Mechanisms of resistance to oncogenic KRAS inhibition in pancreatic cancer.

KRAS inhibitors demonstrate clinical efficacy in pancreatic ductal adenocarcinoma (PDAC); however, resistance is common. Among patients with KRASG12C-mutant PDAC treated with adagrasib or sotorasib, mutations in PIK3CA and KRAS, and amplifications of KRASG12C, MYC, MET, EGFR, and CDK6 emerged at acquired resistance. In PDAC cell lines and organoid models treated with the KRASG12D inhibitor MRTX1133, epithelial-to-mesenchymal transition and PI3K-AKT-mTOR signaling associate with resistance to therapy. MRTX1133 treatment of the KrasLSL-G12D/+;Trp53LSL-R172H/+;p48-Cre (KPC) mouse model yielded deep tumor regressions, but drug resistance ultimately emerged, accompanied by amplifications of Kras, Yap1, Myc, and Cdk6/Abcb1a/b, and co-evolution of drug-resistant transcriptional programs. Moreover, in KPC and PDX models, mesenchymal and basal-like cell states displayed increased response to KRAS inhibition compared to the classical state. Combination treatment with KRASG12D inhibition and chemotherapy significantly improved tumor control in PDAC mouse models. Collectively, these data elucidate co-evolving resistance mechanisms to KRAS inhibition and support multiple combination therapy strategies.

Maintaining the 2D Structure of MXene via Self-Assembled Monolayers for Efficient Lubrication in High Humidity.

MXene is considered as a promising solid lubricant due to facile shearing ability and tuneable surface chemistry. However, it faces challenges in high-humidity environments where excessive water molecules can significantly impact its 2D structure, thus deteriorating its lubricating properties. In this work, the self-assembled monolayers are formed on MXene by surface chlorination (MXene-Cl) and fluorination (MXene-F), and their friction behaviors in high/low humidity are investigated. The results indicate that MXene-F and MXene-Cl can maintain a relatively constant friction coefficient (CoF) (MXene-F ∼0.76, MXene-Cl ∼0.48) under both high (75%) and low (25%)-relative humidity (RH) environments. Meanwhile, the MXene-F and MXene-Cl display a lower CoF than the pristine MXene (MXene CoF∼1.18) in high humidity. The above phenomena are mainly attributed to the preservation of its 2D layered structure, the increased layer spacing, and superficial partial oxidation for SAMs-functionalized MXene under high humidity during friction. Interestingly, MXene-Cl with moderate water resistance has a lower CoF than that of MXene-F with complete water resistance. The nanostructured water adsorption capacity and larger interlayer spacing of MXene-Cl make it exhibit a lower CoF compared to MXene-F. The findings of this study offer valuable guidance for tailoring MXene by surface chemical functionalization as an efficient solid lubricant in high humidity.

Antioxidant and anti-inflammatory function of Eupatorium adenophora Spreng leaves (EASL) on human intestinal Caco-2 cells treated with tert-butyl hydroperoxide.

Chronic non-communicable diseases (CNCDs) pose a significant public health challenge. Addressing this issue, there has been a notable breakthrough in the prevention and mitigation of NCDs through the use of antioxidants and anti-inflammatory agents. In this study, we aim to explore the effectiveness of Eupatorium adenophora Spreng leaves (EASL) as an antioxidant and anti-inflammatory agent, and its potential applications. To construct a cellular model of oxidative damage and inflammation, Caco-2 cells were treated with tert-butyl hydroperoxide (t-BHP). The biocompatibility of EASL-AE with Caco-2 cells was assessed using the MTT assay, while compatibility was further verified by measuring LDH release and the protective effect against oxidative damage was also assessed using the MTT assay. Additionally, we measured intracellular oxidative stress indicators such as ROS and 8-OHdG, as well as inflammatory pathway signalling protein NFκB and inflammatory factors TNF-α and IL-1ß using ELISA, to evaluate the antioxidant and anti-inflammatory capacity of EASL-AE. The scavenging capacity of EASL-AE against free radicals was determined through the DPPH Assay and ABTS Assay. Furthermore, we measured the total phenolic, total flavonoid, and total polysaccharide contents using common chemical methods. The chemical composition of EASL-AE was analyzed using the LC-MS/MS technique. Our findings demonstrate that EASL-AE is biocompatible with Caco-2 cells and non-toxic at experimental levels. Moreover, EASL-AE exhibits a significant protective effect on Caco-2 cells subjected to oxidative damage. The antioxidant effect of EASL-AE involves the scavenging of intracellular ROS, while its anti-inflammatory effect is achieved by down-regulation of the NFκB pathway. Which in turn reduces the release of inflammatory factors TNF-α and IL-1ß. Through LC-MS/MS analysis, we identified 222 compounds in EASL-AE, among which gentianic acid, procaine and L-tyrosine were the compounds with high antioxidant capacity and may be the effective constituent for EASL-AE with antioxidant activity. These results suggest that EASL-AE is a natural and high-quality antioxidant and anti-inflammatory biomaterial that warrants further investigation. It holds great potential for applications in healthcare and other related fields.

