How obesity affects adipocyte turnover.

Cellular turnover is fundamental for tissue homeostasis and integrity. Adipocyte turnover, accounting for 4% of the total cellular mass turnover in humans, is essential for adipose tissue homeostasis during metabolic stress. In obesity, an altered adipose tissue microenvironment promotes adipocyte death. To clear dead adipocytes, macrophages are recruited and form a distinctive structure known as crown-like structure; subsequently, new adipocytes are generated from adipose stem and progenitor cells in the adipogenic niche to replace dead adipocytes. Accumulating evidence indicates that adipocyte death, clearance, and adipogenesis are sophisticatedly orchestrated during adipocyte turnover. In this Review, we summarize our current understandings of each step in adipocyte turnover, discussing its key players and regulatory mechanisms.

Dysfunctional adipocytes promote tumor progression through YAP/TAZ-dependent cancer-associated adipocyte transformation.

Obesity has emerged as a prominent risk factor for the development of malignant tumors. However, the existing literature on the role of adipocytes in the tumor microenvironment (TME) to elucidate the correlation between obesity and cancer remains insufficient. Here, we aim to investigate the formation of cancer-associated adipocytes (CAAs) and their contribution to tumor growth using mouse models harboring dysfunctional adipocytes. Specifically, we employ adipocyte-specific BECN1 KO (BaKO) mice, which exhibit lipodystrophy due to dysfunctional adipocytes. Our results reveal the activation of YAP/TAZ signaling in both CAAs and BECN1-deficient adipocytes, inducing adipocyte dedifferentiation and formation of a malignant TME. The additional deletion of YAP/TAZ from BaKO mice significantly restores the lipodystrophy and inflammatory phenotypes, leading to tumor regression. Furthermore, mice fed a high-fat diet (HFD) exhibit decreased BECN1 and increased YAP/TAZ expression in their adipose tissues. Treatment with the YAP/TAZ inhibitor, verteporfin, suppresses tumor progression in BaKO and HFD-fed mice, highlighting its efficacy against mice with metabolic dysregulation. Overall, our findings provide insights into the key mediators of CAA and their significance in developing a TME, thereby suggesting a viable approach targeting adipocyte homeostasis to suppress cancer growth.

Hippo-YAP/TAZ signalling coordinates adipose plasticity and energy balance by uncoupling leptin expression from fat mass.

Adipose tissues serve as an energy reservoir and endocrine organ, yet the mechanisms that coordinate these functions remain elusive. Here, we show that the transcriptional coregulators, YAP and TAZ, uncouple fat mass from leptin levels and regulate adipocyte plasticity to maintain metabolic homeostasis. Activating YAP/TAZ signalling in adipocytes by deletion of the upstream regulators Lats1 and Lats2 results in a profound reduction in fat mass by converting mature adipocytes into delipidated progenitor-like cells, but does not cause lipodystrophy-related metabolic dysfunction, due to a paradoxical increase in circulating leptin levels. Mechanistically, we demonstrate that YAP/TAZ-TEAD signalling upregulates leptin expression by directly binding to an upstream enhancer site of the leptin gene. We further show that YAP/TAZ activity is associated with, and functionally required for, leptin regulation during fasting and refeeding. These results suggest that adipocyte Hippo-YAP/TAZ signalling constitutes a nexus for coordinating adipose tissue lipid storage capacity and systemic energy balance through the regulation of adipocyte plasticity and leptin gene transcription.

Comparison of Conventional Methods with Pump-Controlled Retrograde Trial off for Weaning Adults with Cardiogenic Shock from Veno-Arterial Extracorporeal Membrane Oxygenation.

