The Relationship Between Childhood Trauma and Non-Suicidal Self-Injury Behavior in Adolescents with Depression: The Mediating Role of Rumination.

Objective: Non-suicidal self-injury (NSSI) behavior is very common in adolescents with depression, and childhood trauma is considered one of the distal risk factors for its exacerbation. Rumination caused by adverse traumatic experiences, which can be transferred through NSSI behavior, can alleviate symptoms of depression in adolescents. The current research focuses on the relationship between the three, further exploring whether rumination is a mediator in the relationship between childhood trauma and NSSI behavior on the basis of previous studies, and provides some suggestions for future early intervention for adolescents with depression. Methods: A total of 833 adolescent patients with depression who met the DSM-5 criteria for depressive episode were recruited from 12 hospitals in China. The Chinese version of the Function Assessment of Self-mutilation, Childhood Trauma Questionnaire, and Rumination Inventory were used as research tools. Results: The scores of childhood trauma and rumination in adolescents with depression in the NSSI group were higher than those in the non-NSSI group. A Pearson's correlation analysis showed that childhood trauma was positively correlated with rumination (r=0.165, P<0.01), different types of childhood trauma were significantly positively correlated with rumination and its three factors, and these results were statistically significant. Rumination partially mediated the relationship between childhood trauma and NSSI behavior in depressed adolescent patients (effect size=0.002), and the effect in female participants (effect size=0.003), was greater than that in male participants (effect size=0.002). Conclusion: Childhood trauma and rumination were key factors for NSSI behavior in adolescents with depression. Childhood trauma not only has a direct effect on NSSI behavior in adolescent depression, but also plays an indirect effect on NSSI behavior through rumination.

Combined PD-L1/TGFß blockade allows expansion and differentiation of stem cell-like CD8 T cells in immune excluded tumors.

TGFß signaling is associated with non-response to immune checkpoint blockade in patients with advanced cancers, particularly in the immune-excluded phenotype. While previous work demonstrates that converting tumors from excluded to inflamed phenotypes requires attenuation of PD-L1 and TGFß signaling, the underlying cellular mechanisms remain unclear. Here, we show that TGFß and PD-L1 restrain intratumoral stem cell-like CD8 T cell (TSCL) expansion and replacement of progenitor-exhausted and dysfunctional CD8 T cells with non-exhausted T effector cells in the EMT6 tumor model in female mice. Upon combined TGFß/PD-L1 blockade IFNγhi CD8 T effector cells show enhanced motility and accumulate in the tumor. Ensuing IFNγ signaling transforms myeloid, stromal, and tumor niches to yield an immune-supportive ecosystem. Blocking IFNγ abolishes the anti-PD-L1/anti-TGFß therapy efficacy. Our data suggest that TGFß works with PD-L1 to prevent TSCL expansion and replacement of exhausted CD8 T cells, thereby maintaining the T cell compartment in a dysfunctional state.

Relationship between borderline personality features, emotion regulation, and non-suicidal self-injury in depressed adolescents: a cross-sectional study.

OBJECTIVE: Non-suicidal self-injury (NSSI) is common among adolescents and has been linked to mental disorders and suicide in addition to physical injuries. According to the empirical avoidance model, adolescents with NSSI have stronger emotional affect and poorer emotional regulation than those without NSSI, and these constitute core features of borderline personality disorder (BPD). The relationship between borderline personality features, emotional regulation, and NSSI in the population is unclear. This study explored these associations to provide a theoretical basis for the treatment of NSSI in the future. METHODS: Depressed adolescents (n = 1192) were evaluated using Chinese versions of the Function Assessment of Self-mutilation Scale, Emotional Regulation Questionnaire for Children and Adolescents, and Borderline Personality Features Scale for Children. RESULTS: The majority of depressed adolescents (71.3%, 850/1192) had demonstrated NSSI in the past year, with cutting or scratching being the most common form (57.4%). Pearson correlation analysis with NSSI as a fixed factor (NSSI = 1, no NSSI = 2) revealed a negative correlation between NSSI and borderline personality features (r = -0.314, P < 0.01) but a positive correlation between NSSI and emotional regulation capacity (r = 0.159, P < 0.01), which was positively correlated with the expression suppression dimension (r = 0.079, p < 0.01); however, there was no significant correlation between the cognitive reappraisal dimension and expression suppression (r = 0.022, p > 0.05). The occurrence of NSSI was also positively correlated with borderline personality features in general (r = 0.314, p < 0.01). These results were statistically significant. Emotional regulation played a mediating role between borderline personality traits and NSSI in adolescents with depression (effect value = 0.151). CONCLUSION: Borderline personality features and emotional regulation ability were significantly correlated with NSSI in depressed adolescents. Borderline personality symptoms not only directly influenced NSSI risk in adolescents with depression, but also indirectly influenced NSSI risk through emotional regulation.

