Memory of obesity stored in adipocytes
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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.
Novel function of TREK-1 in regulating adipocyte differentiation and lipid accumulation
K2P (two-pore domain potassium) channels, a diversified class of K+-selective ion channels, have been found to affect a wide range of physiological processes in the body. Despite their established significance in regulating proliferation and differentiation in multiple cell types, K2P channels’ specific role in adipogenic differentiation (adipogenesis) remains poorly understood. In this study, we investigated the engagement of K2P channels, specifically KCNK2 (also known as TREK-1), in adipogenesis using primary cultured adipocytes and TREK-1 knockout (KO) mice. Our findings showed that TREK-1 expression in adipocytes decreases substantially during adipogenesis. This typically causes an increased Ca2+ influx and alters the electrical potential of the cell membrane in 3T3-L1 cell lines. Furthermore, we observed an increase in differentiation and lipid accumulation in both 3T3-L1 cell lines and primary cultured adipocytes when the TREK-1 activity was blocked with Spadin, the specific inhibitors, and TREK-1 shRNA. Finally, our findings revealed that mice lacking TREK-1 gained more fat mass and had worse glucose tolerance when fed a high-fat diet (HFD) compared to the wild-type controls. The findings demonstrate that increase of the membrane potential at adipocytes through the downregulation of TREK-1 can influence the progression of adipogenesis.
Neurotensin-neurotensin receptor 2 signaling in adipocytes suppresses food intake through regulating ceramide metabolism
Neurotensin (NTS) is a secretory peptide produced by lymphatic endothelial cells. Our previous study revealed that NTS suppressed the activity of brown adipose tissue via interactions with NTSR2. In the current study, we found that the depletion of Ntsr2 in white adipocytes upregulated food intake, while the local treatment of NTS suppressed food intake. Our mechanistic study revealed that suppression of NTS-NTSR2 signaling enhanced the phosphorylation of ceramide synthetase 2, increased the abundance of its products ceramides C20–C24, and downregulated the production of GDF15 in white adipose tissues, which was responsible for the elevation of food intake. We discovered a potential causal and positive correlation between serum C20–C24 ceramide levels and human food intake in four populations with different ages and ethnic backgrounds. Together, our study shows that NTS-NTSR2 signaling in white adipocytes can regulate food intake via its direct control of lipid metabolism and production of GDF15. The ceramides C20–C24 are key factors regulating food intake in mammals.
Error-driven upregulation of memory representations
Learning an association does not always succeed on the first attempt. Previous studies associated increased error signals in posterior medial frontal cortex with improved memory formation. However, the neurophysiological mechanisms that facilitate post-error learning remain poorly understood. To address this gap, participants performed a feedback-based association learning task and a 1-back localizer task. Increased hemodynamic responses in posterior medial frontal cortex were found for internal and external origins of memory error evidence, and during post-error encoding success as quantified by subsequent recall of face-associated memories. A localizer-based machine learning model displayed a network of cognitive control regions, including posterior medial frontal and dorsolateral prefrontal cortices, whose activity was related to face-processing evidence in the fusiform face area. Representation strength was higher during failed recall and increased during encoding when subsequent recall succeeded. These data enhance our understanding of the neurophysiological mechanisms of adaptive learning by linking the need for learning with increased processing of the relevant stimulus category.
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