Pedicled flap versus skin graft for great toe defect repair after wrap-around flap transfer.

This study compared the clinical outcomes of tibial-sided digital artery pedicled flap from the second toe versus full-thickness skin grafting to repair great toe defects after wrap-around flap transfers. The pedicled flap resulted in better pain scores and aesthetic outcomes.

Small molecule conjugates with selective estrogen receptor ß agonism promote anti-aging benefits in metabolism and skin recovery.

Estrogen is imperative to mammalian reproductivity, metabolism, and aging. However, the hormone activating estrogen receptor (ERs) α can cause major safety concerns due to the enrichment of ERα in female tissues and certain malignancies. In contrast, ERß is more broadly expressed in metabolic tissues and the skin. Thus, it is desirable to generate selective ERß agonist conjugates for maximizing the therapeutic effects of ERs while minimizing the risks of ERα activation. Here, we report the design and production of small molecule conjugates containing selective non-steroid ERß agonists Gtx878 or genistein. Treatment of aged mice with our synthesized conjugates improved aging-associated declines in insulin sensitivity, visceral adipose integrity, skeletal muscle function, and skin health, with validation in vitro. We further uncovered the benefits of ERß conjugates in the skin using two inducible skin injury mouse models, showing increased skin basal cell proliferation, epidermal thickness, and wound healing. Therefore, our ERß-selective agonist conjugates offer novel therapeutic potential to improve aging-associated conditions and aid in rejuvenating skin health.

Sensor Head Temperature Distribution Reconstruction of High-Precision Gravitational Reference Sensors with Machine Learning.

Temperature fluctuations affect the performance of high-precision gravitational reference sensors. Due to the limited space and the complex interrelations among sensors, it is not feasible to directly measure the temperatures of sensor heads using temperature sensors. Hence, a high-accuracy interpolation method is essential for reconstructing the surface temperature of sensor heads. In this study, we utilized XGBoost-LSTM for sensor head temperature reconstruction, and we analyzed the performance of this method under two simulation scenarios: ground-based and on-orbit. The findings demonstrate that our method achieves a precision that is two orders of magnitude higher than that of conventional interpolation methods and one order of magnitude higher than that of a BP neural network. Additionally, it exhibits remarkable stability and robustness. The reconstruction accuracy of this method meets the requirements for the key payload temperature control precision specified by the Taiji Program, providing data support for subsequent tasks in thermal noise modeling and subtraction.

IgG is an aging factor that drives adipose tissue fibrosis and metabolic decline.

Aging is underpinned by pronounced metabolic decline; however, the drivers remain obscure. Here, we report that IgG accumulates during aging, particularly in white adipose tissue (WAT), to impair adipose tissue function and metabolic health. Caloric restriction (CR) decreases IgG accumulation in WAT, whereas replenishing IgG counteracts CR's metabolic benefits. IgG activates macrophages via Ras signaling and consequently induces fibrosis in WAT through the TGF-ß/SMAD pathway. Consistently, B cell null mice are protected from aging-associated WAT fibrosis, inflammation, and insulin resistance, unless exposed to IgG. Conditional ablation of the IgG recycling receptor, neonatal Fc receptor (FcRn), in macrophages prevents IgG accumulation in aging, resulting in prolonged healthspan and lifespan. Further, targeting FcRn by antisense oligonucleotide restores WAT integrity and metabolic health in aged mice. These findings pinpoint IgG as a hidden culprit in aging and enlighten a novel strategy to rejuvenate metabolic health.

Abhd2, a Candidate Gene Regulating Airway Remodeling in COPD via TGF-ß.

