Anouk Charlot

Male adipose tissue undergoes profound post-pubertal remodeling characterized by the progressive transition of beige adipocytes toward a white adipocyte phenotype. Although androgen signaling has been implicated in adipose tissue biology, its role in beige adipocyte remodeling and metabolic plasticity remains poorly understood. Here we show that androgen receptor (AR) signaling is dynamically activated in inguinal white adipose tissue during the post-pubertal beige-to-white transition in male mice. Inducible deletion of AR in beige adipocytes impaired this remodeling process, resulting in the persistence of multilocular beige-like adipocytes despite reduced thermogenic competence and marked mitochondrial abnormalities. Transcriptomic and cistromic analyses identified AR as a direct regulator of adipocyte metabolic and differentiation programs, whereas immune-related transcriptional signatures in AR-deficient adipose tissue primarily reflected macrophage infiltration and inflammatory remodeling. Loss of AR promoted mitochondrial dysfunction, mitophagy, and altered glucose handling, while cell-autonomous AR silencing in beige adipocytes recapitulated key defects in mitochondrial organization and adipocyte identity. Longitudinal and metabolic challenge studies further demonstrated that AR signaling is required for age-associated adipose remodeling and adaptive beige adipocyte plasticity during high-fat diet feeding and cold exposure. Together, these findings identify AR as a central regulator of beige adipocyte remodeling, mitochondrial homeostasis, and adaptive metabolic function in male adipose tissue.

Cancer cells require large quantities of glucose to ensure sufficient ATP production through glycolysis, and the liver may facilitate this glucose supply. A high-fat low-carbohydrate ketogenic diet (KD) could represent a strategy to reduce tumor growth. However, the molecular effects of carbohydrate restriction mediated by the KD and its hepatic impact remain poorly understood. To address this question, 6-week-old FVB/N-Tg(MMTV-PyVT)634Mul/J mice, which develop spontaneous mammary tumors, were fed a standard chow diet (SD group) or a KD diet (KD group) until reaching the age of 12 weeks. The effects of carbohydrate restriction were assessed by plasma analyses, as well as histological staining, RT-qPCR and Western Blotting in tumors and liver. We found that carbohydrate restriction reduced tumor growth by 46% and was associated with decreased expression of pro-tumorigenic factors ( Ang2, Hgf, Mki67). Moreover, a decrease of metabolic enzymes ( Pfk, Bdh1, Scot1) highlighted the lack of metabolic flexibility of the tumor cells and underscored their strong dependency on glucose. Conversely, the liver exhibited a strong adaptive response with enhanced ketogenesis and gluconeogenesis, evidenced by elevated blood glucose and upregulation of Pepck, Foxo1, and CREB. A high-fat, low-carbohydrate diet exerts a dual metabolic effect: it suppresses tumor progression through local metabolic reprogramming but simultaneously enhances hepatic glucose production. This highlights the pivotal role of systemic glucose availability in tumorigenesis and underscores the need to consider liver metabolism when designing dietary interventions for cancer therapy.

L’obésité et le cancer sont les principales causes de mortalité dans le monde, et l’augmentation de leur prévalence est liée, en partie, à notre mode de vie. Cependant, le rôle joué par l’alimentation dans leur physiopathologie ainsi que dans leur prise en charge reste un sujet de débat. Dans un modèle murin d’obésité, nous avons montré qu’un régime riche en glucides et en lipides induit le développement de complications liées à l’obésité alors qu’un régime cétogène (KD), riche en lipides et pauvre en glucides, prévient leur apparition malgré un apport calorique similaire. Dans un modèle murin de cancer mammaire spontané, nos travaux démontrent que le développement tumoral induit des adaptations hépatiques avec l’activation des voies endogènes de fabrication de glucose. Supprimer l’apport en glucose via le KD réduit la croissance tumorale, mais et exacerbe l’activation de la néoglucogenèse hépatique. Nos travaux mettent en avant le rôle central du sucre et des glucides dans la physiopathologie de l’obésité et du cancer du sein, et indiquent que le régime KD, via sa restriction en glucides, est une approche thérapeutique intéressante dans leur prise en charge.

