Notch activation shifts the fate decision of senescent progenitors toward myofibrogenesis in human adipose tissue.

Senescence is a key event in the impairment of adipose tissue (AT) function with obesity and aging but the underlying molecular and cellular players remain to be fully defined, particularly with respect to the human AT progenitors. We have found distinct profiles of senescent progenitors based on AT location between stroma from visceral versus subcutaneous AT. In addition to flow cytometry, we characterized the location differences with transcriptomic and proteomic approaches, uncovering the genes and developmental pathways that are underlying replicative senescence. We identified key components to include INBHA as well as SFRP4 and GREM1, antagonists for the WNT and BMP pathways, in the senescence-associated secretory phenotype and NOTCH3 in the senescence-associated intrinsic phenotype. Notch activation in AT progenitors inhibits adipogenesis and promotes myofibrogenesis independently of TGFß. In addition, we demonstrate that NOTCH3 is enriched in the premyofibroblast progenitor subset, which preferentially accumulates in the visceral AT of patients with an early obesity trajectory. Herein, we reveal that NOTCH3 plays a role in the balance of progenitor fate determination preferring myofibrogenesis at the expense of adipogenesis. Progenitor NOTCH3 may constitute a tool to monitor replicative senescence and to limit AT dysfunction in obesity and aging.

Subcutaneous Stromal Cells and Visceral Adipocyte Size Are Determinants of Metabolic Flexibility in Obesity and in Response to Weight Loss Surgery.

Adipose tissue (AT) expansion either through hypertrophy or hyperplasia is determinant in the link between obesity and metabolic alteration. The present study aims to profile the unhealthy subcutaneous and visceral AT (SAT, VAT) expansion in obesity and in the outcomes of bariatric surgery (BS). The repartition of adipocytes according to diameter and the numbers of progenitor subtypes and immune cells of SAT and VAT from 161 obese patients were determined by cell imaging and flow cytometry, respectively. Associations with insulin resistance (IR) prior to BS as well as with the loss of excessive weight (EWL) and IR at 1 and 3 years post-BS were studied; prior to BS, SAT and VAT, unhealthy expansions are characterized by the accumulation of adipogenic progenitors and CD4+ T lymphocytes and by adipocyte hypertrophy and elevated macrophage numbers, respectively. Such SAT stromal profile and VAT adipocyte hypertrophy are associated with adverse BS outcomes. Finally, myofibrogenic progenitors are a common determinant of weight and IR trajectories post-BS; the study suggests that adipogenesis in SAT and adipocyte hypertrophy in VAT are common determinants of metabolic alterations with obesity and of the weight loss and metabolic response to bariatric surgery. The data open up new avenues to better understand and predict individual outcomes in response to changes in energy balance.

The Sexual Dimorphism of Human Adipose Depots.

The amount and the distribution of body fat exhibit trajectories that are sex- and human species-specific and both are determinants for health. The enhanced accumulation of fat in the truncal part of the body as a risk factor for cardiovascular and metabolic diseases is well supported by epidemiological studies. In addition, a possible independent protective role of the gluteofemoral fat compartment and of the brown adipose tissue is emerging. The present narrative review summarizes the current knowledge on sexual dimorphism in fat depot amount and repartition and consequences on cardiometabolic and reproductive health. The drivers of the sex differences and fat depot repartition, considered to be the results of complex interactions between sex determination pathways determined by the sex chromosome composition, genetic variability, sex hormones and the environment, are discussed. Finally, the inter- and intra-depot heterogeneity in adipocytes and progenitors, emphasized recently by unbiased large-scale approaches, is highlighted.