Purpose: The typical characteristic of COPD is airway remodeling, affected by environmental and genetic factors. However, genetic studies on COPD have been limited. Currently, the Abhd2 gene is found to play a critical role in maintaining alveolar architecture and stability. The research aims to investigate the predictive value of Abhd2 for airway remodeling in COPD and its effect on TGF-ß regulation. Methods: In humans, Abhd2 protein was obtained from peripheral blood monocytes. Peripheral blood TGF-ß, pulmonary surfactant proteins (SPs), metalloproteinases, inflammatory indicators (WBC, NEU, NLR, EOS, CRP, PCT, D-Dimer), chest CT (airway diameter and airway wall thickness), pulmonary function, and blood gas analysis were used to assess airway remodeling. In animals, Abhd2 deficient mice (Abhd2Gt/Gt) using gene trapping and C57BL6 mice were injected intraperitoneally with CSE to construct COPD models. HE staining, Masson staining and immunohistochemistry were used to observe the pathological changes of airway in mice, and RT-PCR, WB, ELISA and immunofluorescence were used to detect the expression of secreted proteins and EMT markers. Results: COPD patients with worse pulmonary function and higher airway remodeling-related inflammatory factors had lower Abhd2 protein expression. Moreover, indicators followed the same trend for COPD patients grouped by prognosis (Group A vs Group B). Serum TGF-ß was negatively correlated with Abhd2 protein expression, FEV1/FVC, FEV1, and FEV1% PRED. In mice, Abhd2 depletion promoted deposition of TGF-ß, leading to more pronounced emphysema, airway thickening, increased alveolar macrophage infiltration, decreased AECII number and SPs, and EMT phenomenon. Conclusion: Downregulation of Abhd2 can promote airway remodeling in COPD by modulating repair after injury and EMT via TGF-ß. This study suggests that Abhd2 may serve as a biomarker for assessing airway remodeling and guiding prognosis in COPD.

Intratumoral delivery of a Tim-3 antibody-encoding oncolytic adenovirus engages an effective antitumor immune response in liver cancer.

BACKGROUND AND PURPOSE: The use of oncolytic viruses as a gene therapy vector is an area of active biomedical research, particularly in the context of cancer treatment. However, the actual therapeutic success of this approach to tumor elimination remains limited. As such, the present study was developed with the goal of simultaneously enhancing the antitumor efficacy of oncolytic viruses and the local immune response by combining the Ad-GD55 oncolytic adenovirus and an antibody specific for the TIM-3 immune checkpoint molecule (α-TIM-3). APPROACH AND KEY RESULTS: The results of Virus and cell-mediated cytotoxicity assay, qPCR, and Western immunoblotting showed that Ad-GD55-α-Tim-3 oncolytic adenovirus is capable of inducing α-TIM-3 expression within hepatoma cells upon infection, and Ad-GD55-α-TIM-3 exhibited inhibitory efficacy superior to that of Ad-GD55 when used to treat these tumor cells together with the induction of enhanced intracellular immunity. In vivo experiments revealed that Ad-GD55-α-TIM-3 administration was sufficient to inhibit tumor growth and engage in a more robust local immune response within the simulated tumor immune microenvironment. CONCLUSION AND IMPLICATIONS: These results highlighted the promising therapeutic effects of Ad-GD55-α-TIM-3 oncolytic adenovirus against HCC in vitro and in vivo. As such, this Ad-GD55-α-TIM-3 oncolytic adenovirus may represent a viable approach to the treatment of hepatocellular carcinoma.

Numerical simulation and experiment of double chamber brake based on CFD.

The artillery firing process will instantly produce high-temperature and high-pressure gunpowder gas, this process will produce shock waves. The gunpowder gas has a limited effect on the projectile during the firing and ballistic after-effects period, however, it has a very obvious effect on the stability of the gun body, and the reduction of the stability of the gun body directly affects the firing accuracy and the safety of the firing personnel. Based on the method of Computational Fluid Dynamics (CFD), numerical simulation is carried out, and the structure and flow parameters of the muzzle flow field are obtained by using three-dimensional Euler's control equation, gas equation of state, and k-epsilon model, as well as dynamic mesh technology. By comparing the flow parameters of the brake before and after optimization, and analyzing the results obtained from the 8-round firing experiments, the efficiency of the optimized brake is increased by 8.2%, and the deviation between the experimental data and the simulation results is only 10.5%, which not only verifies the accuracy of the numerical simulation calculations but also verifies the optimized brake's good retracting effect. The results of the study can provide a reference for the optimization and design of the double-chamber brake.