Background: Pump-controlled retrograde trial off (PCRTO) is a safe, simple, and reversible method for weaning patients from veno-arterial extracorporeal membrane oxygenation (VA-ECMO). However, few studies have compared PCRTO to conventional weaning methods. This retrospective study aimed to compare PCRTO to non-PCRTO methods. Methods: This study included patients who were weaned from VA-ECMO from January 2016 to December 2022 at our medical center. Demographic data, ECMO management, ECMO complications, survival to discharge, and cardiogenic shock after VA-ECMO weaning were compared between the 2 groups. Results: Seventy patients who were weaned from VA-ECMO using PCRTO and 85 patients who were weaned with conventional methods were compared. Patient characteristics were not significantly different between the 2 groups. The rate of survival to discharge was significantly higher in the PCRTO group than in the non-PCRTO group (90% vs. 72%, p=0.01). The rates of freedom from all-cause mortality at 10, 30, and 50 days after weaning from ECMO were 75%, 55%, and 35% in the non-PCRTO group and 62%, 60%, and 58% in the PCRTO group, respectively (p=0.1). The incidence of cardiogenic shock after weaning from VA-ECMO was significantly higher in the non-PCRTO group (16% vs. 5%, p=0.04). In logistic regression analysis, PCRTO was a significant factor for survival to discharge (odds ratio, 2.42; 95% confidence interval, 1.29-5.28; p=0.02). Conclusion: Compared to conventional methods, PCRTO is a feasible and reversible method, and it serves as a useful predictor of successful VA-ECMO weaning through a preload stress test.

Ubiquitin ligase RNF20 coordinates sequential adipose thermogenesis with brown and beige fat-specific substrates.

In mammals, brown adipose tissue (BAT) and inguinal white adipose tissue (iWAT) execute sequential thermogenesis to maintain body temperature during cold stimuli. BAT rapidly generates heat through brown adipocyte activation, and further iWAT gradually stimulates beige fat cell differentiation upon prolonged cold challenges. However, fat depot-specific regulatory mechanisms for thermogenic activation of two fat depots are poorly understood. Here, we demonstrate that E3 ubiquitin ligase RNF20 orchestrates adipose thermogenesis with BAT- and iWAT-specific substrates. Upon cold stimuli, BAT RNF20 is rapidly downregulated, resulting in GABPα protein elevation by controlling protein stability, which stimulates thermogenic gene expression. Accordingly, BAT-specific Rnf20 suppression potentiates BAT thermogenic activity via GABPα upregulation. Moreover, upon prolonged cold stimuli, iWAT RNF20 is gradually upregulated to promote de novo beige adipogenesis. Mechanistically, iWAT RNF20 mediates NCoR1 protein degradation, rather than GABPα, to activate PPARγ. Together, current findings propose fat depot-specific regulatory mechanisms for temporal activation of adipose thermogenesis.

p21-activated kinase 4 counteracts PKA-dependent lipolysis by phosphorylating FABP4 and HSL.

Adipose tissue lipolysis is mediated by cAMP-protein kinase A (PKA)-dependent intracellular signalling. Here, we show that PKA targets p21-activated kinase 4 (PAK4), leading to its protein degradation. Adipose tissue-specific overexpression of PAK4 in mice attenuates lipolysis and exacerbates diet-induced obesity. Conversely, adipose tissue-specific knockout of Pak4 or the administration of a PAK4 inhibitor in mice ameliorates diet-induced obesity and insulin resistance while enhancing lipolysis. Pak4 knockout also increases energy expenditure and adipose tissue browning activity. Mechanistically, PAK4 directly phosphorylates fatty acid-binding protein 4 (FABP4) at T126 and hormone-sensitive lipase (HSL) at S565, impairing their interaction and thereby inhibiting lipolysis. Levels of PAK4 and the phosphorylation of FABP4-T126 and HSL-S565 are enhanced in the visceral fat of individuals with obesity compared to their lean counterparts. In summary, we have uncovered an important role for FABP4 phosphorylation in regulating adipose tissue lipolysis, and PAK4 inhibition may offer a therapeutic strategy for the treatment of obesity.

Unique adipose tissue invariant natural killer T cell subpopulations control adipocyte turnover in mice.