High doses of tyramine stimulate glucose transport in human fat cells

Among the dietary amines present in foods and beverages, tyramine has been widely studied since its excessive ingestion can cause catecholamine release and hypertensive crisis. However, tyramine exerts other actions than depleting nerve endings: it activates subtypes of trace amine associated receptors (TAARs) and is oxidized by monoamine oxidases (MAO). Although we have recently described that tyramine is antilipolytic in human adipocytes, no clear evidence has been reported about its effects on glucose transport in the same cell model, while tyramine mimics various insulin-like effects in rodent fat cells, such as activation of glucose transport, lipogenesis, and adipogenesis. Our aim was therefore to characterize the effects of tyramine on glucose transport in human adipocytes. The uptake of the non-metabolizable analogue 2-deoxyglucose (2-DG) was explored in adipocytes from human subcutaneous abdominal adipose tissue obtained from women undergoing reconstructive surgery. Human insulin used as reference agent multiplied by three times the basal 2-DG uptake. Tyramine was ineffective from 0.01 to 10 µM and stimulatory at 100 µM-1 mM, without reaching the maximal effect of insulin. This partial insulin-like effect was not improved by vanadium and was impaired by MAO-A and MAO-B inhibitors. Contrarily to benzylamine, mainly oxidized by semicarbazide-sensitive amine oxidase (SSAO), tyramine activation of glucose transport was not inhibited by semicarbazide. Tyramine effect was not dependent on the Gi-coupled receptor activation but was impaired by antioxidants and reproduced by hydrogen peroxide. In all, the oxidation of high doses of tyramine, already reported to inhibit lipolysis in human fat cells, also partially mimic another effect of insulin in these cells, the glucose uptake activation. Thus, other MAO substrates are potentially able to modulate carbohydrate metabolism. (AU)

High doses of catecholamines activate glucose transport in human adipocytes independently from adrenoceptor stimulation or vanadium addition.

BACKGROUND: When combined with vanadium salts, catecholamines strongly activate glucose uptake in rat and mouse adipocytes. AIM: To test whether catecholamines activate glucose transport in human adipocytes. METHODS: The uptake of 2-deoxyglucose (2-DG) was measured in adipocytes isolated from pieces of abdominal subcutaneous tissue removed from women undergoing reconstructive surgery. Pharmacological approaches with amine oxidase inhibitors, adrenoreceptor agonists and antioxidants were performed to unravel the mechanisms of action of noradrenaline or adrenaline (also named epinephrine). RESULTS: In human adipocytes, 45-min incubation with 100 µmol/L adrenaline or noradrenaline activated 2-DG uptake up to more than one-third of the maximal response to insulin. This stimulation was not reproduced with millimolar doses of dopamine or serotonin and was not enhanced by addition of vanadate to the incubation medium. Among various natural amines and adrenergic agonists tested, no other molecule was more efficient than adrenaline and noradrenaline in stimulating 2-DG uptake. The effect of the catecholamines was not impaired by pargyline and semicarbazide, contrarily to that of benzylamine or methylamine, which are recognized substrates of semicarbazide-sensitive amine oxidase. Hydrogen peroxide at 1 mmol/L activated hexose uptake but not pyrocatechol or benzoquinone, and only the former was potentiated by vanadate. Catalase and the phosphoinositide 3-kinase inhibitor wortmannin inhibited adrenaline-induced activation of 2-DG uptake. CONCLUSION: High doses of catecholamines exert insulin-like actions on glucose transport in human adipocytes. At submillimolar doses, vanadium did not enhance this catecholamine activation of glucose transport. Consequently, this dismantles our previous suggestion to combine the metal ion with catecholamines to improve the benefit/risk ratio of vanadium-based antidiabetic approaches.

High doses of tyramine stimulate glucose transport in human fat cells.