Enhanced degradation of bisphenol A: Influence of optimization of removal, kinetic model studies, application of machine learning and microalgae-bacteria consortia.

Bisphenol A (BPA), a typical endocrine disruptor and a contaminant of emerging concern (CECs), has detrimental impacts not only on the environment and ecosystems, but also on human health. Therefore, it is essential to investigate the degrading processes of BPA in order to diminish its persistent effects on ecological environmental safety. With this objective, the present study reports on the effectiveness of biotic/abiotic factors in optimizing BPA removal and evaluates the kinetic models of the biodegradation processes. The results showed that BPA affected chlorophyll a, superoxide dismutase (SOD) and peroxidase (POD) activities, malondialdehyde (MDA) content, and photosystem intrinsic PSII efficiency (Fv/Fm) in the microalga Chlorella pyrenoidosa, which degraded 43.0 % of BPA (8.0 mg L-1) under general experimental conditions. The bacteria consortium AEF21 could remove 55.4 % of BPA (20 mg L-1) under orthogonal test optimization (temperature was 32 °C, pH was 8.0, inoculum was 6.0 %) and the prediction of artificial neural network (ANN) of machine learning (R2 equal to 0.99 in training, test, and validation phase). The microalgae-bacteria consortia have a high removal rate of 57.5 % of BPA (20.0 mg L-1). The kinetic study revealed that the removal processes of BPA by microalgae, bacteria, and microalgae-bacteria consortia all followed the Monod's kinetic model. This work provided a new perspective to apply artificial intelligence to predict the degradation of BPA and to understand the kinetic processes of BPA biodegradation by integrated biological approaches, as well as a novel research strategy to achieve environmental CECs elimination for long-term ecosystem health.

Effectiveness of mindfulness-based cognitive therapy against suicidal ideation in patients with depression: A systematic review and meta-analysis.

BACKGROUND: Mindfulness-based cognitive therapy (MBCT) can effectively prevent relapse of major depression, but there is currently insufficient evidence for efficacy against suicidal ideation during depressive episodes. We thus conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing MBCT to treatment as usual (TAU) for suppression of suicidal ideation in patients with current depression. METHODS: We systematically searched PubMed, Embase, Cochrane, CNKI, and Wan Fang databases for RCTs published in English or Chinese between January 1, 2000, and August 30, 2021. Pooled data were compared between MBCT and TAU groups using a random-effects model. FINDINGS: Seven RCTs with a total of 479 participants were included. Suicidal ideation and general depression scores were significantly improved following MBCT compared to TAU [Suicidal Ideation: standard mean difference (SMD) = -0.33, 95 % CI, -0.56 to -0.10; Depression: SMD = -0.96, 95%CI, -1.54 to -0.38]. INTERPRETATION: Mindfulness-based cognitive therapy is an effective intervention for reducing depressive symptoms and suicidal ideation in depressed patients. TRIAL REGISTRATION: This meta-analysis was conducted in accordance with PRISMA guidelines and registered at PROSPERO https://www.crd.york.ac.uk/PROSPERO/ (CRD42021285016).

Synergetic effects of microbial-phytoremediation reshape microbial communities and improve degradation of petroleum contaminants.

Microbial-phytoremediation is an effective bioremediation technology that introduces petroleum-degrading bacteria and oil-tolerant plants into oil-contaminated soils in order to achieve effective degradation of total petroleum hydrocarbons (TPH). In this work, natural attenuation (NA), microbial remediation (MR, using Acinetobacter sp. Tust-DM21), phytoremediation (PR, using Suaeda glauca), and microbial-phytoremediation (MPR, using both species) were utilized to degrade petroleum hydrocarbons. We evaluated four different biological treatments, assessing TPH degradation rates, soil enzyme activities, and the structure of microbial community in the petroleum-contaminated soil. This finding revealed that the roots of Suaeda glauca adsorbed small amounts of polycyclic aromatic hydrocarbons, causing the structure of soil microbiota community to reshape. The abundance of petroleum-degrading bacteria and plant growth-promoting rhizobacteria (PGPR) has increased, as has microbial diversity. According to correlation research, these genera increased soil enzyme activity, boosted the number of degradation-functional genes in the petroleum hydrocarbon degradation pathway, and accelerated the dissipation and degradation of TPH in petroleum-contaminated soil. This evidence contributes to a better understanding of the mechanisms involved in the combined microbial-phytoremediation strategies for contaminated soil, specifically the interaction between microflora and plants in co-remediation and the effects on the structural reshaping of rhizosphere microbial communities.