Treatment options for advanced liver disease and hepatocellular carcinoma (HCC) are limited, and strategies to prevent HCC development are lacking. Aiming to discover therapeutic targets, we combined genome-wide transcriptomic analysis of liver tissues from patients with advanced liver disease and HCC and a cell-based system predicting liver disease progression and HCC risk. Computational analysis predicted peroxiredoxin 2 ( PRDX2 ) as a candidate gene mediating hepatocarcinogenesis and HCC risk. Analysis of tissues from patients with HCC confirmed a perturbed expression of PRDX2 in cancer. In vivo perturbation studies in mouse models for hepatocarcinogenesis driven by metabolic dysfunction–associated steatohepatitis showed that specific Prdx2 KO in hepatocytes improved metabolic liver functions, restored AMPK activity, and prevented HCC development by suppressing oncogenic signaling. Perturbation studies in HCC cell lines, a cell line–derived xenograft mouse model, and patient-derived HCC spheroids revealed that PRDX2 also mediates cancer initiation, cancer cell proliferation, and survival through its antioxidant activity. Targeting PRDX2 may therefore be a strategy to prevent HCC development in metabolic liver disease.

This work demonstrates that the spontaneous development of non-metastatic mammary tumors triggers hepatic activation of endogenous glucose production pathways, coinciding with the onset of insulin resistance. This finding suggests a significant cross talk between tumors and the liver during tumorigenesis, aiming at enhancing glucose production to meet the elevated energy demands of the tumor. Understanding this interaction could provide insights into metabolic alterations associated with cancer and lead to potential therapeutic targets to inhibit tumor metabolism.

Weight cycling is a major challenge in obesity management. Caloric restriction is known to promote this phenomenon, but the impact of macronutrient changes during dieting remains unclear. This study aimed to determine the role of macronutrient changes in weight maintenance without caloric restriction by alternating between two hypercaloric diets: a high-carbohydrate, high-fat Western diet (WD) and a low-carbohydrate, high-fat diet (LCHDF). Obesity was induced in 8-week-old C57BL/6 male mice by 10 weeks of WD feeding. Then, the mice were subjected to 12 weeks of LCHFD interspersed with WD (I-WD), 3 periods of 2-week LCHFD followed by 2 periods of 3-week WD, or 12 weeks of continuous WD (C-WD). C-WD and I-WD mice were compared to standard diet (SD) mice. In the I-WD group, each LCHFD period decreased weight gain, but mice regained weight after WD resumption. I-WD mice exhibited obesity, dyslipidemia, and glucose intolerance, similarly to the C-WD mice. I-WD mice also developed nonalcoholic steatohepatitis, associated with an increase in type-III collagen gene expression and a decrease in FGF21 protein levels, in comparison with SD. I-WD mice developed weight cycling despite maintaining a high caloric consumption, suggesting that changes in macronutrients during dieting are also a trigger of weight regain.

La maladie d’Alzheimer (MA), pathologie neurodégénérative en expansion, devient une préoccupation importante de santé publique, en raison d’une absence de traitement curatif efficace. Les mécanismes mis en œuvre dans la physiopathologie de la MA sont de mieux en mieux connus, et incluent l’accumulation de plaques amyloïdes et de dégénérescences neurofibrillaires. L’augmentation de l’inflammation et du stress oxydant et l’altération du métabolisme cérébral du glucose aggravent la pathologie en réduisant l’activité neuronale en perturbant la fonction mitochondriale. À l’heure actuelle, le traitement de cette pathologie regroupe différentes approches bien que ces interventions n’aient pas un effet curatif, mais uniquement compensatoire. L’alimentation cétogène, pauvre en glucides et enrichie en lipides, couplée à une prise de triglycérides à chaîne moyenne (MCT), favorise la production de corps cétoniques, substrats énergétiques qui pourraient présenter des effets neuroprotecteurs bénéfiques pour les personnes atteintes de la MA. Une telle prise en charge nutritionnelle pourrait limiter la progression de la maladie et améliorer les capacités cognitives des patients. Cette revue vise à examiner le rôle éventuel et les mécanismes neuroprotecteurs de l’alimentation cétogène dans la progression de la MA, et décrit les avantages et les limites de son utilisation comme stratégie thérapeutique. Alzheimer’s disease (AD) is a neurodegenerative disease that affects almost 1 million people in France and 55 million in the world. This pathology is a global health preoccupation because of the lack of efficient curative treatment and the increase of its prevalence. During the last decade, the comprehension of pathophysiological mechanisms involved in AD have been improved. Amyloid plaques and neurofibrillary tangles accumulation are characteristic of Alzheimer’s brain patients, accompanied by increased brain inflammation and oxidative stress, impaired cerebral metabolism of glucose and mitochondrial function. Treatment of AD includes different approaches, as pharmacology, psychology support, physiotherapy, and speech therapy. However, these interventions do not have a curative effect, but only compensatory on the disease. Ketogenic diet (KD), a low-carbohydrates and high-fat diet, associated with a medium-chain triglycerides intake (MCTs) might induce benefices for Alzheimer disease patients. Carbohydrate restriction and MCTs promotes the production of ketone bodies from fatty acid degradation. These metabolites replacing glucose, serve the brain as energetic substrates, and induce neuroprotective effects. Such a nutritional support might slow down the disease progression and improve cognitive abilities of patients. This review aims to examine the neuroprotective mechanisms of KD in AD progression and describes the advantages and limitations of KD as a therapeutic strategy.

