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Sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b) is a lipid raft enzyme that regulates plasma membrane (PM) fluidity. Here we report that SMPDL3b excess, as observed in podocytes in diabetic kidney disease (DKD), impairs insulin receptor isoform B-dependent pro-survival insulin signaling by interfering with insulin receptor isoforms binding to caveolin-1 in the PM. SMPDL3b excess affects the production of active sphingolipids resulting in decreased ceramide-1-phosphate (C1P) content as observed in human podocytes in vitro and in kidney cortexes of diabetic db/db mice in vivo. Podocyte-specific Smpdl3b deficiency in db/db mice is sufficient to restore kidney cortex C1P content and to protect from DKD. Exogenous administration of C1P restores IR signaling in vitro and prevents established DKD progression in vivo. Taken together, we identify SMPDL3b as a modulator of insulin signaling and demonstrate that supplementation with exogenous C1P may represent a lipid therapeutic strategy to treat diabetic complications such as DKD. Sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b) is a lipid raft enzyme known to affect membrane lipid composition. Here, Mitrofanova et al. show that increased expression of SMPDL3b in diabetes impairs insulin signaling and ceramide-1-phosphate (C1P) availability in podocytes, and that C1P supplementation protects mice from diabetic kidney disease.

Hepatocytes secrete DPP4, which promotes adipose tissue inflammation and insulin resistance in obese mice, suggesting a new specific target for treatment of metabolic disorders. Liver enzyme DPP4 inflames fatty tissue in obese mice Previous studies have shown that liver secretory factors cause insulin resistance in muscle and impair the ability of pancreatic beta cells to secrete insulin. However, the role of hepatokines in promoting adipose pathobiology in obesity is not well understood. In this paper, Ira Tabas and colleagues show that obesity promotes the synthesis and secretion of hepatocyte dipeptidyl peptidase 4 (DPP4), which acts together with plasma factor Xa to inflame visceral adipose tissue macrophages. Silencing hepatocyte DPP4 improved metabolism in obese mice, suggesting that DPP4 may contribute to insulin resistance and systemic metabolic disease associated with obesity. Obesity-induced metabolic disease involves functional integration among several organs via circulating factors, but little is known about crosstalk between liver and visceral adipose tissue (VAT) 1 . In obesity, VAT becomes populated with inflammatory adipose tissue macrophages (ATMs) 2 , 3 . In obese humans, there is a close correlation between adipose tissue inflammation and insulin resistance 4 , 5 , and in obese mice, blocking systemic or ATM inflammation improves insulin sensitivity 6 , 7 , 8 . However, processes that promote pathological adipose tissue inflammation in obesity are incompletely understood. Here we show that obesity in mice stimulates hepatocytes to synthesize and secrete dipeptidyl peptidase 4 (DPP4), which acts with plasma factor Xa to inflame ATMs. Silencing expression of DPP4 in hepatocytes suppresses inflammation of VAT and insulin resistance; however, a similar effect is not seen with the orally administered DPP4 inhibitor sitagliptin. Inflammation and insulin resistance are also suppressed by silencing expression of caveolin-1 or PAR2 in ATMs; these proteins mediate the actions of DPP4 and factor Xa, respectively. Thus, hepatocyte DPP4 promotes VAT inflammation and insulin resistance in obesity, and targeting this pathway may have metabolic benefits that are distinct from those observed with oral DPP4 inhibitors.

Caveolin-1 (CAV1) is an oncogenic membrane protein associated with endocytosis, extracellular matrix organisation, cholesterol distribution, cell migration and signaling. Recent studies reveal that CAV1 is involved in metabolic alterations – a critical strategy adopted by cancer cells to their survival advantage. Consequently, research findings suggest that CAV1, which is altered in several cancer types, influences tumour development or progression by controlling metabolism. Understanding the molecular interplay between CAV1 and metabolism could help uncover druggable metabolic targets or pathways of clinical relevance in cancer therapy. Here we review from a cancer perspective, the findings that CAV1 modulates cell metabolism with a focus on glycolysis, mitochondrial bioenergetics, glutaminolysis, fatty acid metabolism, and autophagy.