Growth performance, antioxidant response, biodegradation and transcriptome analysis of Chlorella pyrenoidosa after nonylphenol exposure.

Chlorella pyrenoidosa was exposed to nonylphenol (NP) to investigate the tolerance, antioxidant response, removal efficiency, and biodegradation mechanism. We conducted studies on algal biomass, chlorophyll a content, and photosynthetic activity, and found that C. pyrenoidosa exhibited a high tolerance even at 8 mg L-1 of NP. Changes in peroxidase (POD) and superoxide dismutase (SOD) activities indicated that the NP-induced oxidative stress caused oxidant damage, which increased the malondialdehyde (MDA) content. After culturing for 120 h, the NP removal efficiency of C. pyrenoidosa was 89%, 59%, 49%, and 48% in the 2, 4, 6, and 8 mg L-1 treatment groups, respectively. Degradation intermediates determined by GC-MS suggested that the biodegradation of NP in C. pyrenoidosa originated from the long alkyl chain. In addition, transcriptome analysis indicated that NP affected photosynthesis, antioxidase, and oxidoreductase activity-related genes. In summary, our results indicated that C. pyrenoidosa is a species that exhibits high tolerance and biodegradation capacity toward NP.

Concurrent Disruption of the Ras/MAPK and NF-κB Pathways Induces Circadian Deregulation and Hepatocarcinogenesis.

The Ras/Erk and NF-κB pathways play critical roles in cell proliferation and are known to drive oncogenesis when overactivated. Herein we report a gatekeeper function of the two pathways by working in synergy to suppress liver tumorigenesis. Hepatocyte-specific deletion of both Shp2/Ptpn11 and Ikkß in mice, which promote Ras/Erk and NF-κB signaling, respectively, exacerbated chemical carcinogenesis and even triggered spontaneous development of hepatocellular carcinoma (HCC). We show that the unanticipated severe tumor phenotype was contributed collectively by severe cholestasis, metabolic changes, upregulated cell-cycle progression, and disruption of circadian rhythm in mutant hepatocytes. Remarkably, human HCCs with dysregulated circadian gene expression displayed downregulation of Ras/Erk and NF-κB signaling and poor prognosis. Together, these data indicate that at the ground state, the two central pathways, previously known as oncogenic, cooperate to sustain tumor-suppressive physiologic homeostasis and to prevent hepatic damage. Disruption of this intricate signaling network is carcinogenic in the liver. IMPLICATIONS: We demonstrate here that basal levels of the Ras/MAPK and NF-κB pathways, while promoting tumorigenesis if overactivated, are required to maintain physiologic homeostasis and regulate circadian rhythm in the liver, which are antitumorigenic.

CRIg on liver macrophages clears pathobionts and protects against alcoholic liver disease.

Complement receptor of immunoglobulin superfamily (CRIg) is expressed on liver macrophages and directly binds complement component C3b or Gram-positive bacteria to mediate phagocytosis. CRIg plays important roles in several immune-mediated diseases, but it is not clear how its pathogen recognition and phagocytic functions maintain homeostasis and prevent disease. We previously associated cytolysin-positive Enterococcus faecalis with severity of alcohol-related liver disease. Here, we demonstrate that CRIg is reduced in liver tissues from patients with alcohol-related liver disease. CRIg-deficient mice developed more severe ethanol-induced liver disease than wild-type mice; disease severity was reduced with loss of toll-like receptor 2. CRIg-deficient mice were less efficient than wild-type mice at clearing Gram-positive bacteria such as Enterococcus faecalis that had translocated from gut to liver. Administration of the soluble extracellular domain CRIg-Ig protein protected mice from ethanol-induced steatohepatitis. Our findings indicate that ethanol impairs hepatic clearance of translocated pathobionts, via decreased hepatic CRIg, which facilitates progression of liver disease.

Hepatocyte-derived exosomes from early onset obese mice promote insulin sensitivity through miR-3075.