Chemotherapy is a common therapy to treat patients with breast cancer but also leads to skeletal muscle deconditioning. Skeletal muscle deconditioning is multifactorial and intermuscular adipose tissue (IMAT) accumulation is closely linked to muscle dysfunction. To date, there is no clinical study available investigating IMAT development through a longitudinal protocol and the underlying mechanisms remain unknown. Our study was dedicated to investigating IMAT content in patients with early breast cancer who were treated with chemotherapy and exploring the subsequent cellular mechanisms involved in its development. We included 13 women undergoing chemotherapy. Muscle biopsies and ultrasonography assessment were performed before and after chemotherapy completion. Histological and Western blotting analyses were conducted. We found a substantial increase in protein levels of three mature adipocyte markers (perilipin, +901%; adiponectin, +135%; FABP4, +321%; P < 0.05). These results were supported by an increase in oil red O-positive staining (+358%; P < 0.05). A substantial increase in PDGFRα protein levels was observed (+476%; P < 0.05) highlighting an increase in fibro-adipogenic progenitors (FAPs) content. The cross-sectional area of the vastus lateralis muscle fibers substantially decreased (−21%; P < 0.01), and muscle architecture was altered, as shown by a decrease in fascicle length (−15%; P < 0.05) and a decreasing trend in muscle thickness (−8%; P = 0.08). We demonstrated both IMAT development and muscle atrophy in patients with breast cancer who were treated with chemotherapy. FAPs, critical stem cells inducing both IMAT development and skeletal muscle atrophy, also increased, suggesting that FAPs likely play a critical role in the skeletal muscle deconditioning observed in patients with breast cancer who were treated with chemotherapy.

Background: Medium Chain Fatty Acids (MCFAs) are a dietary supplement that exhibit interesting properties, due to their smaller molecular size. The acute consumption of MCFAs is expected to enhance exercise performance. However, the short-term effects of MCFAs on endurance performance remains poorly understood. The aim of our study is to evaluate the octanoic acid (C8)-rich diet effect on endurance capacity, and to explore their molecular and cellular effects. Methods: C57BL/6J mice were fed with a chow diet (Control group) or an octanoic acid-rich diet (C8 diet) for 6 weeks. Spontaneous activity, submaximal and maximal exercise tests were carried out to characterize the exercise capacities of the mice. Beta-oxidation and mitochondrial biogenesis pathways were explored in skeletal muscle by RT-qPCR, Western Blot (Quadriceps) and histochemical staining (Gastrocnemius). Results: Mice fed with a C8-rich diet presented a higher spontaneous activity (p < 0.05) and endurance capacities (p < 0.05) than the control, but no effect on maximal effort was observed. They also presented changes in the skeletal muscle metabolic phenotype, with a higher number of the oxidative fibers, rich in mitochondria. At the molecular level, the C8-diet induced an AMPK activation (p < 0.05), associated with a significant increase in PGC1a and CS gene expression and protein levels. Conclusion: Our study provided evidence that C8-enrichment as a food supplementation improves endurance capacities and activates mitochondrial biogenesis pathways leading to higher skeletal muscle oxidative capacities.

Metabolic syndrome (MetS) is a major societal concern due to its increasing prevalence and its high risk of cardiovascular complications. The ketogenic diet (KD), a high fat, low carbohydrate, and non-caloric restrictive diet, is a new popular weight loss intervention but its beneficial effects are controversial. This study aims to gather all of the relevant studies using KD for metabolic disease treatment to determine its beneficial effects and evaluate its safety and efficacy for patients. Following the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, we included 20 articles in the final review. Overall, most of the studies showed a significant effect of KD on weight loss (17/19 articles), BMI (7/7), glucose levels (9/13), insulin levels (7/9), HOMA-IR (4/5), HbA1c (7/7), total cholesterol (6/9), TG (13/15), AST (3/4), and ALT (3/5), and no major side effects. The results heterogeneity seems to be explained by a difference of diet composition and duration. In conclusion, KD is a safety diet which seems to be a promising approach for obesity and MetS treatment, even if the optimal carbohydrate proportion and diet duration must be explored to enhance the beneficial effects of KD.