Lactate fluxes mediated by the monocarboxylate transporter-1 are key determinants of the metabolic activity of beige adipocytes.

Activation of energy-dissipating brown/beige adipocytes represents an attractive therapeutic strategy against metabolic disorders. While lactate is known to induce beiging through the regulation of Ucp1 gene expression, the role of lactate transporters on beige adipocytes' ongoing metabolic activity remains poorly understood. To explore the function of the lactate-transporting monocarboxylate transporters (MCTs), we used a combination of primary cell culture studies, 13C isotopic tracing, laser microdissection experiments, and in situ immunofluorescence of murine adipose fat pads. Dissecting white adipose tissue heterogeneity revealed that the MCT1 is expressed in inducible beige adipocytes as the emergence of uncoupling protein 1 after cold exposure was restricted to a subpopulation of MCT1-expressing adipocytes suggesting MCT1 as a marker of inducible beige adipocytes. We also observed that MCT1 mediates bidirectional and simultaneous inward and outward lactate fluxes, which were required for efficient utilization of glucose by beige adipocytes activated by the canonical ß3-adrenergic signaling pathway. Finally, we demonstrated that significant lactate import through MCT1 occurs even when glucose is not limiting, which feeds the oxidative metabolism of beige adipocytes. These data highlight the key role of lactate fluxes in finely tuning the metabolic activity of beige adipocytes according to extracellular metabolic conditions and reinforce the emerging role of lactate metabolism in the control of energy homeostasis.

Lactate induces FGF21 expression in adipocytes through a p38-MAPK pathway.

FGF21 (fibroblast growth factor 21), first described as a main fasting-responsive molecule in the liver, has been shown to act as a true metabolic regulator in additional tissues, including muscle and adipose tissues. In the present study, we found that the expression and secretion of FGF21 was very rapidly increased following lactate exposure in adipocytes. Using different pharmacological and knockout mice models, we demonstrated that lactate regulates Fgf21 expression through a NADH/NAD-independent pathway, but requires active p38-MAPK (mitogen activated protein kinase) signalling. We also demonstrated that this effect is not restricted to lactate as additional metabolites including pyruvate and ketone bodies also activated the FGF21 stress response. FGF21 release by adipose cells in response to an excess of intermediate metabolites may represent a physiological mechanism by which the sensing of environmental metabolic conditions results in the release of FGF21 to improve metabolic adaptations.

Weak neuronal glycolysis sustains cognition and organismal fitness.

The energy cost of neuronal activity is mainly sustained by glucose1,2. However, in an apparent paradox, neurons modestly metabolize glucose through glycolysis3-6, a circumstance that can be accounted for by the constant degradation of 6-phosphofructo-2-kinase-fructose-2,6-bisphosphatase-3 (PFKFB3)3,7,8, a key glycolysis-promoting enzyme. To evaluate the in vivo physiological importance of this hypoglycolytic metabolism, here we genetically engineered mice with their neurons transformed into active glycolytic cells through Pfkfb3 expression. In vivo molecular, biochemical and metabolic flux analyses of these neurons revealed an accumulation of anomalous mitochondria, complex I disassembly, bioenergetic deficiency and mitochondrial redox stress. Notably, glycolysis-mediated nicotinamide adenine dinucleotide (NAD+) reduction impaired sirtuin-dependent autophagy. Furthermore, these mice displayed cognitive decline and a metabolic syndrome that was mimicked by confining Pfkfb3 expression to hypothalamic neurons. Neuron-specific genetic ablation of mitochondrial redox stress or brain NAD+ restoration corrected these behavioural alterations. Thus, the weak glycolytic nature of neurons is required to sustain higher-order organismal functions.

[Recruitment and activation of brown and/or BRITE adipocytes : potential therapeutic against metabolic diseases]. / Le recrutement et l'activation d'adipocytes bruns et/ou BRITE - Une perspective réelle pour le traitement des maladies métaboliques ?

In mammals, typically two types of adipose tissues are described: the white and the brown adipose tissue (WAT and BAT respectively). Whereas WAT represents the main energy storage in the organism, BAT dissipates energy as heat through the expression of the uncoupling protein UCP1 (uncoupling protein-1) that uncouples the functioning of the respiratory chain from ATP synthase. While both white and brown adipocytes have been considered for a long time as two very close cellular types sharing a common precursor, recent data challenge these conclusions and propose the existence of a new possible type of adipocyte, the BRITE (brown-in-white) adipocyte. In parallel, the recent discovery of significant amounts of BAT in human adults has renewed the interest of the scientific community for this tissue. Given its considerable capacity to dissipate substrates, BAT appears again as a therapeutic target against metabolic diseases such as diabetes and obesity. This review's objective is to discuss recent literature and to highlight elements to be clarified.

