrosis, focal calcifications, and perivascular lymphocytic infiltrates The tumor composed of bundles of monotonous cells with bizarre nuclei. Mitoses were brisk (44 mitoses per 10HPF). The tumor appeared to infiltrate adipose tissue and it had peritheliomatous pattern of proliferation. Beta-catenin, inhibin, BCL2, and Pan-TRK were positive in the spindle cells. PAX8 showed patchy positivity. EMA, CAM5.2, DOG-1, CD117, ALK1, CD34, HMB45, STAT6, SMA, CD31, S100, CD99, p63, SALL-4, CD10 were negative. Trichrome highlighted the intervening fibrous septae. Molecular Next Generation Sequencing studies showed a structural genomic alteration between the KMT2D and BCOR genes [t(12;X)(12q13.11;Xp11.4)]. Conclusion Tumors harboring rare fusion variants of BCOR, such as BCOR- KMT2D, were also positive for pan-TRK staining and NTRK3 overexpression. These rearrangements are so rare. And therefore, efficient diagnosis of BCOR rearranged sarcomas can be achieved by using a combination of FISH and RT-PCR assays. The therapeutic implication of this finding awaits further investigation.

Adipose stem cells drive T cell infiltration in obesity

Obesity is often associated with adipose tissue (AT) inflammation and immune cell infiltration. Writing recently in Cell Reports, Liao et al. investigated the mechanisms of T cell infiltration of AT using single cell (sc)RNA-sequencing (RNA-seq), transplantation studies, in vitro co-cultures, and knock-out mice. They highlighted the crucial role of C-C motif chemokine ligand 5 (CCL5)-secreting adipose stem cells (ASCs), offering insights for potential therapies.

Dipeptidyl peptidase-4 disturbs adipocyte differentiation via the negative regulation of the glucagon-like peptide-1/adiponectin-cathepsin K axis in mice under chronic stress conditions.

Exposure to chronic psychosocial stress is a risk factor for metabolic disorders. Because dipeptidyl peptidase-4 (DPP4) and cysteinyl cathepsin K (CTSK) play important roles in human pathobiology, we investigated the role(s) of DPP4 in stress-related adipocyte differentiation, with a focus on the glucagon-like peptide-1 (GLP-1)/adiponectin-CTSK axis invivo and invitro. Plasma and inguinal adipose tissue from non-stress wild-type (DPP4+/+), DPP4-knockout (DPP4-/-) and CTSK-knockout (CTSK-/-) mice, and stressed DPP4+/+, DPP4-/-, CTSK-/-, and DPP4+/+ mice underwent stress exposure plus GLP-1 receptor agonist exenatide loading for 2 weeks and then were analyzed for stress-related biological and/or morphological alterations. On day 14 under chronic stress, stress decreased the weights of adipose tissue and resulted in harmful changes in the plasma levels of DPP4, GLP-1, CTSK, adiponectin, and tumor necrosis factor-α proteins and the adipose tissue levels of CTSK, preadipocyte factor-1, fatty acid binding protein-4, CCAAT/enhancer binding protein-α, GLP-1 receptor, peroxisome proliferator-activated receptor-γ, perilipin2, secreted frizzled-related protein-4, Wnt5α, Wnt11 and β-catenin proteins and/or mRNAs as well as macrophage infiltration in adipose tissue; these changes were rectified by DPP4 deletion. GLP-1 receptor activation and CTSK deletion mimic the adipose benefits of DPP4 deficiency. Invitro, CTSK silencing and overexpression respectively prevented and facilitated stress serum and oxidative stress-induced adipocyte differentiation accompanied with changes in the levels of pref-1, C/EBP-α, and PPAR-γ in 3T3-L1 cells. Thus, these findings indicated that increased DPP4 plays an essential role in stress-related adipocyte differentiation, possibly through a negative regulation of GLP-1/adiponectin-CTSK axis activation in mice under chronic stress conditions.