Among the dietary amines present in foods and beverages, tyramine has been widely studied since its excessive ingestion can cause catecholamine release and hypertensive crisis. However, tyramine exerts other actions than depleting nerve endings: it activates subtypes of trace amine associated receptors (TAARs) and is oxidized by monoamine oxidases (MAO). Although we have recently described that tyramine is antilipolytic in human adipocytes, no clear evidence has been reported about its effects on glucose transport in the same cell model, while tyramine mimics various insulin-like effects in rodent fat cells, such as activation of glucose transport, lipogenesis, and adipogenesis. Our aim was therefore to characterize the effects of tyramine on glucose transport in human adipocytes. The uptake of the non-metabolizable analogue 2-deoxyglucose (2-DG) was explored in adipocytes from human subcutaneous abdominal adipose tissue obtained from women undergoing reconstructive surgery. Human insulin used as reference agent multiplied by three times the basal 2-DG uptake. Tyramine was ineffective from 0.01 to 10 µM and stimulatory at 100 µM-1 mM, without reaching the maximal effect of insulin. This partial insulin-like effect was not improved by vanadium and was impaired by MAO-A and MAO-B inhibitors. Contrarily to benzylamine, mainly oxidized by semicarbazide-sensitive amine oxidase (SSAO), tyramine activation of glucose transport was not inhibited by semicarbazide. Tyramine effect was not dependent on the Gi-coupled receptor activation but was impaired by antioxidants and reproduced by hydrogen peroxide. In all, the oxidation of high doses of tyramine, already reported to inhibit lipolysis in human fat cells, also partially mimic another effect of insulin in these cells, the glucose uptake activation. Thus, other MAO substrates are potentially able to modulate carbohydrate metabolism.

Expression of the Adipocyte Progenitor Markers MSCA1 and CD36 is Associated With Adipose Tissue Function in Children.

CONTEXT: MSCA1 (mesenchymal stem cell antigen 1) and CD36 (cluster of differentiation 36) have been described as novel adipocyte progenitor markers in adults with a potential relevance for obesity and adipocyte progenitor function. OBJECTIVE: With the early manifestation of obesity in children and formation of adipose tissue (AT) dysfunction, children provide the opportunity to characterize the function of MSCA1 and CD36 during physiological AT accumulation and with obesity and related disease. METHODS: We investigated MSCA1 and CD36 expression in adipocytes and stroma vascular fraction (SVF) cells from 133 children of the Leipzig AT Childhood cohort with regard to AT accumulation and biology. In a subsample we analyzed how MSCA1 and CD36 expression is related to adipose progenitor capacities in vitro (ie, proliferation, differentiation and mitochondrial function). RESULTS: Both MSCA1 and CD36 are differentially expressed in adipocytes and SVF cells of children. MSCA1 expression is positively correlated to obesity-associated AT dysfunction (ie, adipocyte hypertrophy and serum high-sensitivity C-reactive protein), and high SVF MSCA1 expression is associated with increased mitochondrial respiration in vitro. CD36 expression is not associated with AT dysfunction but SVF CD36 expression is downregulated in children with overweight and obesity and shows a positive association with the differentiation capacity of SVF cells ex vivo and in vitro. CONCLUSION: Both MSCA1 and CD36 are associated with obesity-related alterations in AT of children. In particular, CD36 expression predicts adipogenic potential of SVF cells, indicating a potential role in the regulation of adipocyte hyperplasia and hypertrophy with obesity development in children.

Network Analyses Reveal Negative Link Between Changes in Adipose Tissue GDF15 and BMI During Dietary-induced Weight Loss.

CONTEXT: Adipose tissue (AT) transcriptome studies provide holistic pictures of adaptation to weight and related bioclinical settings changes. OBJECTIVE: To implement AT gene expression profiling and investigate the link between changes in bioclinical parameters and AT gene expression during 3 steps of a 2-phase dietary intervention (DI). METHODS: AT transcriptome profiling was obtained from sequencing 1051 samples, corresponding to 556 distinct individuals enrolled in a weight loss intervention (8-week low-calorie diet (LCD) at 800 kcal/day) followed with a 6-month ad libitum randomized DI. Transcriptome profiles obtained with QuantSeq sequencing were benchmarked against Illumina RNAseq. Reverse transcription quantitative polymerase chain reaction was used to further confirm associations. Cell specificity was assessed using freshly isolated cells and THP-1 cell line. RESULTS: During LCD, 5 modules were found, of which 3 included at least 1 bioclinical variable. Change in body mass index (BMI) connected with changes in mRNA level of genes with inflammatory response signature. In this module, change in BMI was negatively associated with changes in expression of genes encoding secreted protein (GDF15, CCL3, and SPP1). Through all phases of the DI, change in GDF15 was connected to changes in SPP1, CCL3, LIPA and CD68. Further characterization showed that these genes were specific to macrophages (with LIPA, CD68 and GDF15 expressed in anti-inflammatory macrophages) and GDF15 also expressed in preadipocytes. CONCLUSION: Network analyses identified a novel AT feature with GDF15 upregulated with calorie restriction induced weight loss, concomitantly to macrophage markers. In AT, GDF15 was expressed in preadipocytes and macrophages where it was a hallmark of anti-inflammatory cells.