A glimpse of the connection between PPARγ and macrophage.

Nuclear receptors are ligand-regulated transcription factors that regulate vast cellular activities and serve as an important class of drug targets. Among them, peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor family and have been extensively studied for their roles in metabolism, differentiation, development, and cancer, among others. Recently, there has been considerable interest in understanding and defining the function of PPARs and their agonists in regulating innate and adaptive immune responses and their pharmacological potential in combating chronic inflammatory diseases. In this review, we focus on emerging evidence for the potential role of PPARγ in macrophage biology, which is the prior innate immune executive in metabolic and tissue homeostasis. We also discuss the role of PPARγ as a regulator of macrophage function in inflammatory diseases. Lastly, we discuss the possible application of PPARγ antagonists in metabolic pathologies.

Deciphering the decline of metabolic elasticity in aging and obesity.

Organisms must adapt to fluctuating nutrient availability to maintain energy homeostasis. Here, we term the capacity for such adaptation and restoration "metabolic elasticity" and model it through ad libitum-fasting-refeeding cycles. Metabolic elasticity is achieved by coordinate versatility in gene expression, which we call "gene elasticity." We have developed the gene elasticity score as a systematic method to quantify the elasticity of the transcriptome across metabolically active tissues in mice and non-human primates. Genes involved in lipid and carbohydrate metabolism show high gene elasticity, and their elasticity declines with age, particularly with PPARγ dysregulation in adipose tissue. Synchronizing PPARγ activity with nutrient conditions through feeding-timed agonism optimizes their metabolic benefits and safety. We further broaden the conceptual scope of metabolic and gene elasticity to dietary challenges, revealing declines in diet-induced obesity similar to those in aging. Altogether, our findings provide a dynamic perspective on the dysmetabolic consequences of aging and obesity.

Correlation between the setting of gating window width and setup accuracy in left breast cancer radiotherapy based on deep inspiration breath hold.

Personalized precision irradiation of patients with left-sided breast cancer is possible by examining the setup errors of 3- and 4-mm gated window widths for those treated with deep inspiration breath-hold (DIBH) treatment. An observational study was performed via a retrospective analysis of 250 cone-beam computed tomography (CBCT) images of 60 left-breast cancer patients who underwent whole-breast radiotherapy with the DIBH technique between January 2021 and 2022 at our hospital. Among them, 30 patients had a gated window width of 3 mm, while the remaining 30 had a gated window width of 4 mm; both groups received radiotherapy using DIBH technology. All patients underwent CBCT scans once a week, and the setup errors in the left-right (x-axis), inferior-superior (y-axis), and anterior-posterior (z-axis) directions were recorded. The clinical-to-planning target volume (CTV-PTV) margins of the two gating windows were calculated using established methods. The setup error in the Y direction was 1.69 ± 1.33 mm for the 3-mm - wide gated window and 2.42 ± 3.02 mm for the 4-mm - wide gated window. The two groups had statistically significant differences in the overall mean setup error (Dif 0.7, 95% CI 0.15-1.31, t = 2.48, p= 0.014). The Z-direction setup error was 2.32 ± 2.12 mm for the 3-mm - wide gated window and 3.15 ± 3.34 mm for the 4-mm - wide gated window. The overall mean setup error was statistically significant between the two groups (Dif 0.8, 95% CI 0.13-1.53, t= 2.34, p = 0.020). There was no significant difference in the X-direction setup error (p > 0.05). Therefore, the CTV-PTV margin values for a 3-mm gated window width in the X, Y, and Z directions are 5.51, 5.15, and 7.28 mm, respectively; those for a 4-mm gated window width in the X, Y, and Z directions are 5.52, 8.16, and 10.21 mm, respectively. The setup errors of the 3-mm - wide gating window are smaller than those of the 4-mm - wide gating window in the three dimensions. Therefore, when the patient's respiratory gating window width is reduced, the margin values of CTV-PTV can be reduced to increase the distance between the PTV and the organs at risk (OARs), which ensures adequate space for the dose to decrease, resulting in lower dose exposure to the OARs (heart, lungs, etc.), thus sparing the OARs from further damage. However, some patients with poor pulmonary function or unstable breathing amplitudes must be treated with a slightly larger gating window. Therefore, this study lays a theoretical basis for personalized precision radiotherapy, which can save time and reduce manpower in the delivery of clinical treatment to a certain extent. Another potential benefit of this work is to bring awareness to the potential implications of a slightly larger gating window during treatment without considering the resulting dosimetric impact.