Metabolic dysfunction is associated with alterations in gut microbiota in obese adolescents

Abstract The gut microbiota (MB) has been implicated in adult metabolic dysfunction given evidence of dysbiosis in obesity and type 2 diabetes. However, few studies have investigated the relationship between metabolic disease, inflammation and the gut microbiota in children. We characterized the gut MB and immunometabolic profile of a cohort of obese, non-diabetic adolescents (MI4D) using high throughput fecal DNA sequencing with absolute bacterial quantitation. In the absence of antibiotics, we observed multi-log differences in fecal biomass correlated with stool water content and MB composition. Moreover, fecal bacterial biomass was associated with metabolic measures including serum triglycerides and insulin resistance in a sex-dependent manner. Mass cytometry demonstrated no significant associations of major immune cell subsets to fecal biomass or metabolic markers. In contrast, there were male-specific associations between serum markers of systemic inflammation and neutrophil activity with fecal biomass and waist circumference. Given the infiltration of visceral adipose tissue by myeloid cells in metabolic inflammation, our findings suggest that lower fecal biomass is associated with elevated systemic inflammation, especially in obese adolescent males. This study expands the understanding of sex-specific mechanism driving metabolic dysfunction in obese youth and suggests that gut MB alterations contribute to their metabolic and inflammatory dysregulation before diabetes diagnosis.

Gamma-aminobutyric acid supplementation improves olanzapine-induced insulin resistance by inhibiting macrophage infiltration in mice subcutaneous adipose tissue.

To investigate whether gamma-aminobutyric acid (GABA) supplementation improves insulin resistance during olanzapine treatment in mice and to explore the underlying mechanisms. Insulin resistance and body weight gain were induced in mice by 10 weeks of olanzapine treatment. Simultaneously, the mice were administered GABA after 4 weeks of olanzapine administration. We found that mice treated with olanzapine had lower GABA levels in serum and subcutaneous white adipose tissue (sWAT). GABA supplementation restored GABA levels and improved olanzapine-induced lipid metabolism disorders and insulin resistance. Chronic inflammation in adipose tissue is one of the main contributors to insulin resistance. We found that GABA supplementation inhibited olanzapine-induced adipose tissue macrophage infiltration and M1-like polarization, especially in sWAT. In vitro studies showed that stromal vascular cells, rather than adipocytes, were sensitive to GABA. Furthermore, the results suggested that GABA improves olanzapine-induced insulin resistance at least in part through a GABAB receptor-dependent pathway. These findings suggest that targeting GABA may be a potential therapeutic approach for olanzapine-induced metabolic disorders.

CD28-expressing δ T cells are increased in perivascular adipose tissue of hypertensive mice and in subcutaneous adipose tissue of obese humans.

γδ T-lymphocytes play a role in angiotensin II (AngII)-induced hypertension, vascular injury and T-cell infiltration in perivascular adipose tissue (PVAT) in mice. Mesenteric arteries of hypertensive mice and subcutaneous arteries from obese humans present similar remodeling. We hypothesized that γδ T-cell subtypes in mesenteric vessels with PVAT (MV/PVAT) from hypertensive mice and subcutaneous adipose tissue (SAT) from obese humans, who are prone to develop hypertension, would be similar. Mice were infused with AngII for 14 days. MV/PVAT T-cells were used for single-cell RNA-sequencing (scRNA-seq). scRNA-seq data (GSE155960) of SAT CD45 + cells from three lean and three obese women were downloaded from the Gene Expression Omnibus database. δ T-cell subclustering identified six δ T-cell subtypes. AngII increased T-cell receptor δ variable 4 ( Trdv4 ) + γδ T-effector memory cells and Cd28high δ T EM -cells, changes confirmed by flow cytometry. δ T-cell subclustering identified nine δ T-cell subtypes in human SAT. CD28 expressing δ T-cell subclustering demonstrated similar δ T-cell subpopulations in murine MV/PVAT and human SAT. Cd28+ γδ NKT EM and Cd28high δ T EM -cells increased in MV/PVAT from hypertensive mice and CD28high δ T EM -cells in SAT from obese women compared to the lean women. Similar CD28 + δ T-cells were identified in murine MV/PVAT and human SAT. CD28 high δ T EM -cells increased in MV/PVAT in hypertensive mice and in SAT from humans with obesity, a prehypertensive condition. CD28 + δ T-lymphocytes could have a pathogenic role in human hypertension associated with obesity, and could be a potential target for therapy.