Oligovascular coupling contributes to white matter vascular homeostasis. However, little is known about the effects of oligovascular interaction on oligodendrocyte precursor cell (OPC) changes in chronic cerebral ischemia. Here, using a mouse of bilateral carotid artery stenosis, we show a gradual accumulation of OPCs on vasculature with impaired oligodendrogenesis. Mechanistically, chronic ischemia induces a substantial loss of endothelial caveolin-1 (Cav-1), leading to vascular secretion of heat shock protein 90α (HSP90α). Endothelial-specific over-expression of Cav-1 or genetic knockdown of vascular HSP90α restores normal vascular-OPC interaction, promotes oligodendrogenesis and attenuates ischemic myelin damage. miR-3074(−1)−3p is identified as a direct inducer of Cav-1 reduction in mice and humans. Endothelial uptake of nanoparticle-antagomir improves myelin damage and cognitive deficits dependent on Cav-1. In summary, our findings demonstrate that vascular abnormality may compromise oligodendrogenesis and myelin regeneration through endothelial Cav-1, which may provide an intercellular mechanism in ischemic demyelination. OPC-vascular coupling contributes to myelin maintenance. Here the authors show Cav-1 stabilizes interactions and mediates OPC maturation in ischemia.

Cell migration during the invasion-metastasis cascade requires cancer cells to navigate a spatially complex microenvironment that presents directional choices to migrating cells. Here, we investigate cellular energetics during migration decision-making in confined spaces. Theoretical and experimental data show that energetic costs for migration through confined spaces are mediated by a balance between cell and matrix compliance as well as the degree of spatial confinement to direct decision-making. Energetic costs, driven by the cellular work needed to generate force for matrix displacement, increase with increasing cell stiffness, matrix stiffness, and degree of spatial confinement, limiting migration. By assessing energetic costs between possible migration paths, we can predict the probability of migration choice. Our findings indicate that motility in confined spaces imposes high energetic demands on migrating cells, and cells migrate in the direction of least confinement to minimize energetic costs. Therefore, therapeutically targeting metabolism may limit cancer cell migration and metastasis. Migrating cells tune their energy utilization in response to their microenvironment, but how cellular energetics direct navigation remains unclear. Here, the authors report that energetic costs for motility, regulated by cell mechanics and confinement, predict the probability of migration choice.

Despite their emerging relevance to fully understand disease pathogenesis, we have as yet a poor understanding as to how biomechanical signals are integrated with specific biochemical pathways to determine cell behaviour. Mesothelial-to-mesenchymal transition (MMT) markers colocalized with TGF-β1-dependent signaling and yes-associated protein (YAP) activation across biopsies from different pathologies exhibiting peritoneal fibrosis, supporting mechanotransduction as a central driving component of these class of fibrotic lesions and its crosstalk with specific signaling pathways. Transcriptome and proteome profiling of the response of mesothelial cells (MCs) to linear cyclic stretch revealed molecular changes compatible with bona fide MMT, which (i) overlapped with established YAP target gene subsets, and were largely dependent on endogenous TGF-β1 signaling. Importantly, TGF-β1 blockade blunts the transcriptional upregulation of these gene signatures, but not the mechanical activation and nuclear translocation of YAP per se. We studied the role therein of caveolin-1 (CAV1), a plasma membrane mechanotransducer. Exposure of CAV1-deficient MCs to cyclic stretch led to a robust upregulation of MMT-related gene programs, which was blunted upon TGF-β1 inhibition. Conversely, CAV1 depletion enhanced both TGF-β1 and TGFBRI expression, whereas its re-expression blunted mechanical stretching-induced MMT. CAV1 genetic deficiency exacerbated MMT and adhesion formation in an experimental murine model of peritoneal ischaemic buttons. Taken together, these results support that CAV1-YAP/TAZ fine-tune the fibrotic response through the modulation of MMT, onto which TGF-β1-dependent signaling coordinately converges. Our findings reveal a cooperation between biomechanical and biochemical signals in the triggering of MMT, representing a novel potential opportunity to intervene mechanically induced disorders coursing with peritoneal fibrosis, such as post-surgical adhesions.

In response to different types and intensities of mechanical force, cells modulate their physical properties and adapt their plasma membrane (PM). Caveolae are PM nano-invaginations that contribute to mechanoadaptation, buffering tension changes. However, whether core caveolar proteins contribute to PM tension accommodation independently from the caveolar assembly is unknown. Here we provide experimental and computational evidence supporting that caveolin-1 confers deformability and mechanoprotection independently from caveolae, through modulation of PM curvature. Freeze-fracture electron microscopy reveals that caveolin-1 stabilizes non-caveolar invaginations—dolines—capable of responding to low-medium mechanical forces, impacting downstream mechanotransduction and conferring mechanoprotection to cells devoid of caveolae. Upon cavin-1/PTRF binding, doline size is restricted and membrane buffering is limited to relatively high forces, capable of flattening caveolae. Thus, caveolae and dolines constitute two distinct albeit complementary components of a buffering system that allows cells to adapt efficiently to a broad range of mechanical stimuli. Lolo et al. show caveolin-1 functions in non-caveolae structures termed dolines. Whereas caveolae respond to high forces over a mechanical threshold, dolines transduce low and medium mechanical forces gradually in a complementary buffering system.