Periostin Plasma Levels and Changes on Physical and Cognitive Capacities in Community-Dwelling Older Adults.

Periostin, involved in extracellular matrix development and support, has been shown to be elevated in senescent tissues and fibrotic states, transversal signatures of aging. We aimed to explore associations between plasma periostin and physical and cognitive capacity evolution among older adults. Our hypothesis was that higher levels of plasma periostin will be associated with worse physical and mental capacities along time. Analyses included 1 096 participants (mean age = 75.3 years ± 4.4; 63.9% women) from the Multidomain Alzheimer Preventive Trial. Periostin levels (pg/mL) were measured in plasma collected at year 1. Periostin was used in continuous variable, and as a dichotomous variable highest quartile (POSTN+) versus lowest 3 quartiles (POSTN-) were used. Outcomes were measured annually over 4 years and included: gait speed (GS), short physical performance battery (SPPB) score, 5-times sit-to-stand test (5-STS), and handgrip strength (HS) as physical and cognitive composite z-score (CCS) and the Mini-Mental State Examination (MMSE) as cognitive endpoints. Plasma periostin as a continuous variable was associated with the worsening of physical and cognitive capacities over 4 years of follow-up, specifically the SPPB score, the 5-STS, and CCS in full-adjusted models. POSTN+ was associated with worse evolution in the physical (GS: [ß = -0.057, 95% confidence interval (CI) = -0.101, -0.013], SPPB score [ß = -0.736, 95% CI = -1.091, -0.381], 5-STS [ß = 1.681, 95% CI = 0.801, 2.561]) as well as cognitive (CCS [ß = -0.215, 95% CI = -0.335, -0.094]) domains compared to POSTN- group. No association was found with HS or the MMSE score. Our study showed for the first time that increased plasma periostin levels were associated with declines in both physical and cognitive capacities in older adults over a 4-year follow-up. Further research is needed to evaluate whether periostin might be used as a predictive biomarker of functional decline at an older age.

Scalable Generation of Pre-Vascularized and Functional Human Beige Adipose Organoids.

Obesity and type 2 diabetes are becoming a global sociobiomedical burden. Beige adipocytes are emerging as key inducible actors and putative relevant therapeutic targets for improving metabolic health. However, in vitro models of human beige adipose tissue are currently lacking and hinder research into this cell type and biotherapy development. Unlike traditional bottom-up engineering approaches that aim to generate building blocks, here a scalable system is proposed to generate pre-vascularized and functional human beige adipose tissue organoids using the human stromal vascular fraction of white adipose tissue as a source of adipose and endothelial progenitors. This engineered method uses a defined biomechanical and chemical environment using tumor growth factor ß (TGFß) pathway inhibition and specific gelatin methacryloyl (GelMA) embedding parameters to promote the self-organization of spheroids in GelMA hydrogel, facilitating beige adipogenesis and vascularization. The resulting vascularized organoids display key features of native beige adipose tissue including inducible Uncoupling Protein-1 (UCP1) expression, increased uncoupled mitochondrial respiration, and batokines secretion. The controlled assembly of spheroids allows to translate organoid morphogenesis to a macroscopic scale, generating vascularized centimeter-scale beige adipose micro-tissues. This approach represents a significant advancement in developing in vitro human beige adipose tissue models and facilitates broad applications ranging from basic research to biotherapies.

CD36 Drives Metastasis and Relapse in Acute Myeloid Leukemia.

Identifying mechanisms underlying relapse is a major clinical issue for effective cancer treatment. The emerging understanding of the importance of metastasis in hematologic malignancies suggests that it could also play a role in drug resistance and relapse in acute myeloid leukemia (AML). In a cohort of 1,273 AML patients, we uncovered that the multifunctional scavenger receptor CD36 was positively associated with extramedullary dissemination of leukemic blasts, increased risk of relapse after intensive chemotherapy, and reduced event-free and overall survival. CD36 was dispensable for lipid uptake but fostered blast migration through its binding with thrombospondin-1. CD36-expressing blasts, which were largely enriched after chemotherapy, exhibited a senescent-like phenotype while maintaining their migratory ability. In xenograft mouse models, CD36 inhibition reduced metastasis of blasts and prolonged survival of chemotherapy-treated mice. These results pave the way for the development of CD36 as an independent marker of poor prognosis in AML patients and a promising actionable target to improve the outcome of patients. SIGNIFICANCE: CD36 promotes blast migration and extramedullary disease in acute myeloid leukemia and represents a critical target that can be exploited for clinical prognosis and patient treatment.