PPARγ Acetylation in Adipocytes Exacerbates BAT Whitening and Worsens Age-Associated Metabolic Dysfunction.

Aging and obesity are the two prominent driving forces of metabolic dysfunction, yet the common underlying mechanisms remain elusive. PPARγ, a central metabolic regulator and primary drug target combatting insulin resistance, is hyperacetylated in both aging and obesity. By employing a unique adipocyte-specific PPARγ acetylation-mimetic mutant knock-in mouse model, namely aKQ, we demonstrate that these mice develop worsened obesity, insulin resistance, dyslipidemia, and glucose intolerance as they age, and these metabolic deregulations are resistant to intervention by intermittent fasting. Interestingly, aKQ mice show a whitening phenotype of brown adipose tissue (BAT) manifested in lipid filling and suppressed BAT markers. Diet-induced obese aKQ mice retain an expected response to thiazolidinedione (TZD) treatment, while BAT function remains impaired. This BAT whitening phenotype persists even with the activation of SirT1 through resveratrol treatment. Moreover, the adverse effect of TZDs on bone loss is exacerbated in aKQ mice and is potentially mediated by their increased Adipsin levels. Our results collectively suggest pathogenic implications of adipocyte PPARγ acetylation, contributing to metabolic dysfunction in aging and thus posing as a potential therapeutic target.

Establishment and validation of a nomogram based on coagulation parameters to predict the prognosis of pancreatic cancer.

BACKGROUND: In recent years, multiple coagulation and fibrinolysis (CF) indexes have been reported to be significantly related to the progression and prognosis of some cancers. OBJECTIVE: The purpose of this study was to comprehensively analyze the value of CF parameters in prognosis prediction of pancreatic cancer (PC). METHODS: The preoperative coagulation related data, clinicopathological information, and survival data of patients with pancreatic tumor were collected retrospectively. Mann Whitney U test, Kaplan-Meier analysis, and Cox proportional hazards regression model were applied to analyze the differences of coagulation indexes between benign and malignant tumors, as well as the roles of these indexes in PC prognosis prediction. RESULTS: Compared with benign tumors, the preoperative levels of some traditional coagulation and fibrinolysis (TCF) indexes (such as TT, Fibrinogen, APTT, and D-dimer) were abnormally increased or decreased in patients with pancreatic cancer, as well as Thromboelastography (TEG) parameters (such as R, K, α Angle, MA, and CI). Kaplan Meier survival analysis based on resectable PC patients showed that the overall survival (OS) of patients with elevated α angle, MA, CI, PT, D-dimer, or decreased PDW was markedly shorter than other patients; moreover, patients with lower CI or PT have longer disease-free survival. Further univariate and multivariate analysis revealed that PT, D-dimer, PDW, vascular invasion (VI), and tumor size (TS) were independent risk factors for poor prognosis of PC. According to the results of modeling group and validation group, the nomogram model based on independent risk factors could effectively predict the postoperative survival of PC patients. CONCLUSION: Many abnormal CF parameters were remarkably correlated with PC prognosis, including α Angle, MA, CI, PT, D-dimer, and PDW. Furthermore, only PT, D-dimer, and PDW were independent prognostic indicators for poor prognosis of PC, and the prognosis prediction model based on these indicators was an effective tool to predict the postoperative survival of PC.

Functional and aesthetic recovery of the second toe defect using a wrap-around pedicled flap from the great toe.

We report the results of using a fibula-sided digital artery pedicled flap from the great toe to cover the second toe free flap donor site, which avoids delayed wound healing, and prevents pain and skin ulceration. This study included 15 patients who had second toe wrap-around free flaps to reconstruct thumb and finger defects. All 15 pedicled flaps used to cover the defect healed uneventfully. All patients were able to stand and walk and were satisfied with the postoperative aesthetic outcome at the 6-month follow-up. We conclude that this an effective procedure for preventing donor site defects after second toe wrap-around free flap transfer.Level of evidence: IV.

Unraveling the pathophysiology of schizophrenia: insights from structural magnetic resonance imaging studies.

