Cellular plasticity is a transformation of a terminally differentiated cell into another cell type, which has been long known to occur in disease and regeneration. However, white adipocytes (fat cells) have only recently been observed to undergo different types of cellular plasticity. Adipocyte transdifferentiation into myofibroblasts and cancer-associated fibroblasts occurs in fibrosis and cancer, respectively. On the other hand, reversible adipocyte dedifferentiation into adipocyte progenitor cells (preadipocytes) has been demonstrated in mammary gland and in dermal adipose tissue. Here we discuss the research on adipocyte plasticity, including the experimental approaches that allowed to detect and study it, the current state of the knowledge, major research questions which remain to be addressed, and the advances required to stimulate adipocyte plasticity research. In the future, the knowledge of the molecular mechanisms of adipocyte plasticity can be utilized both to prevent adipocyte plasticity in disease and to stimulate it for use in regenerative medicine.

High cholesterol levels are associated with an increased risk of cardiovascular disease, specifically atherosclerosis, a leading cause of death worldwide. Atherosclerosis occurs when cholesterol and fat build up in plaques along blood vessel walls, restricting blood flow and preventing nutrients and oxygen from diffusing in and out of the bloodstream. High-density lipoprotein cholesterol (HDL) particles prevent the build-up of such plaques, removing excess cholesterol from the peripheral tissues and delivering it to the liver, where it can be removed from the body. This pathway is known as reverse cholesterol transport (RCT). Because HDL plays a key role in preventing plaque buildup, understanding how this molecule and RCT function in the body could help us develop much-needed new atherosclerosis therapies and prevention strategies. However, HDL metabolism is complex, and research on HDL has been less favoured than research investigating a much better-understood molecule, low-density lipoprotein cholesterol, as a treatment target. More specifically, the receptors involved in the process of taking up HDL within the liver and their relationships to one another, along with the mechanism of whole, or holoparticle uptake of HDL remain to be clarified. In this review, we discuss several outstanding mysteries in HDL metabolism, consider why previous clinical trials to improve cardiovascular health by modulating HDL levels have been unsuccessful and argue that understanding HDL metabolism is essential for crafting interventions to reduce cardiovascular disease risk.

The secreted protein isthmin-1 (Ism1) mitigates diabetes by increasing adipocyte and skeletal muscle glucose uptake by activating the PI3K-Akt pathway. However, while both Ism1 and insulin converge on these common targets, Ism1 has distinct cellular actions suggesting divergence in downstream intracellular signaling pathways. To understand the biological complexity of Ism1 signaling, we performed phosphoproteomic analysis after acute exposure, revealing overlapping and distinct pathways of Ism1 and insulin. We identify a 53% overlap between Ism1 and insulin signaling and Ism1-mediated phosphoproteome-wide alterations in ~450 proteins that are not shared with insulin. Interestingly, we find several unknown phosphorylation sites on proteins related to protein translation, mTOR pathway, and, unexpectedly, muscle function in the Ism1 signaling network. Physiologically, Ism1 ablation in mice results in altered proteostasis, including lower muscle protein levels under fed and fasted conditions, reduced amino acid incorporation into proteins, and reduced phosphorylation of the key protein synthesis effectors Akt and downstream mTORC1 targets. As metabolic disorders such as diabetes are associated with accelerated loss of skeletal muscle protein content, these studies define a non-canonical mechanism by which this antidiabetic circulating protein controls muscle biology.

Background and Aims: Metabolic dysfunction–associated fatty liver disease (MASLD) is the most prevalent chronic liver pathology in western countries, with serious public health consequences. Efforts to identify causal genes for MASLD have been hampered by the relative paucity of human data from gold standard magnetic resonance quantification of hepatic fat. To overcome insufficient sample size, genome-wide association studies using MASLD surrogate phenotypes have been used, but only a small number of loci have been identified to date. In this study, we combined genome-wide association studies of MASLD composite surrogate phenotypes with genetic colocalization studies followed by functional in vitro screens to identify bona fide causal genes for MASLD. Approach and Results: We used the UK Biobank to explore the associations of our novel MASLD score, and genetic colocalization to prioritize putative causal genes for in vitro validation. We created a functional genomic framework to study MASLD genes in vitro using CRISPRi. Our data identify VKORC1, TNKS, LYPLAL1, and GPAM as regulators of lipid accumulation in hepatocytes and suggest the involvement of VKORC1 in the lipid storage related to the development of MASLD. Conclusions: Complementary genetic and genomic approaches are useful for the identification of MASLD genes. Our data supports VKORC1 as a bona fide MASLD gene. We have established a functional genomic framework to study at scale putative novel MASLD genes from human genetic association studies.

Human genetics has been instrumental in identification of genetic variants linked to type 2 diabetes. Recently a rare, putative loss-of-function mutation in the orphan G-protein coupled receptor 151 (GPR151) was found to be associated with lower odds ratio for type 2 diabetes, but the mechanism behind this association has remained elusive. Here we show that Gpr151 is a fasting- and glucagon-responsive hepatic gene which regulates hepatic gluconeogenesis. Gpr151 ablation in mice leads to suppression of hepatic gluconeogenesis genes and reduced hepatic glucose production in response to pyruvate. Importantly, the restoration of hepatic Gpr151 levels in the Gpr151 knockout mice reverses the reduced hepatic glucose production. In this work, we establish a previously unknown role of Gpr151 in the liver that provides an explanation to the lowered type 2 diabetes risk in individuals with nonsynonymous mutations in GPR151.

Adipogenesis is a process in which fat-specific progenitor cells (preadipocytes) differentiate into adipocytes that carry out the key metabolic functions of the adipose tissue, including glucose uptake, energy storage, and adipokine secretion. Several cell lines are routinely used to study the molecular regulation of adipogenesis, in particular the immortalized mouse 3T3-L1 line and the primary human Simpson-Golabi-Behmel syndrome (SGBS) line. However, the cell-to-cell variability of transcriptional changes prior to and during adipogenesis in these models is not well understood. Here, we present a single-cell RNA-Sequencing (scRNA-Seq) dataset collected before and during adipogenic differentiation of 3T3-L1 and SGBS cells. To minimize the effects of experimental variation, we mixed 3T3-L1 and SGBS cells and used computational analysis to demultiplex transcriptomes of mouse and human cells. In both models, adipogenesis results in the appearance of three cell clusters, corresponding to preadipocytes, early and mature adipocytes. These data provide a groundwork for comparative studies on these widely used in vitro models of human and mouse adipogenesis, and on cell-to-cell variability during this process.