In chronic obesity, hepatocytes become insulin resistant and exert important effects on systemic metabolism. Here we show that in early onset obesity (4 weeks high-fat diet), hepatocytes secrete exosomes that enhance insulin sensitivity both in vitro and in vivo. These beneficial effects were due to exosomal microRNA miR-3075, which is enriched in these hepatocyte exosomes. FA2H is a direct target of miR-3075 and small interfering RNA depletion of FA2H in adipocytes, myocytes and primary hepatocytes leads to increased insulin sensitivity. In chronic obesity (16-18 weeks of a high-fat diet), hepatocyte exosomes promote a state of insulin resistance. These chronic obese hepatocyte exosomes do not directly cause impaired insulin signalling in vitro but do promote proinflammatory activation of macrophages. Taken together, these studies show that in early onset obesity, hepatocytes produce exosomes that express high levels of the insulin-sensitizing miR-3075. In chronic obesity, this compensatory effect is lost and hepatocyte-derived exosomes from chronic obese mice promote insulin resistance.

Fibroblast-macrophage reciprocal interactions in health, fibrosis, and cancer.

Fibroblasts and macrophages are present in all tissues, and mounting evidence supports that these cells engage in direct communication to influence the overall tissue microenvironment and affect disease outcomes. Here, we review the current understanding of the molecular mechanisms that underlie fibroblast-macrophage interactions in health, fibrosis, and cancer. We present an integrated view of fibroblast-macrophage interactions that is centered on the CSF1-CSF1R axis and discuss how additional molecular programs linking these cell types can underpin disease onset, progression, and resolution. These programs may be tissue and context dependent, affected also by macrophage and fibroblast origin and state, as seen most clearly in cancer. Continued efforts to understand these cells and the means by which they interact may provide therapeutic approaches for the treatment of fibrosis and cancer.

ß Cell GHS-R Regulates Insulin Secretion and Sensitivity.

Growth hormone secretagogue receptor (GHS-R) is widely known to regulate food intake and adiposity, but its role in glucose homeostasis is unclear. In this study, we investigated the expression of GHS-R in mouse pancreatic islets and its role in glycemic regulation. We used Ghsr-IRES-tauGFP mice, with Green Fluorescent Protein (GFP) as a surrogate for GHS-R, to demonstrate the GFP co-localization with insulin and glucagon expression in pancreatic islets, confirming GHS-R expression in ß and α cells. We then generated ß-cell-specific GHSR-deleted mice with MIP-Cre/ERT and validated that GHS-R suppression was restricted to the pancreatic islets. MIP-Cre/ERT;Ghsrf/f mice showed normal energy homeostasis with similar body weight, body composition, and indirect calorimetry profile. Interestingly, MIP-Cre/ERT;Ghsrf/f mice exhibited an impressive phenotype in glucose homeostasis. Compared to controls, MIP-Cre/ERT;Ghsrf/f mice showed lower fasting blood glucose and insulin; reduced first-phase insulin secretion during a glucose tolerance test (GTT) and glucose-stimulated insulin secretion (GSIS) test in vivo. The isolated pancreatic islets of MIP-Cre/ERT;Ghsrf/f mice also showed reduced insulin secretion during GSIS ex vivo. Further, MIP-Cre/ERT;Ghsrf/f mice exhibited improved insulin sensitivity during insulin tolerance tests (ITT). Overall, our results confirmed GHS-R expression in pancreatic ß and α cells; GHS-R cell-autonomously regulated GSIS and modulated systemic insulin sensitivity. In conclusion, ß cell GHS-R was an important regulator of glucose homeostasis, and GHS-R antagonists may have therapeutic potential for Type 2 Diabetes.

Transcriptional regulation of Treg homeostasis and functional specification.

CD4+Foxp3+ regulatory T (Treg) cells are key players in keeping excessive inflammation in check. Mounting evidence has shown that Treg cells exert much more diverse functions in both immunological and non-immunological processes. The development, maintenance and functional specification of Treg cells are regulated by multilayered factors, including antigens and TCR signaling, cytokines, epigenetic modifiers and transcription factors (TFs). In the review, we will focus on TFs by summarizing their unique and redundant roles in Treg cells under physiological and pathophysiological conditions. We will also discuss the recent advances of Treg trajectories between lymphoid organs and non-lymphoid tissues. This review will provide an updated view of the newly identified TFs and new functions of known TFs in Treg biology.

Immune regulation of islet homeostasis and adaptation.

