Biology subjects

Valet, P.

Publications and source records attributed to Valet, P..

7 recordsLinked to original sources

bioRxiv2025

Red bone marrow hosts metabolically active anucleate adipocytes that support hematopoiesis

Bone marrow adipocytes (BMAds) are a major component of the bone marrow (BM) that regulate bone turnover and hematopoiesis. In rodents, two distinct adipocyte populations exist: constitutive BMAds (cBMAds), located in areas devoid of hematopoietic cells and resistant to metabolic cues, and regulatory BMAds (rBMAds), interspersed within hematopoietic niches and responsive to energy stress. Despite their potential importance, rBMAds have remained poorly characterized due to their scarcity in rodents. Here, we used a high-yield method to isolate human rBMAds, enabling structural, proteomic, lipidomic, and functional analyses. Remarkably, human rBMAds are anucleate yet retain organelles and maintain lipid and glucose metabolism, but unlike their rodent counterparts, they lack lipolytic activity. They actively secrete factors that support hematopoiesis in vitro, implicating them as functional contributors to the BM niche. These findings suggest that human rBMAds may arise from cBMAds through terminal differentiation and define a novel adipocyte subtype critical for BM homeostasis.

cell biology↗

bioRxiv2023

Apelin-VEGF-C mRNA delivery as therapeutic for the treatment of secondary lymphedema

Secondary lymphedema (LD) corresponds to a severe lymphatic dysfunction leading to the accumulation of fluid and fibrotic adipose tissue in a limb. Here, we identified apelin (APLN) as a powerful molecule for regenerating lymphatic function in LD. We identified the loss of APLN expression in lymphedematous arm compared to normal arm in patients. The role of APLN in LD was confirmed in APLN-knockout mice, in which LD is increased and associated with fibrosis and dermal backflow. This was reversed by intradermal injection of APLN-lentivectors. Mechanistically, APLN stimulates lymphatic endothelial cell gene expression and induces the binding of E2F8 transcription factor to the promoter of CCBE1 that controls VEGF-C processing. In addition, APLN induces Akt and eNOS pathways to stimulate lymphatic collector pumping. Our results show that APLN represents a novel partner for VEGF-C to restore lymphatic function in both initial and collecting vessels. As LD appears after cancer treatment, we validated the APLN-VEGF-C combination using a novel class of safe and non-integrative RNA-delivery LentiFlash(R) vector that will be evaluated for phase I/IIa clinical trial.

pathology↗

bioRxiv2023

Collagen remodeling leads to inflammation-free expansion of periprostatic adipose tissue and promotes prostate cancer progression

One of the most striking features of the adipose depot surrounding the prostate (periprostatic adipose tissue, PPAT) is that its accumulation is independent of body mass index. Its volume varies considerably between individual with some patients exhibiting abundant PPATs that have been correlated to occurrence of aggressive prostate cancer (PCa). However, abundant PPAT are not defined at biological levels. We used a new statistical approach to define abundant PPAT by normalizing PPAT volume to prostate volume in a cohort of 351 patients with a linear regression model. Applying this definition, we confirmed the link between abundant PPAT and PCa aggressiveness, therefore validating our approach. At biological levels, we showed that abundant PPAT exhibited extensive extracellular matrix remodeling, notably of the collagen network, decreasing the mechanical constraints in hypertrophic adipocytes leading to an inflammation free-expansion. Degradation of the most abundant collagen in AT, collagen VI was associated with increased production of endotrophin, a signaling peptide derived from AT, that was also elevated in the urine of patients with abundant PPAT confirming the clinical relevance of our results. These results highlight a unique mechanism of expansion of an adipose depot and open new mechanistic avenues to explain its role in prostate-related disorders.

cancer biology↗

bioRxiv2021

Nuclear HMGB1 protects from non-alcoholic fatty liver diseases through negative regulation of liver X receptor