Background: Schizophrenia affects about 1% of the global population. In addition to the complex etiology, linking this illness to genetic, environmental, and neurobiological factors, the dynamic experiences associated with this disease, such as experiences of delusions, hallucinations, disorganized thinking, and abnormal behaviors, limit neurological consensuses regarding mechanisms underlying this disease. Methods: In this study, we recruited 72 patients with schizophrenia and 74 healthy individuals matched by age and sex to investigate the structural brain changes that may serve as prognostic biomarkers, indicating evidence of neural dysfunction underlying schizophrenia and subsequent cognitive and behavioral deficits. We used voxel-based morphometry (VBM) to determine these changes in the three tissue structures: the gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF). For both image processing and statistical analysis, we used statistical parametric mapping (SPM). Results: Our results show that patients with schizophrenia exhibited a significant volume reduction in both GM and WM. In particular, GM volume reductions were more evident in the frontal, temporal, limbic, and parietal lobe, similarly the WM volume reductions were predominantly in the frontal, temporal, and limbic lobe. In addition, patients with schizophrenia demonstrated a significant increase in the CSF volume in the left third and lateral ventricle regions. Conclusion: This VBM study supports existing research showing that schizophrenia is associated with alterations in brain structure, including gray and white matter, and cerebrospinal fluid volume. These findings provide insights into the neurobiology of schizophrenia and may inform the development of more effective diagnostic and therapeutic approaches.

Transforming Growth Factor-ß Blockade in Pancreatic Cancer Enhances Sensitivity to Combination Chemotherapy.

BACKGROUND & AIMS: Transforming growth factor-b (TGFb) plays pleiotropic roles in pancreatic cancer, including promoting metastasis, attenuating CD8 T-cell activation, and enhancing myofibroblast differentiation and deposition of extracellular matrix. However, single-agent TGFb inhibition has shown limited efficacy against pancreatic cancer in mice or humans. METHODS: We evaluated the TGFß-blocking antibody NIS793 in combination with gemcitabine/nanoparticle (albumin-bound)-paclitaxel or FOLFIRINOX (folinic acid [FOL], 5-fluorouracil [F], irinotecan [IRI] and oxaliplatin [OX]) in orthotopic pancreatic cancer models. Single-cell RNA sequencing and immunofluorescence were used to evaluate changes in tumor cell state and the tumor microenvironment. RESULTS: Blockade of TGFß with chemotherapy reduced tumor burden in poorly immunogenic pancreatic cancer, without affecting the metastatic rate of cancer cells. Efficacy of combination therapy was not dependent on CD8 T cells, because response to TGFß blockade was preserved in CD8-depleted or recombination activating gene 2 (RAG2-/-) mice. TGFß blockade decreased total α-smooth muscle actin-positive fibroblasts but had minimal effect on fibroblast heterogeneity. Bulk RNA sequencing on tumor cells sorted ex vivo revealed that tumor cells treated with TGFß blockade adopted a classical lineage consistent with enhanced chemosensitivity, and immunofluorescence for cleaved caspase 3 confirmed that TGFß blockade increased chemotherapy-induced cell death in vivo. CONCLUSIONS: TGFß regulates pancreatic cancer cell plasticity between classical and basal cell states. TGFß blockade in orthotropic models of pancreatic cancer enhances sensitivity to chemotherapy by promoting a classical malignant cell state. This study provides scientific rationale for evaluation of NIS793 with FOLFIRINOX or gemcitabine/nanoparticle (albumin-bound) paclitaxel chemotherapy backbone in the clinical setting and supports the concept of manipulating cancer cell plasticity to increase the efficacy of combination therapy regimens.

Uncoupling Lipid Synthesis from Adipocyte Development.

Obesity results from the expansion of adipose tissue, a versatile tissue regulating energy homeostasis, adipokine secretion, thermogenesis, and inflammation. The primary function of adipocytes is thought to be lipid storage through lipid synthesis, which is presumably intertwined with adipogenesis. However, during prolonged fasting, adipocytes are depleted of lipid droplets yet retain endocrine function and an instant response to nutrients. This observation led us to question whether lipid synthesis and storage can be uncoupled from adipogenesis and adipocyte function. By inhibiting key enzymes in the lipid synthesis pathway during adipocyte development, we demonstrated that a basal level of lipid synthesis is essential for adipogenesis initiation but not for maturation and maintenance of adipocyte identity. Furthermore, inducing dedifferentiation of mature adipocytes abrogated adipocyte identity but not lipid storage. These findings suggest that lipid synthesis and storage are not the defining features of adipocytes and raise the possibility of uncoupling lipid synthesis from adipocyte development to achieve smaller and healthier adipocytes for the treatment of obesity and related disorders.