Interleukin-16 is increased in obesity and alters adipogenesis and inflammation in vitro.

Obesity is a chronic condition associated with low-grade inflammation mainly due to immune cell infiltration of white adipose tissue (WAT). WAT is distributed into two main depots: subcutaneous WAT (sWAT) and visceral WAT (vWAT), each with different biochemical features and metabolic roles. Proinflammatory cytokines including interleukin (IL)-16 are secreted by both adipocytes and infiltrated immune cells to upregulate inflammation. IL-16 has been widely studied in the peripheral proinflammatory immune response; however, little is known about its role in adipocytes in the context of obesity. We aimed to study the levels of IL-16 in WAT derived from sWAT and vWAT depots of humans with obesity and the role of this cytokine in palmitate-exposed 3T3-L1 adipocytes. The results demonstrated that IL-16 expression was higher in vWAT compared with sWAT in individuals with obesity. In addition, IL-16 serum levels were higher in patients with obesity compared with normal-weight individuals, increased at 6 months after bariatric surgery, and at 12 months after surgery decreased to levels similar to before the intervention. Our in vitro models showed that IL-16 could modulate markers of adipogenesis (Pref1), lipid metabolism (Plin1, Cd36, and Glut4), fibrosis (Hif1a, Col4a, Col6a, and Vegf), and inflammatory signaling (IL6) during adipogenesis and in mature adipocytes. In addition, lipid accumulation and glycerol release assays suggested lipolysis alteration. Our results suggest a potential role of IL-16 in adipogenesis, lipid and glucose homeostasis, fibrosis, and inflammation in an obesity context.

Immune metabolic mechanisms of acupuncture in improving glycolipid metabolic disorders explored through pancreatic adipose tissue.

Pancreatic adipose tissue serves as a crucial structural basis for the development of glycolipid metabolic disorders. Understanding the mechanisms underlying pancreatic adipose tissue infiltration and regulatory strategies is essential for early intervention in glycolipid metabolic disorders. Pancreatic adipose tissue functions as a significant medium linking systemic immune metabolism, while the pancreatic vascular system emerges as a novel target for sensing pancreatic immune responses and maintaining the body's energy homeostasis, collectively participating in the development of glycolipid metabolic disorders. Acupuncture possesses potential effects in modulating the interaction between resident macrophages and adipocytes in the pancreas, leading to the reversible reduction of excessive pancreatic adipose accumulation, with its action being vascular-dependent.

New Histopathologic Findings in Scarring Alopecias: The Role of Adipose Tissue and Eccrine Sweat Coils in Frontal Fibrosing Alopecia, Fibrosing Alopecia in a Pattern Distribution, and Lichen Planopilaris.

Clinical, dermoscopic, and histologic diagnostic criteria may overlap in cases with scarring and nonscarring alopecia, making diagnosis difficult for clinicians and pathologists. New histopathologic discoveries indicate that the cutaneous adnexal structural and homeostatic unit made up of the pilosebaceous unit, eccrine sweat gland coils (ESGCs), and dermal white adipose tissue may have a role in hair follicle renewal. To verify the presence of adipose tissue in the dermis at the level of the isthmus, infiltrating the bundles of the arrector pili muscle in biopsies from the scalp of 3 scarring alopecias: frontal fibrosing alopecia (FFA), fibrosing alopecia in a pattern distribution (FAPD), and lichen planopilaris (LPP). We performed a retrospective and descriptive survey of 71 female scalp biopsies from 2016 to 2022 diagnosed at the Dermatopathology Laboratory at Fluminense Federal University of Rio de Janeiro. Two pathologists reviewed and diagnosed the cases, correlating pathologic features with clinical and dermoscopic findings. The histopathologic findings of adipose tissue infiltration in the dermis at the level of the isthmus and in the bundles of the arrector pili muscle and the displacement of ESGCs were more frequently identified in FFA, followed by FAPD and less frequently found in LPP. According to our research, adipose tissue infiltration in the dermis at the level of the isthmus and in the bundles of the arrector pili muscle and the displacement of ESGCs were observed in 3 scarring alopecias (FFA, FAPD, and LPP) and seems to be involved in the development of scarring alopecia.