Focal adhesion (FA) assembly, mediated by integrin activation, responds to matrix stiffness; however, the underlying mechanisms are unclear. Here, we showed that β1 integrin and caveolin-1 (Cav1) levels were decreased with declining matrix stiffness. Soft matrix selectively downregulated β1 integrin by endocytosis and subsequent lysosomal degradation. Disruption of lipid rafts with methyl-β-cyclodextrin or nystatin, or knockdown of Cav1 by siRNA decreased cell spreading, FA assembly, and β1 integrin protein levels in cells cultured on stiff matrix. Overexpression of Cav1, particularly the phospho-mimetic mutant Cav1-Y14D, averted soft matrix-induced decreases in β1 integrin protein levels, cell spreading, and FA assembly in NMuMG cells. Interestingly, overexpression of an auto-clustering β1 integrin hindered soft matrix-induced reduction of Cav1 and cell spreading, which suggests a reciprocal regulation between β1 integrin and Cav1. Finally, co-expression of this auto-clustering β1 integrin and Cav1-Y14D synergistically enhanced cell spreading, and FA assembly in HEK293T cells cultured on either stiff ( > G Pa) or soft (0.2 kPa) matrices. Collectively, these results suggest that matrix stiffness governs the expression of β1 integrin and Cav1, which reciprocally control each other, and subsequently determine FA assembly and turnover.

Caveolin-1 (CAV1) is commonly considered to function as a cell surface protein, for instance in the genesis of caveolae. Nonetheless, it is also present in many intracellular organelles and compartments. The contributions of these intracellular pools to CAV1 function are generally less well understood, and this is also the case in the context of cancer. This review will summarize literature available on the role of CAV1 in cancer, highlighting particularly our understanding of the canonical (CAV1 in the plasma membrane) and non-canonical pathways (CAV1 in organelles and exosomes) linked to the dual role of the protein as a tumor suppressor and promoter of metastasis. With this in mind, we will focus on recently emerging concepts linking CAV1 function to the regulation of intracellular organelle communication within the same cell where CAV1 is expressed. However, we now know that CAV1 can be released from cells in exosomes and generate systemic effects. Thus, we will also elaborate on how CAV1 participates in intracellular communication between organelles as well as signaling between cells (non-canonical pathways) in cancer.

Postmenopausal osteoporosis is a prevalent metabolic bone disorder characterized by a decrease in bone mineral density and deterioration of bone microstructure. Despite the high prevalence of this disease, no effective treatment for osteoporosis has been developed. Exercise has long been considered a potent anabolic factor that promotes bone mass via upregulation of myokines secreted by skeletal muscle, exerting long‐term osteoprotective effects and few side effects. Irisin was recently identified as a novel myokine that is significantly upregulated by exercise and could increase bone mass. However, the mechanisms underlying exercise‐induced muscle‐bone crosstalk remain unclear. Here, we identified that polyunsaturated fatty acids (arachidonic acid and docosahexaenoic acid) are increased in skeletal muscles following a 10‐week treadmill exercise programme, which then promotes the expression and release of FNDC5/irisin. In osteoblasts, irisin binds directly to Cav1, which recruits and interacts with AMP‐activated protein kinase α (AMPKα) to activate the AMPK pathway. Nrf2 is the downstream target of the AMPK pathway and increases the transcription of HMOX1 and Fpn. HMOX1 is involved in regulating the cell cycle and promotes the proliferation of osteoblasts. Moreover, upregulation of Fpn in osteoblasts enhanced iron removal, thereby suppressing ferroptosis in osteoblasts. Additionally, we confirmed that myotube‐derived exosomes are involved in the transportation of irisin and enter osteoblasts through caveolae‐mediated endocytosis. In conclusion, our findings highlight the crucial role of irisin, present in myotube‐derived exosomes, as a crucial regulator of exercise‐induced protective effects on bone, which provides novel insights into the mechanisms underlying exercise‐dependent treatment of osteoporosis. Exercise increases levels of arachidonic acid (AA) and DHA in skeletal muscle, promoting the expression and release of FNDC5/irisin via PGC1α. FNDC5/Irisin traffics to osteoblasts via exosomes and enters osteoblasts through caveolae‐mediated endocytosis dependent on Cav1. FNDC5/irisin then interacts with Cav1, which recruits AMPKα to activate the AMPK pathway. Nrf2 is thereby increased and promotes the transcription of HMOX1 and Fpn, resulting in increased proliferation and decreased ferroptosis of osteoblasts.