Adipose tissue invariant natural killer T (iNKT) cells are a crucial cell type for adipose tissue homeostasis in obese animals. However, heterogeneity of adipose iNKT cells and their function in adipocyte turnover are not thoroughly understood. Here, we investigate transcriptional heterogeneity in adipose iNKT cells and their hierarchy using single-cell RNA sequencing in lean and obese mice. We report that distinct subpopulations of adipose iNKT cells modulate adipose tissue homeostasis through adipocyte death and birth. We identify KLRG1+ iNKT cells as a unique iNKT cell subpopulation in adipose tissue. Adoptive transfer experiments showed that KLRG1+ iNKT cells are selectively generated within adipose tissue microenvironment and differentiate into a CX3CR1+ cytotoxic subpopulation in obese mice. In addition, CX3CR1+ iNKT cells specifically kill enlarged and inflamed adipocytes and recruit macrophages through CCL5. Furthermore, adipose iNKT17 cells have the potential to secrete AREG, and AREG is involved in stimulating adipose stem cell proliferation. Collectively, our data suggest that each adipose iNKT cell subpopulation plays key roles in the control of adipocyte turnover via interaction with adipocytes, adipose stem cells, and macrophages in adipose tissue.

Is It Safe to Preserve Left Atrial Appendage During Maze Procedure?

BACKGROUND AND OBJECTIVES: The left atrial appendage (LAA) can contribute significantly to LA mechanical contraction. Nevertheless, the preventive effect of LAA occlusion during the maze procedure against cerebral infarction remains controversial. In this study, we compared the surgical, cardiac hemodynamic, and neurologic outcomes between LAA preservation and occlusion performed during the maze procedure. METHODS: Between January 2015 and August 2021, 252 patients underwent the maze procedure using cryoablation at our medical center. After excluding patients according to our exclusion criteria (i.e., mechanical prosthesis implantation, preexisting LAA thrombus), LAA was preserved in 113 patients (non-occlusion group) and occluded in 75 patients (occlusion group). Outcomes were compared using propensity score matching (PSM). RESULTS: PSM did not reveal significant intergroup differences in baseline characteristics between the non-occlusion (n=53) and occlusion (n=53) groups. During a median follow-up of 44 months, 2 patients in the non-occlusion group (3.8%) experienced ischemic strokes. There was no significant difference in the rate of freedom from stroke (p=0.19) and major adverse cardiac events (p=0.43) between the 2 groups. Through echocardiography at 1-year follow-up, a statistically significant difference in LA mechanical contraction was observed between the non-occlusion group and occlusion group (24 of 33 [72.7%] vs. 18 of 37 [48.6%], respectively; p=0.04). CONCLUSIONS: In this study, preservation of the LAA during the maze procedure resulted in better LA function than LAA occlusion, with similar rates of stroke.

Surgical Results of the Superior Vena Cava Intimal Layer-Only Suture Technique in Heart Transplantation.

Background: Superior vena cava (SVC) stenosis during follow-up is a major concern after heart transplantation, and many technical modifications have been introduced. We analyzed the surgical results of the SVC intima layer-only suture technique in heart transplantation. Methods: We performed SVC anastomosis with sutures placed only in the intima during heart transplantation. We measured the area of the SVC at 3 different points (above the anastomosis, at the anastomosis, and below the anastomosis) in an axial view by freely drawing regions of interest, and then evaluated the degree of stenosis. Patients who underwent cardiac computed tomography (CT) at 2 years postoperatively between June 2017 and May 2020 were included in this study. Results: We performed heart transplantation in 41 patients. Among them, 24 patients (16 males and 8 females) underwent follow-up cardiac CT at 2 years postoperatively. The mean age at operation was 49.4±4.9 years. The diagnoses at time of operation were dilated cardiomyopathy (n=12), ischemic heart disease (n=8), valvular heart disease (n=2), hypertrophic cardiomyopathy (n=1), and congenital heart disease (n=1). No cases of postoperative bleeding requiring intervention occurred. The mean CT follow-up duration was 1.9±0.7 years. At follow-up, the mean areas at the 3 key points were 2.7±0.8 cm2, 2.7±0.8 cm2, and 2.7±1.0 cm2 (p=0.996). There were no SVC stenosis-related symptoms during follow-up. Conclusion: The suture technique using only the SVC intimal layer is a safe and effective method for use in heart transplantation.

Physiological and pathological roles of lipogenesis.