The New Challenge of Obesity - Obesity-Associated Nephropathy.

In recent years, obesity has become one of the major diseases that affect human health and consume human health resources, especially when it causes comorbidities such as hypertension, diabetes, cardiovascular disease and kidney disease. Many studies have demonstrated that obesity is associated with the development of chronic kidney disease and can exacerbate the progression of end-stage renal disease. This review described the mechanisms associated with the development of obesity-associated nephropathy and the current relevant therapeutic modalities, with the aim of finding new therapeutic targets for obesity-associated nephropathy. The mechanisms of obesity-induced renal injury include, in addition to the traditional alterations in renal hemodynamics, the involvement of various mechanisms such as macrophage infiltration in adipose tissue, alterations in adipokines (leptin and adiponectin), and ectopic deposition of lipids. At present, there is no "point-to-point" treatment for obesity-induced kidney injury. The renin-angiotensin-aldosterone system (RAAS) inhibitors, sodium-dependent glucose transporter 2 (SGLT-2) inhibitors and bariatric surgery described in this review can reduce urinary protein to varying degrees and delay the progression of kidney disease. In addition, recent studies on the therapeutic effects of intestinal flora on obesity may reduce the incidence of obesity-related kidney disease from the perspective of primary prevention. Both of these interventions have their own advantages and disadvantages, so the continuous search for the mechanism of obesity-induced related kidney disease will be extremely helpful for the future treatment of obesity-related kidney disease.

Clinicopathological Characteristics and Outcome of Cytophagic Histiocytic Panniculitis: A Single-Center, Retrospective Study.

Cytophagic histiocytic panniculitis (CHP) is a rare panniculitis associated with systemic features characterized by the infiltration of subcutaneous adipose tissue by benign-appearing T lymphocytes and phagocytic histiocytes, mimicking hemophagocytic lymphohistiocytosis (HLH) and subcutaneous panniculitis-like T-cell lymphoma (SPTCL). To establish the clinicopathological features and response to treatment of CHP and evaluate the prognosis of patients and guide therapy based on the current state of knowledge. Clinical, laboratory, histopathological, and outcome data of 12 patients with CHP were retrospectively collected between 2009 and 2022. All the patients presented with plaques or nodules, mostly located in the lower extremities (11/12). Fewer cases involved systemic symptoms (9/12) and laboratory abnormalities (6/12), and none were positive for serum Epstein-Barr virus (EBV)-DNA. Histopathological examination revealed mixed septal and lobular inflammatory infiltration of histiocytes and lymphocytes. Large or atypical lymphocytes were rarely present (2/12). In some patients, varying proportions of plasma cells, neutrophils, and eosinophils were observed. The extent of histocytophagy was mild (9/12), moderate (2/12), and severe (1/12). HLH was not observed in any of our cases, none of which were fatal. The uniqueness of our study lies in the presence of neutrophil-rich dermal and subcutaneous infiltrates, associated with connective tissue disorders (CTD) and streptococcal infections. Our study reveals that EBV-negative CHP tends to a better prognosis than previously research, filling the gap in the much-needed details of CHP in the Chinese population. Moreover, CHP may present as a reactive process in combined primary diseases; further studies are required to validate these findings.

Trimethylamine N-Oxide as a Mediator Linking Peripheral to Central Inflammation: An In Vitro Study.