Isothermal microcalorimetry measures UCP1-mediated thermogenesis in mature brite adipocytes.

The activation of thermogenesis in adipose tissue has emerged as an important target for the development of novel anti-obesity therapies. Using multi-well isothermal microcalorimetry, we have demonstrated that mature murine brown and brite adipocytes produce quantifiable heat upon ß3-AR stimulation, independently of any anaerobic mechanisms. Additionally, in brite adipocytes lacking UCP1 protein, ß3-AR stimulation still induces heat production, albeit to a much lower extent than in their wildtype counterparts, suggesting that UCP1 is an essential component of adrenergic induced thermogenesis in murine brite adipocytes exvivo. Similarly, we could observe an increase in heat production in human-derived adipocytes (hMADS) upon ß-AR stimulation. Collectively, these results establish the use of isothermal microcalorimetry as a sensitive and accurate technique for measuring thermogenic responses in intact mature brite adipocytes from murine and human origin.

Novel Facet of an Old Dietary Molecule? Direct Influence of Caffeine on Glucose and Biogenic Amine Handling by Human Adipocytes.

Caffeine is a plant alkaloid present in food and beverages consumed worldwide. It has high lipid solubility with recognized actions in the central nervous system and in peripheral tissues, notably the adipose depots. However, the literature is scant regarding caffeine's influence on adipocyte functions other than lipolysis, such as glucose incorporation into lipids (lipogenesis) and amine oxidation. The objective of this study was to explore the direct effects of caffeine and of isobutylmethylxanthine (IBMX) on these adipocyte functions. Glucose transport into fat cells freshly isolated from mice, rats, or humans was monitored by determining [3H]-2-deoxyglucose (2-DG) uptake, while the incorporation of radiolabeled glucose into cell lipids was used as an index of lipogenic activity. Oxidation of benzylamine by primary amine oxidase (PrAO) was inhibited by increasing doses of caffeine in human adipose tissue preparations with an inhibition constant (Ki) in the millimolar range. Caffeine inhibited basal and insulin-stimulated glucose transport as well as lipogenesis in rodent adipose cells. The antilipogenic action of caffeine was also observed in adipocytes from mice genetically invalidated for PrAO activity, indicating that PrAO activity was not required for lipogenesis inhibition. These caffeine inhibitory properties were extended to human adipocytes: relative to basal 2-DG uptake, set at 1.0 ± 0.2 for 6 individuals, 0.1 mM caffeine tended to reduce uptake to 0.83 ± 0.08. Insulin increased uptake by 3.86 ± 1.11 fold when tested alone at 100 nM, and by 3.21 ± 0.80 when combined with caffeine. Our results reinforce the recommendation of caffeine's potential in the treatment or prevention of obesity complications.

Thermogenic recruitment of brown and brite/beige adipose tissues is not obligatorily associated with macrophage accretion or attrition.

Cold- and diet-induced recruitment of brown adipose tissue (BAT) and the browning of white adipose tissue (WAT) are dynamic processes, and the recruited state attained is a state of dynamic equilibrium, demanding continuous stimulation to be maintained. An involvement of macrophages, classical proinflammatory (M1) or alternatively activated anti-inflammatory (M2), is presently discussed as being an integral part of these processes. If these macrophages play a mediatory role in the recruitment process, such an involvement would have to be maintained in the recruited state. We have, therefore, investigated whether the recruited state of these tissues is associated with macrophage accretion or attrition. We found no correlation (positive or negative) between total UCP1 mRNA levels (as a measure of recruitment) and proinflammatory macrophages in any adipose depot. We found that in young chow-fed mice, cold-induced recruitment correlated with accretion of anti-inflammatory macrophages; however, such a correlation was not seen when cold-induced recruitment was studied in diet-induced obese mice. Furthermore, the anti-inflammatory macrophage accretion was mediated via ß1/ß2-adrenergic receptors; yet, in their absence, and thus in the absence of macrophage accretion, recruitment proceeded normally. We thus conclude that the classical recruited state in BAT and inguinal (brite/beige) WAT is not paralleled by macrophage accretion or attrition. Our results make mediatory roles for macrophages in the recruitment process less likely.NEW & NOTEWORTHY A regulatory or mediatory role-positive or negative-for macrophages in the recruitment of brown adipose tissue is presently discussed. As the recruited state in the tissue is a dynamic process, maintenance of the recruited state would need persistent alterations in macrophage complement. Contrary to this expectation, we demonstrate here an absence of alterations in macrophage complement in thermogenically recruited brown-or brite/beige-adipose tissues. Macrophage regulation of thermogenic capacity is thus less likely.