The islet of Langerhans produces endocrine hormones to regulate glucose homeostasis. The normal function of the islet relies on the homeostatic regulations of cellular composition and cell-cell interactions within the islet microenvironment. Immune cells populate the islet during embryonic development and participate in islet organogenesis and function. In obesity, a low-grade inflammation manifests in multiple organs, including pancreatic islets. Obesity-associated islet inflammation is evident in both animal models and humans, characterized by the accumulation of immune cells and elevated production of inflammatory cytokines/chemokines and metabolic mediators. Myeloid lineage cells (monocytes and macrophages) are the dominant types of immune cells in islet inflammation during the development of obesity and type 2 diabetes mellitus (T2DM). In this review, we will discuss the role of the immune system in islet homeostasis and inflammation and summarize recent findings of the cellular and molecular factors that alter islet microenvironment and ß cell function in obesity and T2DM.

A wave of Foxp3+ regulatory T cell accumulation in the neonatal liver plays unique roles in maintaining self-tolerance.

Newborn animals require tightly regulated local and systemic immune environments to govern the development and maturation of multiple organs/tissues even though the immune system itself is far from mature during the neonatal period. Regulatory T cells (Tregs) are essential for maintaining immune tolerance/homeostasis and modulating inflammatory responses. The features of Tregs in the neonatal liver under steady-state conditions are not well understood. The present study aimed to investigate the phenotype, functions, and significance of neonatal Tregs in the liver. We found a wave of thymus-derived Treg influx into the liver during 1-2 weeks of age. Depletion of these Tregs between days 7 and 11 after birth rapidly resulted in Th1-type liver inflammation and metabolic disorder. More Tregs in the neonatal liver than in the spleen underwent MHC II-dependent activation and proliferation, and the liver Tregs acquired stronger suppressive functions. The transcriptomic profile of these neonatal liver Tregs showed elevated expression of PPARγ and T-bet and features of Tregs that utilize lipid metabolic machinery and are capable of regulating Th1 responses. The accumulation of Tregs with unique features in the neonatal liver is critical to ensure self-tolerance and liver maturation.

The role of macrophages in obesity-associated islet inflammation and ß-cell abnormalities.

Chronic, unresolved tissue inflammation is a well-described feature of obesity, type 2 diabetes mellitus (T2DM) and other insulin-resistant states. In this context, adipose tissue and liver inflammation have been particularly well studied; however, abundant evidence demonstrates that inflammatory processes are also activated in pancreatic islets from obese animals and humans with obesity and/or T2DM. In this Review, we focus on the characteristics of immune cell-mediated inflammation in islets and the consequences of this with respect to ß-cell function. In contrast to type 1 diabetes mellitus, the dominant immune cell type causing inflammation in obese and T2DM islets is the macrophage. The increased macrophage accumulation in T2DM islets primarily arises through local proliferation of resident macrophages, which then provide signals (such as platelet-derived growth factor) that drive ß-cell hyperplasia (a classic feature of obesity). In addition, islet macrophages also impair the insulin secretory capacity of ß-cells. Through these mechanisms, islet-resident macrophages underlie the inflammatory response in obesity and mechanistically participate in the ß-cell hyperplasia and dysfunction that characterizes this insulin-resistant state. These findings point to the possibility of therapeutics that target islet inflammation to elicit beneficial effects on ß-cell function and glycaemia.

Development of boronic acid-functionalized mesoporous silica-coated core/shell magnetic microspheres with large pores for endotoxin removal.

