Obesity alters cholesterol homeostasis in regulatory T cells of visceral adipose tissue
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Tumors exhibit an increased ability to obtain and metabolize nutrients. Here, we implant engineered adipocytes that outcompete tumors for nutrients and show that they can substantially reduce cancer progression, a technology termed adipose manipulation transplantation (AMT). Adipocytes engineered to use increased amounts of glucose and fatty acids by upregulating UCP1 were placed alongside cancer cells or xenografts, leading to significant cancer suppression. Transplanting modulated adipose organoids in pancreatic or breast cancer genetic mouse models suppressed their growth and decreased angiogenesis and hypoxia. Co-culturing patient-derived engineered adipocytes with tumor organoids from dissected human breast cancers significantly suppressed cancer progression and proliferation. In addition, cancer growth was impaired by inducing engineered adipose organoids to outcompete tumors using tetracycline or placing them in an integrated cell-scaffold delivery platform and implanting them next to the tumor. Finally, we show that upregulating UPP1 in adipose organoids can outcompete a uridine-dependent pancreatic ductal adenocarcinoma for uridine and suppress its growth, demonstrating the potential customization of AMT.
Role of pancreatic lipase inhibition in obesity treatment: mechanisms and challenges towards current insights and future directions
The worldwide health emergency of obesity is closely connected to how dietary fats are metabolized, whereas the process is significantly influenced by pancreatic lipase (PL), an enzyme critical for lipid hydrolysis into fatty acids. This narrative review employs a methodological approach utilizing literature searches of PubMed data up to March 2024. The search term criteria encompasses keywords related to the role, mechanism, challenges, and current and future treatments of pancreatic lipase in obesity with an overall references is 106. This paper offers a comprehensive explanation of the role of PL, underlining its significance in the digestive process and lipid imbalances that contribute to obesity and by extension, its impact on obesity development and progression. Additionally, it delves into the dual functionality of the pancreas, emphasizing its impact on metabolism and energy utilization which, when dysregulated, promotes obesity. A focal point of this review is the investigation into the efficacy, challenges, and adverse effects of current pancreatic lipase inhibitors, with orlistat being highlighted as a primary current drug delivery. By discussing advanced obesity treatments, including the exploration of novel anti-obesity medications that target specific biological pathways, this review underscores the complexity of obesity treatment and the necessity for a multifaceted approach. In conclusion, this paper emphasizing the importance of understanding the role of enzymes like pancreatic lipase mechanistic and adopting a multidisciplinary approach to treatment and side effects of current obesity drugs and explore new emerging therapeutic strategies for more effective obesity management.
Cellular and molecular mechanisms underlying obesity in degenerative spine and joint diseases
Degenerative spine and joint diseases, including intervertebral disc degeneration (IDD), ossification of the spinal ligaments (OSL), and osteoarthritis (OA), are common musculoskeletal diseases that cause pain or disability to the patients. However, the pathogenesis of these musculoskeletal disorders is complex and has not been elucidated clearly to date. As a matter of fact, the spine and joints are not independent of other organs and tissues. Recently, accumulating evidence demonstrates the association between obesity and degenerative musculoskeletal diseases. Obesity is a common metabolic disease characterized by excessive adipose tissue or abnormal adipose distribution in the body. Excessive mechanical stress is regarded as a critical risk factor for obesity-related pathology. Additionally, obesity-related factors, mainly including lipid metabolism disorder, dysregulated pro-inflammatory adipokines and cytokines, are reported as plausible links between obesity and various human diseases. Importantly, these obesity-related factors are deeply involved in the regulation of cell phenotypes and cell fates, extracellular matrix (ECM) metabolism, and inflammation in the pathophysiological processes of degenerative spine and joint diseases. In this study, we systematically discuss the potential cellular and molecular mechanisms underlying obesity in these degenerative musculoskeletal diseases, and hope to provide novel insights for developing targeted therapeutic strategies.
Cholesterol homeostasis and lipid raft dynamics at the basis of tumor-induced immune dysfunction in chronic lymphocytic leukemia
Autologous T-cell therapies show limited efficacy in chronic lymphocytic leukemia (CLL), where acquired immune dysfunction prevails. In CLL, disturbed mitochondrial metabolism has been linked to defective T-cell activation and proliferation. Recent research suggests that lipid metabolism regulates mitochondrial function and differentiation in T cells, yet its role in CLL remains unexplored. This comprehensive study compares T-cell lipid metabolism in CLL patients and healthy donors, revealing critical dependence on exogenous cholesterol for human T-cell expansion following TCR-mediated activation. Using multi-omics and functional assays, we found that T cells present in viably frozen samples of patients with CLL (CLL T cells) showed impaired adaptation to cholesterol deprivation and inadequate upregulation of key lipid metabolism transcription factors. CLL T cells exhibited altered lipid storage, with increased triacylglycerols and decreased cholesterol, and inefficient fatty acid oxidation (FAO). Functional consequences of reduced FAO in T cells were studied using samples from patients with inherent FAO disorders. Reduced FAO was associated with lower T-cell activation but did not affect proliferation. This implicates low cholesterol levels as a primary factor limiting T-cell proliferation in CLL. CLL T cells displayed fewer and less clustered lipid rafts, potentially explaining the impaired immune synapse formation observed in these patients. Our findings highlight significant disruptions in lipid metabolism as drivers of functional deficiencies in CLL T cells, underscoring the pivotal role of cholesterol in T-cell proliferation. This study suggests that modulating cholesterol metabolism could enhance T-cell function in CLL, presenting novel immunotherapeutic approaches to improve outcome in this challenging disease.
Modulation of the human GlyT1 by clinical drugs and cholesterol
Glycine transporter 1 (GlyT1) is a key player in shaping extracellular glutamatergic signaling processes and holds promise for treating cognitive impairments associated with schizophrenia by inhibiting its activity and thus enhancing the function of NMDA receptors. Despite its significant role in physiological and pharmacology, its modulation mechanism by clinical drugs and internal lipids remains elusive. Here, we determine cryo-EM structures of GlyT1 in its apo state and in complex with clinical trial drugs iclepertin and sarcosine. The GlyT1 in its apo state is determined in three distinct conformations, exhibiting a conformational equilibrium of the transport cycle. The complex structures with inhibitor iclepertin and sarcosine elucidate their unique binding poses with GlyT1. Three binding sites of cholesterol are determined in GlyT1, two of which are conformation-dependent. Transport kinetics studies reveal that a delicate binding equilibrium for cholesterol is crucial for the conformational transition of GlyT1. This study significantly enhances our understanding of the physiological and pharmacological aspects of GlyT1.
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