Opipramol Inhibits Lipolysis in Human Adipocytes without Altering Glucose Uptake and Differently from Antipsychotic and Antidepressant Drugs with Adverse Effects on Body Weight Control.

Treatment with several antipsychotic drugs exhibits a tendency to induce weight gain and diabetic complications. The proposed mechanisms by which the atypical antipsychotic drug olanzapine increases body weight include central dysregulations leading to hyperphagia and direct peripheral impairment of fat cell lipolysis. Several investigations have reproduced in vitro direct actions of antipsychotics on rodent adipocytes, cultured preadipocytes, or human adipose tissue-derived stem cells. However, to our knowledge, no such direct action has been described in human mature adipocytes. The aim of the present study was to compare in human adipocytes the putative direct alterations of lipolysis by antipsychotics (haloperidol, olanzapine, ziprazidone, risperidone), antidepressants (pargyline, phenelzine), or anxiolytics (opipramol). Lipolytic responses to the tested drugs, and to recognized lipolytic (e.g., isoprenaline) or antilipolytic agents (e.g., insulin) were determined, together with glucose transport and amine oxidase activities in abdominal subcutaneous adipocytes from individuals undergoing plastic surgery. None of the tested drugs were lipolytic. Surprisingly, only opipramol exhibited substantial antilipolytic properties in the micromolar to millimolar range. An opipramol antilipolytic effect was evident against isoprenaline-, forskolin-, or atrial natriuretic peptide-stimulated lipolysis. Opipramol did not impair insulin activation of glucose transport but inhibited monoamine oxidase (MAO) activity to the same extent as antidepressants recognized as MAO inhibitors (pargyline, harmine, or phenelzine), whereas antipsychotics were inefficient. Considering its unique properties, opipramol, which is not associated with weight gain in treated patients, is a good candidate for drug repurposing because it limits exaggerated lipolysis, prevents hydrogen peroxide release by amine oxidases in adipocytes, and is thereby of potential use to limit lipotoxicity and oxidative stress, two deleterious complications of diabetes and obesity.

Growth and differentiation factor 15 is secreted by skeletal muscle during exercise and promotes lipolysis in humans.

We hypothesized that skeletal muscle contraction produces a cellular stress signal, triggering adipose tissue lipolysis to sustain fuel availability during exercise. The present study aimed at identifying exercise-regulated myokines, also known as exerkines, able to promote lipolysis. Human primary myotubes from lean healthy volunteers were submitted to electrical pulse stimulation (EPS) to mimic either acute intense or chronic moderate exercise. Conditioned media (CM) experiments with human adipocytes were performed. CM and human plasma samples were analyzed using unbiased proteomic screening and/or ELISA. Real-time qPCR was performed in cultured myotubes and muscle biopsy samples. CM from both acute intense and chronic moderate exercise increased basal lipolysis in human adipocytes. Growth and differentiation factor 15 (GDF15) gene expression and secretion increased rapidly upon skeletal muscle contraction. GDF15 protein was upregulated in CM from both acute and chronic exercise-stimulated myotubes. We further showed that physiological concentrations of recombinant GDF15 protein increased lipolysis in human adipose tissue, while blocking GDF15 with a neutralizing antibody abrogated EPS CM-mediated lipolysis. We herein provide the first evidence to our knowledge that GDF15 is a potentially novel exerkine produced by skeletal muscle contraction and able to target human adipose tissue to promote lipolysis.