In this study, the plausible role of trimethylamine N-oxide (TMAO), a microbiota metabolite, was investigated as a link between peripheral inflammation and the inflammation of the central nervous system using different cell lines. TMAO treatment favored the differentiation of adipocytes from preadipocytes (3T3-L1 cell line). In macrophages (RAW 264.7 cell line), which infiltrate adipose tissue in obesity, TMAO increased the expression of pro-inflammatory cytokines. The treatment with 200 μM of TMAO seemed to disrupt the blood-brain barrier as it induced a significant decrease in the expression of occludin in hCMECs. TMAO also increased the expression of pro-inflammatory cytokines in primary neuronal cultures, induced a pro-inflammatory state in primary microglial cultures, and promoted phagocytosis. Data obtained from this project suggest that microbial dysbiosis and increased TMAO secretion could be a key link between peripheral and central inflammation. Thus, TMAO-decreasing compounds may be a promising therapeutic strategy for neurodegenerative diseases.

Myeloid SENP3 deficiency protects mice from diet and age-induced obesity via regulation of YAP1 SUMOylation

Obesity is characterized by chronic low-grade inflammation, which is driven by macrophage infiltration in adipose tissue and leads to elevated cytokines such as interleukin-1β (IL-1β) in the circulation and tissues. Previous studies demonstrate that SENP3, a redox-sensitive SUMO2/3-specific protease, is strongly implicated in the development and progression of cancer and cardiovascular diseases. However, the role of SENP3 in obesity-associated inflammation remains largely unknown. To better understand the effects of SENP3 on adipose tissue macrophage (ATM) activation and function within the context of obesity, we generated mice with myeloid-specific deletion of SENP3 (Senp3flox/flox;Lyz2-Cre mice). We found that the expression of SENP3 is dramatically increased in ATMs during high-fat diet (HFD)-induced obesity in mice. Senp3flox/flox;Lyz2-Cre mice show lower body weight gain and reduced adiposity and adipocyte size after challenged with HFD and during aging. Myeloid-specific SENP3 deletion attenuates macrophage infiltration in adipose tissue and reduces serum levels of inflammatory factors during diet and age-induced obesity. Furthermore, we found that SENP3 knockout markedly inhibits cytokine release from macrophage after lipopolysaccharide and palmitic acid treatment in vitro. Mechanistically, in cultured peritoneal macrophages, SENP3 protein level is enhanced by IL-1β, in parallel with the upregulation of Yes-associated protein 1 (YAP1). Moreover, we demonstrated that SENP3 modulates de-SUMO modification of YAP1 and SENP3 deletion abolishes the upregulation of YAP1 induced by IL-1β. Most importantly, SENP3 deficiency reduces YAP1 protein level in adipose tissue during obesity. Our results highlight the important role of SENP3 in ATM inflammation and diet and age-induced obesity.

Palmitoleic acid on top of HFD ameliorates insulin resistance independent of diacylglycerols and alters gut microbiota in C57BL/6J mice

With the prevalence of obesity and obesity-related metabolic syndrome, such as insulin resistance in recent years, it is urgent to explore effective interventions to prevent the progression of obesity-related metabolic syndrome. Palmitoleic acid is a monounsaturated fatty acid that is available from dietary sources, mainly derived from marine products. Palmitoleic acid plays a positive role in maintaining glucose homeostasis and reducing inflammation. However, it is still unknow the mechanism of palmitoleic acid in ameliorating insulin resistance. Here, we investigated the effects of palmitoleic acid on chow diet (CD)-fed and high-fat diet (HFD)-fed mice, which were fed CD or HFD for 12 weeks before administration. We administrated mice with BSA (control), oleic acid, or palmitoleic acid for 6 weeks on top of CD or HFD feeding. We found that palmitoleic acid only improved glucose homeostasis in HFD-fed obese mice by increasing glucose clearance and reducing HOMA-IR. Further study explored that palmitoleic acid changed the composition of gut microbiota by decreasing Firmicutes population and increasing Bacteroidetes population. In colon, palmitoleic acid increased intestinal tight junction integrity and reduced inflammation. Moreover, palmitoleic acid decreased macrophage infiltration in liver and adipose tissue and increase glucose uptake in adipose tissue. Diacylglycerol (DAG) in tissue (for example, liver) is found to positively correlated with HOMA-IR. HFD enhanced the levels of DAGs in liver but not in adipose tissue in this study. Palmitoleic acid did not reverse the high DAG levels induced by HFD in liver. Therefore, in HFD-fed mice, palmitoleic acid reduced insulin resistance by an independent-manner of DAGs. It might be associated with the beneficial effects of palmitoleic acid on altering the gut microbiota composition, improving of intestinal barrier function, and downregulating the inflammation in colon, liver, and adipose tissue.