Dysregulations of lipid metabolism in the liver may trigger steatosis progression leading to potentially severe clinical consequences such as non-alcoholic fatty liver diseases (NAFLD). Molecular mechanisms underlying liver lipogenesis are very complex and fine-tuned by chromatin dynamics and the activity of multiple key transcription factors. Here, we demonstrate that the nuclear factor HMGB1 acts as a strong repressor of liver lipogenesis during metabolic stress in NAFLD. Mice with liver-specific Hmgb1-deficiency display exacerbated liver steatosis and hepatic insulin resistance when subjected to a high-fat diet or after fasting/refeeding. Global transcriptome and functional analysis revealed that the deletion of Hmgb1 gene enhances LXR activity resulting in increased lipogenesis. HMGB1 repression is not mediated through nucleosome landscape re-organization but rather via a preferential DNA occupation in region carrying genes regulated by LXR. Together these findings suggest that hepatocellular HMGB1 protects from liver steatosis development. HMGB1 may constitute a new attractive option to therapeutically target LXR axis during NAFLD.

pathology↗

bioRxiv2020

Antibody-based delivery of Interleukin-9 to neovascular structures: therapeutic evaluation in cancer and arthritis

Interleukin-9 (IL9) is a cytokine with multiple functions, including the ability to activate group 2 innate lymphoid cells (ILC2s), which has been postulated to be therapeutically active in mouse models of arthritis. Similarly, IL9 has been suggested to play an important role in tumor immunity. Here, we describe the cloning, expression and characterization of three fusion proteins based on murine IL9 and the F8 antibody, specific to the alternatively-spliced EDA domain of fibronectin. EDA is strongly expressed in cancer and in various arthritic conditions, while being undetectable in the majority of healthy organs. IL9-based fusion proteins with an irrelevant antibody specific to hen egg lysozyme served as negative control in our study. The fusion proteins were characterized by quantitative biodistribution analysis in tumor-bearing mice using radioiodinated protein preparations. The highest tumor uptake and best tumor:organ ratios were observed for a format, in which the IL9 moiety was flanked by two units of the F8 antibody in single-chain Fv format. Biological activity of IL9 was retained when the payload was fused to antibodies. However, the targeted delivery of IL9 to the disease site resulted in a modest anti-tumor activity in three different murine models of cancer (K1735M2, CT26 and F9), while no therapeutic benefit was observed in a collagen induced model of arthritis. Collectively, these results confirm the possibility to deliver IL9 to the site of disease but cast doubts about the alleged therapeutic activity of this cytokine in cancer and arthritis, which has been postulated in previous publications.

bioengineering↗

bioRxiv2019

Adipocyte vesicles: ‘all-in-one’ packages that stimulate tumor mitochondrial metabolism and dynamics

Extracellular vesicles are emerging key actors in adipocyte communication. Notably, small extracellular vesicles shed by adipocytes promote melanoma aggressiveness through fatty acid oxidation, with a heightened effect in obesity. However, the vesicular actors and cellular processes involved remain largely unknown. Here, we elucidate the mechanisms linking adipocyte extracellular vesicles to metabolic remodeling and cell migration. We show that adipocyte vesicles stimulate melanoma fatty acid oxidation by providing both enzymes and substrates. In obesity, the heightened effect of extracellular vesicles depends on increased transport of fatty acids, not fatty acid oxidation-related enzymes. These fatty acids, stored within lipid droplets in cancer cells, drive fatty acid oxidation after release through lipophagy. This increase in mitochondrial activity redistributes mitochondria to membrane protrusions of migrating cells, which is necessary to increase cell migration in the presence of adipocyte vesicles. Our results provide key insights into the role of extracellular vesicles in the metabolic cooperation that takes place between adipocytes and tumors with particular relevance in obesity.

cancer biology↗

bioRxiv2019

Yellow adipocytes comprise a new adipocyte sub-type present in human bone marrow

During energy demanding conditions, white adipocytes store triglycerides and release fatty acids through lipolysis. In contrast, bone marrow adipocytes (BM-Ad) increase in size during caloric restriction, suggesting this fat depot exhibits precise metabolic specificity. We found subcutaneous adipocytes (SC-Ad) and BM-Ad share morphological features, but possess distinct lipid metabolism. BM-Ad show enrichment in cholesterol-oriented metabolism that correlates with increased free cholesterol content, while proteins involved in lipolysis were downregulated. A strong down-regulation in expression of monoacylglycerol (MG) lipase was observed leading to an accumulation of major MG species and accordingly the basal and induced lipolytic responses were absent in BM-Ad. These features are not recapitulated in vitro using differentiated bone marrow mesenchymal stem cells. Since our data demonstrate that BM-Ad comprise a distinct class of adipocytes, we propose renaming them yellow adipocytes.

physiology↗