Methylamine Activates Glucose Uptake in Human Adipocytes Without Overpassing Action of Insulin or Stimulating its Secretion in Pancreatic Islets.

Background: Methylamine, a natural soluble amine present in foods, is known to be a substrate of primary amine oxidase (PrAO) widely expressed in animal tissues. Methylamine has been reported to activate glucose transport in fat cells and to facilitate glucose disposal in rabbits but the interests and limits of such insulin-mimicking actions have not been further explored. This work aimed to perform a preclinical study of the inter-individual variations of these biological properties to study the putative link between PrAO activity and insulin resistance. Methods: Methylamine was tested on human adipocyte preparations and in rabbit pancreatic islets to determine its influence on glucose uptake and insulin release, respectively. PrAO activity and related responses were determined in adipose tissues obtained from two cohorts of non-obese and obese women. Results: Adipose tissue PrAO activity was negatively correlated with insulin resistance in high-risk obese women. PrAO-dependent activation of glucose uptake was negatively correlated with body mass index and reflected the decrease of insulin responsiveness of human fat cells with increasing obesity. Methylamine exhibited antilipolytic properties in adipocytes but was unable to directly activate insulin secretion in isolated pancreatic islets. Conclusions: PrAO activation by its substrates, e.g., methylamine, increases glucose utilization in human adipocytes in a manner that is linked to insulin responsiveness. Methylamine/PrAO interaction can therefore contribute to adipose tissue enlargement but should be considered as potentially useful for diabetes prevention since it could limit lipotoxicity and facilitate glucose handling, at the expense of favoring healthy fat accumulation.

Glucocorticoid-Induced Obesity Develops Independently of UCP1.

An excess of glucocorticoids leads to the development of obesity in both mice and humans, but the mechanism for this is unknown. Here, we determine the extent to which decreased BAT thermogenic capacity (as a result of glucocorticoid treatment) contributes to the development of obesity. Contrary to previous suggestions, we show that only in mice housed at thermoneutrality (30°C) does corticosterone treatment reduce total BAT UCP1 protein. This reduction is reflected in reduced brown adipocyte cellular and mitochondrial UCP1-dependent respiration. However, glucocorticoid-induced obesity develops to the same extent in animals housed at 21°C and 30°C, whereas total BAT UCP1 protein levels differ 100-fold between the two groups. In corticosterone-treated wild-type and UCP1 knockout mice housed at 30°C, obesity also develops to the same extent. Thus, our results demonstrate that the development of glucocorticoid-induced obesity is not caused by a decreased UCP1-dependent thermogenic capacity.

Effects of the amino acid derivatives, ß-hydroxy-ß-methylbutyrate, taurine, and N-methyltyramine, on triacylglycerol breakdown in fat cells.

Various amino acid (AA) metabolites are used as supplements to facilitate metabolic control and enhance responsiveness of insulin-sensitive tissues. ß-hydroxy-ß-methylbutyrate (HMB) is a leucine metabolite proposed to prevent muscle wasting and to mitigate insulin resistance. Taurine, commonly added to energizing drinks, is a metabolite of methionine and cysteine present in bile juice, and proposed to be involved in lipid digestion and to be pro-lipolytic in adipocytes. N-methyltyramine (NMT) is a phenylalanine metabolite found in orange juices at 0.1-3 ppm while its effects on lipid mobilization remain controversial. Here, the putative lipolytic effects of these AA metabolites were studied and it was tested whether they could enhance insulin antilipolytic response in adipocytes. Release of glycerol and non-esterified fatty acids (NEFAs) was measured after a 2-h incubation of adipocytes obtained from control and diet-induced obese mice or from obese patients. In mouse, none of the tested AA derivatives was lipolytic from 1 µM to 1 mM. These compounds did not improve insulin antilipolytic effect or isoprenaline lipolytic action, except for 1 mM NMT that impaired triacylglycerol breakdown in obese mice. In human adipocytes, HMB and taurine were not lipolytic, while NMT weakly activated glycerol and NEFA release at 1 mM. However, 100 µM NMT impaired isoprenaline-stimulated lipolysis in a manner that was hardly added to insulin antilipolytic effect. Since none of these AA derivatives acutely helped or replaced insulin antilipolytic effect in adipocytes, the present in vitro observations do not support their proposed insulin-sensitizing properties. Moreover, NMT, HMB, and taurine were not notably lipolytic.