Understanding the Consequences of Fatty Bone and Fatty Muscle: How the Osteosarcopenic Adiposity Phenotype Uncovers the Deterioration of Body Composition.

Adiposity is central to aging and several chronic diseases. Adiposity encompasses not just the excess adipose tissue but also body fat redistribution, fat infiltration, hypertrophy of adipocytes, and the shifting of mesenchymal stem cell commitment to adipogenesis. Bone marrow adipose tissue expansion, inflammatory adipokines, and adipocyte-derived extracellular vesicles are central to the development of osteopenic adiposity. Adipose tissue infiltration and local adipogenesis within the muscle are critical in developing sarcopenic adiposity and subsequent poorer functional outcomes. Ultimately, osteosarcopenic adiposity syndrome is the result of all the processes noted above: fat infiltration and adipocyte expansion and redistribution within the bone, muscle, and adipose tissues, resulting in bone loss, muscle mass/strength loss, deteriorated adipose tissue, and subsequent functional decline. Increased fat tissue, typically referred to as obesity and expressed by body mass index (the latter often used inadequately), is now occurring in younger age groups, suggesting people will live longer with the negative effects of adiposity. This review discusses the role of adiposity in the deterioration of bone and muscle, as well as adipose tissue itself. It reveals how considering and including adiposity in the definition and diagnosis of osteopenic adiposity, sarcopenic adiposity, and osteosarcopenic adiposity will help in better understanding the pathophysiology of each and accelerate possible therapies and prevention approaches for both relatively healthy individuals or those with chronic disease.

Brown adipocyte mineralocorticoid receptor deficiency impairs metabolic regulation in diet-induced obese mice

Activation of brown adipose tissue (BAT) contributes to energy dissipation and metabolic health. Although mineralocorticoid receptor (MR) antagonists have been demonstrated to improve metabolism under obesity, the underlying mechanisms remain incompletely understood. We aimed to evaluate the role of BAT MR in metabolic regulation. After 8 weeks of high-fat diet (HFD) feeding, BAT MR KO (BMRKO) mice manifested significantly increased bodyweight, fat mass, serum fasting glucose, and impaired glucose homeostasis compared with littermate control (LC) mice, although insulin resistance and fasting serum insulin were not significantly changed. Metabolic cage experiments showed no change in O2 consumption, CO2 production, or energy expenditure in obese BMRKO mice. RNA sequencing analysis revealed downregulation of genes related to fatty acid metabolism in BAT of BMRKO-HFD mice compared with LC-HFD mice. Moreover, H&E and immunohistochemical staining demonstrated that BMRKO exacerbated HFD-induced macrophage infiltration and proinflammatory genes in epididymal white adipose tissue (eWAT). BMRKO-HFD mice also manifested significantly increased liver weights and hepatic lipid accumulation, an increasing trend of genes related to lipogenesis and lipid uptake, and significantly decreased genes related to lipolytic and fatty acid oxidation in the liver. Finally, the level of insulin-induced AKT phosphorylation was substantially blunted in eWAT but not liver or skeletal muscle of BMRKO-HFD mice compared with LC-HFD mice. These data suggest that BAT MR is required to maintain metabolic homeostasis, likely through its regulation of fatty acid metabolism in BAT and impacts on eWAT and liver.