Lactate Fluxes and Plasticity of Adipose Tissues: A Redox Perspective.

Lactate, a metabolite produced when the glycolytic flux exceeds mitochondrial oxidative capacities, is now viewed as a critical regulator of metabolism by acting as both a carbon and electron carrier and a signaling molecule between cells and tissues. In recent years, increasing evidence report its key role in white, beige, and brown adipose tissue biology, and highlights new mechanisms by which lactate participates in the maintenance of whole-body energy homeostasis. Lactate displays a wide range of biological effects in adipose cells not only through its binding to the membrane receptor but also through its transport and the subsequent effect on intracellular metabolism notably on redox balance. This study explores how lactate regulates adipocyte metabolism and plasticity by balancing intracellular redox state and by regulating specific signaling pathways. We also emphasized the contribution of adipose tissues to the regulation of systemic lactate metabolism, their roles in redox homeostasis, and related putative physiopathological repercussions associated with their decline in metabolic diseases and aging.

The emerging roles of lactate as a redox substrate and signaling molecule in adipose tissues.

Thermogenic (brown and beige) adipose tissues improve glucose and lipid homeostasis and therefore represent putative targets to cure obesity and related metabolic diseases including type II diabetes. Beside decades of research and the very well-described role of noradrenergic signaling, mechanisms underlying adipocytes plasticity and activation of thermogenic adipose tissues remain incompletely understood. Recent studies show that metabolites such as lactate control the oxidative capacity of thermogenic adipose tissues. Long time viewed as a metabolic waste product, lactate is now considered as an important metabolic substrate largely feeding the oxidative metabolism of many tissues, acting as a signaling molecule and as an inter-cellular and inter-tissular redox carrier. In this review, we provide an overview of the recent findings highlighting the importance of lactate in adipose tissues, from its production to its role as a browning inducer and its metabolic links with brown adipose tissue. We also discuss additional function(s) than thermogenesis ensured by brown and beige adipose tissues, i.e., their ability to dissipate high redox pressure and oxidative stress thanks to the activity of the uncoupling protein-1, helping to maintain tissue and whole organism redox homeostasis and integrity.

Atrial Natriuretic Peptide Orchestrates a Coordinated Physiological Response to Fuel Non-shivering Thermogenesis.

Atrial natriuretic peptide (ANP) is a cardiac hormone controlling blood volume and pressure in mammals. It is still unclear whether ANP controls cold-induced thermogenesis in vivo. Here, we show that acute cold exposure induces cardiac ANP secretion in mice and humans. Genetic inactivation of ANP promotes cold intolerance and suppresses half of cold-induced brown adipose tissue (BAT) activation in mice. While white adipocytes are resistant to ANP-mediated lipolysis at thermoneutral temperature in mice, cold exposure renders white adipocytes fully responsive to ANP to activate lipolysis and a thermogenic program, a physiological response that is dramatically suppressed in ANP null mice. ANP deficiency also blunts liver triglycerides and glycogen metabolism, thus impairing fuel availability for BAT thermogenesis. ANP directly increases mitochondrial uncoupling and thermogenic gene expression in human white and brown adipocytes. Together, these results indicate that ANP is a major physiological trigger of BAT thermogenesis upon cold exposure in mammals.

Short exposure to cold atmospheric plasma induces senescence in human skin fibroblasts and adipose mesenchymal stromal cells.

Cold Atmospheric Plasma (CAP) is a novel promising tool developed in several biomedical applications such as cutaneous wound healing or skin cancer. Nevertheless, in vitro studies are lacking regarding to CAP effects on cellular actors involved in healthy skin healing and regarding to the mechanism of action. In this study, we investigated the effect of a 3 minutes exposure to CAP-Helium on human dermal fibroblasts and Adipose-derived Stromal Cells (ASC) obtained from the same tissue sample. We observed that CAP treatment did not induce cell death but lead to proliferation arrest with an increase in p53/p21 and DNA damages. Interestingly we showed that CAP treated dermal fibroblasts and ASC developed a senescence phenotype with p16 expression, characteristic morphological changes, Senescence-Associated ß-galactosidase expression and the secretion of pro-inflammatory cytokines defined as the Senescence-Associated Secretory Phenotype (SASP). Moreover this senescence phenotype is associated with a glycolytic switch and an increase in mitochondria content. Despite this senescence phenotype, cells kept in vitro functional properties like differentiation potential and immunomodulatory effects. To conclude, we demonstrated that two main skin cellular actors are resistant to cell death but develop a senescence phenotype while maintaining some functional characteristics after 3 minutes of CAP-Helium treatment in vitro.