Lipids are essential metabolites, which function as energy sources, structural components and signalling mediators. Most cells are able to convert carbohydrates into fatty acids, which are often converted into neutral lipids for storage in the form of lipid droplets. Accumulating evidence suggests that lipogenesis plays a crucial role not only in metabolic tissues for systemic energy homoeostasis but also in immune and nervous systems for their proliferation, differentiation and even pathophysiological roles. Thus, excessive or insufficient lipogenesis is closely associated with aberrations in lipid homoeostasis, potentially leading to pathological consequences, such as dyslipidaemia, diabetes, fatty liver, autoimmune diseases, neurodegenerative diseases and cancers. For systemic energy homoeostasis, multiple enzymes involved in lipogenesis are tightly controlled by transcriptional and post-translational modifications. In this Review, we discuss recent findings regarding the regulatory mechanisms, physiological roles and pathological importance of lipogenesis in multiple tissues such as adipose tissue and the liver, as well as the immune and nervous systems. Furthermore, we briefly introduce the therapeutic implications of lipogenesis modulation.

The Profile of Early Sedation Depth and Clinical Outcomes of Mechanically Ventilated Patients in Korea.

BACKGROUND: Current international guidelines recommend against deep sedation as it is associated with worse outcomes in the intensive care unit (ICU). However, in Korea the prevalence of deep sedation and its impact on patients in the ICU are not well known. METHODS: From April 2020 to July 2021, a multicenter, prospective, longitudinal, noninterventional cohort study was performed in 20 Korean ICUs. Sedation depth extent was divided into light and deep using a mean Richmond Agitation-Sedation Scale value within the first 48 hours. Propensity score matching was used to balance covariables; the outcomes were compared between the two groups. RESULTS: Overall, 631 patients (418 [66.2%] and 213 [33.8%] in the deep and light sedation groups, respectively) were included. Mortality rates were 14.1% and 8.4% in the deep and light sedation groups (P = 0.039), respectively. Kaplan-Meier estimates showed that time to extubation (P < 0.001), ICU length of stay (P = 0.005), and death (P = 0.041) differed between the groups. After adjusting for confounders, early deep sedation was only associated with delayed time to extubation (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.55-0.80; P < 0.001). In the matched cohort, deep sedation remained significantly associated with delayed time to extubation (HR, 0.68; 95% CI, 0.56-0.83; P < 0.001) but was not associated with ICU length of stay (HR, 0.94; 95% CI, 0.79-1.13; P = 0.500) and in-hospital mortality (HR, 1.19; 95% CI, 0.65-2.17; P = 0.582). CONCLUSION: In many Korean ICUs, early deep sedation was highly prevalent in mechanically ventilated patients and was associated with delayed extubation, but not prolonged ICU stay or in-hospital death.

Safety of low-dose anticoagulation in extracorporeal membrane oxygenation using the Permanent Life Support System: a retrospective observational study.

BACKGROUND: Bleeding and thrombosis are major complications associated with high mortality in extracorporeal membrane oxygenation (ECMO) management. Anticoagulant therapy should be adequate to reduce thrombosis. However, related studies are limited. METHODS: We retrospectively reviewed all patients supported with ECMO at a single institution between January 2014 and July 2022 and included those on all types of ECMO using the Permanent Life Support System. Patients were classified into two groups according to their measured mean activated partial thromboplastin time (aPTT) during ECMO management: a high-anticoagulation (AC) group (aPTT, ≥55 seconds; n=52) and a low-AC group (aPTT, <55 seconds; n=79). The primary outcome was thrombotic or bleeding events during ECMO. RESULTS: We identified 10 patients with bleeding; significantly more of these patients were in the high-AC group (n=8) than in the low-AC group (15.4% vs. 2.5%, p=0.01). However, thrombus events and oxygenator change-free times were not significantly different between the two groups. Four patients in the high-AC group died of bleeding complications (brain hemorrhage, two; hemopericardium, one; and gastrointestinal bleeding, one). One patient in the low-AC group developed a thrombus and died of ECMO dysfunction due to circuit thrombosis. CONCLUSION: Heparin did not significantly improve thrombotic outcomes. However, maintaining an aPTT of ≥55 seconds was a significant risk factor for bleeding events, especially those associated with mortality.