Endotoxins are found almost everywhere and possess high toxicity in vivo and in vitro. Here we design a novel boronate affinity material, called boronic acid-functionalized mesoporous silica-coated core/shell magnetic microspheres (Fe3O4@nSiO2@mSiO2-BA) with large pores (pore size > 20 nm) based on the chemical structure and physical properties of endotoxins, for facile and highly efficient removal of endotoxins. Dual modes for endotoxin removal were proposed and confirmed in this work: the endotoxin aggregates with size < 20 nm were bound with boronic acid ligands chemically modified on the inner and outer surface of the large pores of Fe3O4@nSiO2@mSiO2-BA microspheres; while the larger endotoxin micelles (size >20 nm) were absorbed on the outer surface of the prepared material based on boronate affinity. Transmission electron microscopy (TEM), X-ray diffraction (XRD), nitrogen adsorption/desorption isotherms and Fourier transform infrared (FT-IR) spectroscopy confirm that Fe3O4@nSiO2@mSiO2-BA microspheres possess core/shell structure, uniform diameter (520 nm), high surface area (205.57 m2/g), large mesopores (21.8 nm) and boronic acid ligands. The purification procedures of Fe3O4@nSiO2@mSiO2-BA microspheres for endotoxin were optimized, and 50 mM NH4HCO3 (pH 8.0) and 0.05 M fructose were selected as loading/washing, elution buffers, respectively. The binding capacity of Fe3O4@nSiO2@mSiO2-BA microspheres for endotoxin was calculated to be 60.84 EU/g under the optimized conditions. Finally, the established analytical method was applied to remove endotoxins from plasmid DNA. After endotoxin removal, the endotoxin content in plasmid DNA was reduced from 0.0026 to 0.0006 EU/mL for two-fold concentration, and from 0.0088 to 0.0022 EU/mL for five-fold concentration after binding, respectively. Additional advantages of the prepared boronate affinity material include excellent stability, reusability/repeatability, and low cost. Boronate affinity materials with large pores could thus prove to be powerful adsorbents for endotoxin removal and the potential applications in the aspects of biological research, pharmaceutical industry, and life health.

TCF1 and LEF1 Control Treg Competitive Survival and Tfr Development to Prevent Autoimmune Diseases.

CD4+ Foxp3+ T regulatory (Treg) cells are key players in preventing lethal autoimmunity. Tregs undertake differentiation processes and acquire diverse functional properties. However, how Treg's differentiation and functional specification are regulated remains incompletely understood. Here, we report that gradient expression of TCF1 and LEF1 distinguishes Tregs into three distinct subpopulations, particularly highlighting a subset of activated Treg (aTreg) cells. Treg-specific ablation of TCF1 and LEF1 renders the mice susceptible to systemic autoimmunity. TCF1 and LEF1 are dispensable for Treg's suppressive capacity but essential for maintaining a normal aTreg pool and promoting Treg's competitive survival. As a consequence, the development of T follicular regulatory (Tfr) cells, which are a subset of aTreg, is abolished in TCF1/LEF1-conditional knockout mice, leading to unrestrained T follicular helper (Tfh) and germinal center B cell responses. Thus, TCF1 and LEF1 act redundantly to control the maintenance and functional specification of Treg subsets to prevent autoimmunity.

Expansion of Islet-Resident Macrophages Leads to Inflammation Affecting ß Cell Proliferation and Function in Obesity.

The nature of obesity-associated islet inflammation and its impact on ß cell abnormalities remains poorly defined. Here, we explore immune cell components of islet inflammation and define their roles in regulating ß cell function and proliferation. Islet inflammation in obese mice is dominated by macrophages. We identify two islet-resident macrophage populations, characterized by their anatomical distributions, distinct phenotypes, and functional properties. Obesity induces the local expansion of resident intra-islet macrophages, independent of recruitment from circulating monocytes. Functionally, intra-islet macrophages impair ß cell function in a cell-cell contact-dependent manner. Increased engulfment of ß cell insulin secretory granules by intra-islet macrophages in obese mice may contribute to restricting insulin secretion. In contrast, both intra- and peri-islet macrophage populations from obese mice promote ß cell proliferation in a PDGFR signaling-dependent manner. Together, these data define distinct roles and mechanisms for islet macrophages in the regulation of islet ß cells.

PPARγ deacetylation dissociates thiazolidinedione's metabolic benefits from its adverse effects.

Thiazolidinediones (TZDs) are PPARγ agonists with potent insulin-sensitizing effects. However, their use has been curtailed by substantial adverse effects on weight, bone, heart, and hemodynamic balance. TZDs induce the deacetylation of PPARγ on K268 and K293 to cause the browning of white adipocytes. Here, we show that targeted PPARγ mutations resulting in constitutive deacetylation (K268R/K293R, 2KR) increased energy expenditure and protected from visceral adiposity and diet-induced obesity by augmenting brown remodeling of white adipose tissues. Strikingly, when 2KR mice were treated with rosiglitazone, they maintained the insulin-sensitizing, glucose-lowering response to TZDs, while displaying little, if any, adverse effects on fat deposition, bone density, fluid retention, and cardiac hypertrophy. Thus, deacetylation appears to fulfill the goal of dissociating the metabolic benefits of PPARγ activation from its adverse effects. Strategies to leverage PPARγ deacetylation may lead to the design of safer, more effective agonists of this nuclear receptor in the treatment of metabolic diseases.