Regionalization of browning revealed by whole subcutaneous adipose tissue imaging.

OBJECTIVE: White and brown adipose tissues play a major role in the regulation of metabolic functions. With the explosion of obesity and metabolic disorders, the interest in adipocyte biology is growing constantly. While several studies have demonstrated functional differences between adipose fat pads, especially in their involvement in metabolic diseases, there are no data available on possible heterogeneity within an adipose depot. METHODS: This study investigated the three-dimensional (3-D) organization of the inguinal fat pad in adult mice by combining adipose tissue clearing and autofluorescence signal acquisition by confocal microscopy. In addition, the study analyzed the expression of genes involved in adipocyte biology and browning at the mARN and protein levels in distinct areas of the inguinal adipose tissue, in control conditions and after cold exposure. RESULTS: Semiautomated 3-D image analysis revealed an organization of the fat depot showing two regions: the core was structured into segmented lobules, whereas the periphery appeared unsegmented. Perilipin immunostaining showed that most of the adipocytes located in the core region had smaller lipid droplets, suggesting a brown-like phenotype. qPCR analysis showed a higher expression of the browning markers Ucp1, Prdm16, Ppargc1a, and Cidea in the core region than at the periphery. Finally, cold exposure induced upregulation of thermogenic gene expression associated with an increase of UCP1 protein, specifically in the core region of the inguinal fat depot. CONCLUSIONS: Altogether, these data demonstrate a structural and functional heterogeneity of the inguinal fat pad, with an anatomically restricted browning process in the core area.

A New Role for Browning as a Redox and Stress Adaptive Mechanism?

The worldwide epidemic of obesity and metabolic disorders is focusing the attention of the scientific community on white adipose tissue (WAT) and its biology. This tissue is characterized not only by its capability to change in size and shape but also by its heterogeneity and versatility. WAT can be converted into brown fat-like tissue according to different physiological and pathophysiological situations. The expression of uncoupling protein-1 in brown-like adipocytes changes their function from energy storage to energy dissipation. This plasticity, named browning, was recently rediscovered and convergent recent accounts, including in humans, have revived the idea of using these oxidative cells to fight against metabolic diseases. Furthermore, recent reports suggest that, beside the increased energy dissipation and thermogenesis that may have adverse effects in situations such as cancer-associated cachexia and massive burns, browning could be also considered as an adaptive stress response to high redox pressure and to major stress that could help to maintain tissue homeostasis and integrity. The aim of this review is to summarize the current knowledge concerning brown adipocytes and the browning process and also to explore unexpected putative role(s) for these cells. While it is important to find new browning inducers to limit energy stores and metabolic diseases, it also appears crucial to develop new browning inhibitors to limit adverse energy dissipation in wasting-associated syndromes.

Browning of white adipose cells by intermediate metabolites: an adaptive mechanism to alleviate redox pressure.

The presence of brown adipose tissue (BAT) in human adults opens attractive perspectives to treat metabolic disorders. Indeed, BAT dissipates energy as heat via uncoupling protein (UCP)1. Brown adipocytes are located in specific deposits or can emerge among white fat through the so-called browning process. Although numerous inducers have been shown to drive this process, no study has investigated whether it could be controlled by specific metabolites. Here, we show that lactate, an important metabolic intermediate, induces browning of murine white adipose cells with expression of functional UCP1. Lactate-induced browning also occurs in human cells and in vivo. Lactate controls Ucp1 expression independently of hypoxia-inducible factor-1α and PPARα pathways but requires active PPARγ signaling. We demonstrate that the lactate effect on Ucp1 is mediated by intracellular redox modifications as a result of lactate transport through monocarboxylate transporters. Further, the ketone body ß-hydroxybutyrate, another metabolite that impacts redox state, is also a strong browning inducer. Because this redox-dependent increase in Ucp1 expression promotes an oxidative phenotype with mitochondria, browning appears as an adaptive mechanism to alleviate redox pressure. Our findings open new perspectives for the control of adipose tissue browning and its physiological relevance.