VLDL-VLDLR axis facilitates brown fat thermogenesis through replenishment of lipid fuels and PPARß/δ activation.

In mammals, brown adipose tissue (BAT) is specialized to conduct non-shivering thermogenesis for survival under cold acclimation. Although emerging evidence suggests that lipid metabolites are essential for heat generation in cold-activated BAT, the underlying mechanisms of lipid uptake in BAT have not been thoroughly understood. Here, we show that very-low-density lipoprotein (VLDL) uptaken by VLDL receptor (VLDLR) plays important roles in thermogenic execution in BAT. Compared with wild-type mice, VLDLR knockout mice exhibit impaired thermogenic features. Mechanistically, VLDLR-mediated VLDL uptake provides energy sources for mitochondrial oxidation via lysosomal processing, subsequently enhancing thermogenic activity in brown adipocytes. Moreover, the VLDL-VLDLR axis potentiates peroxisome proliferator activated receptor (PPAR)ß/δ activity with thermogenic gene expression in BAT. Accordingly, VLDL-induced thermogenic capacity is attenuated in brown-adipocyte-specific PPARß/δ knockout mice. Collectively, these data suggest that the VLDL-VLDLR axis in brown adipocytes is a key factor for thermogenic execution during cold exposure.

Hyperglycemia and Hypoglycemia Are Associated with In-Hospital Mortality among Patients with Coronavirus Disease 2019 Supported with Extracorporeal Membrane Oxygenation.

Metabolic abnormalities, such as preexisting diabetes or hyperglycemia or hypoglycemia during hospitalization aggravated the severity of COVID-19. We evaluated whether diabetes history, hyperglycemia before and during extracorporeal membrane oxygenation (ECMO) support, and hypoglycemia were risk factors for mortality in patients with COVID-19. This study included data on 195 patients with COVID-19, who were aged ≥19 years and were treated with ECMO. The proportion of patients with diabetes history among nonsurvivors was higher than that among survivors. Univariate Cox regression analysis showed that in-hospital mortality after ECMO support was associated with diabetes history, renal replacement therapy (RRT), and body mass index (BMI) < 18.5 kg/m2. Glucose at admission >200 mg/dL and glucose levels before ventilator >200 mg/dL were not associated with in-hospital mortality. However, glucose levels before ECMO >200 mg/dL and minimal glucose levels during hospitalization <70 mg/dL were associated with in-hospital mortality. Multivariable Cox regression analysis showed that glucose >200 mg/dL before ECMO and minimal glucose <70 mg/dL during hospitalization remained risk factors for in-hospital mortality after adjustment for age, BMI, and RRT. In conclusion, glucose >200 mg/dL before ECMO and minimal glucose level <70 mg/dL during hospitalization were risk factors for in-hospital mortality among COVID-19 patients who underwent ECMO.

Targeted erasure of DNA methylation by TET3 drives adipogenic reprogramming and differentiation.

DNA methylation is a crucial epigenetic modification in the establishment of cell-type-specific characteristics. However, how DNA methylation is selectively reprogrammed at adipocyte-specific loci during adipogenesis remains unclear. Here, we show that the transcription factor, C/EBPδ, and the DNA methylation eraser, TET3, cooperatively control adipocyte differentiation. We perform whole-genome bisulfite sequencing to explore the dynamics and regulatory mechanisms of DNA methylation in adipocyte differentiation. During adipogenesis, DNA methylation selectively decreases at adipocyte-specific loci carrying the C/EBP binding motif, which correlates with the activity of adipogenic promoters and enhancers. Mechanistically, we find that C/EBPδ recruits a DNA methylation eraser, TET3, to catalyse DNA demethylation at the C/EBP binding motif and stimulate the expression of key adipogenic genes. Ectopic expression of TET3 potentiates in vitro and in vivo adipocyte differentiation and recovers downregulated adipogenic potential, which is observed in aged mice and humans. Taken together, our study highlights how targeted reprogramming of DNA methylation through cooperative action of the transcription factor C/EBPδ, and the DNA methylation eraser TET3, controls adipocyte differentiation.

Adipocyte HIF2α functions as a thermostat via PKA Cα regulation in beige adipocytes.

Thermogenic adipocytes generate heat to maintain body temperature against hypothermia in response to cold. Although tight regulation of thermogenesis is required to prevent energy sources depletion, the molecular details that tune thermogenesis are not thoroughly understood. Here, we demonstrate that adipocyte hypoxia-inducible factor α (HIFα) plays a key role in calibrating thermogenic function upon cold and re-warming. In beige adipocytes, HIFα attenuates protein kinase A (PKA) activity, leading to suppression of thermogenic activity. Mechanistically, HIF2α suppresses PKA activity by inducing miR-3085-3p expression to downregulate PKA catalytic subunit α (PKA Cα). Ablation of adipocyte HIF2α stimulates retention of beige adipocytes, accompanied by increased PKA Cα during re-warming after cold stimuli. Moreover, administration of miR-3085-3p promotes beige-to-white transition via downregulation of PKA Cα and mitochondrial abundance in adipocyte HIF2α deficient mice. Collectively, these findings suggest that HIF2α-dependent PKA regulation plays an important role as a thermostat through dynamic remodeling of beige adipocytes.

Hepatic GSK3ß-Dependent CRY1 Degradation Contributes to Diabetic Hyperglycemia.

Excessive hepatic glucose production (HGP) is a key factor promoting hyperglycemia in diabetes. Hepatic cryptochrome 1 (CRY1) plays an important role in maintaining glucose homeostasis by suppressing forkhead box O1 (FOXO1)-mediated HGP. Although downregulation of hepatic CRY1 appears to be associated with increased HGP, the mechanism(s) by which hepatic CRY1 dysregulation confers hyperglycemia in subjects with diabetes is largely unknown. In this study, we demonstrate that a reduction in hepatic CRY1 protein is stimulated by elevated E3 ligase F-box and leucine-rich repeat protein 3 (FBXL3)-dependent proteasomal degradation in diabetic mice. In addition, we found that GSK3ß-induced CRY1 phosphorylation potentiates FBXL3-dependent CRY1 degradation in the liver. Accordingly, in diabetic mice, GSK3ß inhibitors effectively decreased HGP by facilitating the effect of CRY1-mediated FOXO1 degradation on glucose metabolism. Collectively, these data suggest that tight regulation of hepatic CRY1 protein stability is crucial for maintaining systemic glucose homeostasis.

Regulating Pseudo-Jahn-Teller Effect and Superstructure in Layered Cathode Materials for Reversible Alkali-Ion Intercalation.

The Jahn-Teller effect (JTE) is one of the most important determinators of how much stress layered cathode materials undergo during charge and discharge; however, many reports have shown that traces of superstructure exist in pristine layered materials and irreversible phase transitions occur even after eliminating the JTE. A careful consideration of the energy of cationic distortion using a Taylor expansion indicated that second-order JTE (pseudo-JTE) is more widespread than the aforementioned JTE because of the various bonding states that occur between bonding and antibonding molecular orbitals in transition-metal octahedra. As a model case, a P2-type Mn-rich cathode (Na3/4MnO2) was investigated in detail. MnO6 octahedra are well known to undergo either elongation or contraction in a specific direction due to JTE. Here, the substitution of Li for Mn (Na3/4(Li1/4Mn3/4)O2) helped to oxidize Mn3+ to Mn4+ suppressing JTE; however, the MnO6 octahedra remained asymmetric with a clear trace of the superstructure. With various advanced analyses, we disclose the pseudo-JTE as a general reason for the asymmetric distortions of the MnO6 octahedra. These distortions lead to the significant electrochemical degradation of Na3/4Li1/4Mn3/4O2. The suppression of the pseudo-JTE modulates phase transition behaviors during Na intercalation/deintercalation and thereby improves all of the electrochemical properties. The insight obtained by coupling a theoretical background for the pseudo-JTE with verified layered cathode material lattice changes implies that many previous approaches can be rationalized by regulating pseudo-JTE. This suggests that the pseudo-JTE should be thought more important than the well-known JTE for layered cathode materials.