Past, Present and Future Anti-Obesity Effects of Flavin-Containing and/or Copper-Containing Amine Oxidase Inhibitors.

Background: Two classes of amine oxidases are found in mammals: those with a flavin adenine dinucleotide as a cofactor, such as monoamine oxidases (MAO) and lysine-specific demethylases (LSD), and those with copper as a cofactor, including copper-containing amine oxidases (AOC) and lysyl oxidases (LOX). All are expressed in adipose tissue, including a semicarbazide-sensitive amine oxidase/vascular adhesion protein-1 (SSAO/VAP-1) strongly present on the adipocyte surface. Methods: Previously, irreversible MAO inhibitors have been reported to limit food intake and/or fat extension in rodents; however, their use for the treatment of depressed patients has not revealed a clear anti-obesity action. Semicarbazide and other molecules inhibiting SSAO/VAP-1 also reduce adiposity in obese rodents. Results: Recently, a LOX inhibitor and a subtype-selective MAO inhibitor have been shown to limit fattening in high-fat diet-fed rats. Phenelzine, which inhibits MAO and AOC, limits adipogenesis in cultured preadipocytes and impairs lipogenesis in mature adipocytes. When tested in rats or mice, phenelzine reduces food intake and/or fat accumulation without cardiac adverse effects. Novel amine oxidase inhibitors have been recently characterized in a quest for promising anti-inflammatory or anti-cancer approaches; however, their capacity to mitigate obesity has not been studied so far. Conclusions: The present review of the diverse effects of amine oxidase inhibitors impairing adipocyte differentiation or limiting excessive fat accumulation indicates that further studies are needed to reveal their potential anti-obesity properties.

The Dietary Antioxidant Piceatannol Inhibits Adipogenesis of Human Adipose Mesenchymal Stem Cells and Limits Glucose Transport and Lipogenic Activities in Adipocytes.

Phenolic compounds are among the most investigated herbal remedies, as is especially the case for resveratrol. Many reports have shown its anti-aging properties and the ability to reduce obesity and diabetes induced by high-fat diet in mice. However, such beneficial effects hardly translate from animal models to humans. The scientific community has therefore tested whether other plant phenolic compounds may surpass the effects of resveratrol. In this regard, it has been reported that piceatannol reproduces in rodents the anti-obesity actions of its parent polyphenol. However, the capacity of piceatannol to inhibit adipocyte differentiation in humans has not been characterized so far. Here, we investigated whether piceatannol was antiadipogenic and antilipogenic in human preadipocytes. Human mesenchymal stem cells (hMSC), isolated from adipose tissues of lean and obese individuals, were differentiated into mature adipocytes with or without piceatannol, and their functions were explored. Fifty µM of piceatannol deeply limited synthesis/accumulation of lipids in both murine and hMSC-derived adipocytes. Interestingly, this phenomenon occurred irrespective of being added at the earlier or later stages of adipocyte differentiation. Moreover, piceatannol lowered glucose transport into adipocytes and decreased the expression of key elements of the lipogenic pathway (PPARγ, FAS, and GLUT4). Thus, the confirmation of the antiadipogenic properties of piceatanol in vitro warrants the realization of clinical studies for the application of this compound in the treatment of the metabolic complications associated with obesity.

The ß3-adrenergic receptor is dispensable for browning of adipose tissues.

Brown and brite/beige adipocytes are attractive therapeutic targets to treat metabolic diseases. To maximally utilize their functional potential, further understanding is required about their identities and their functional differences. Recent studies with ß3-adrenergic receptor knockout mice reported that brite/beige adipocytes, but not classical brown adipocytes, require the ß3-adrenergic receptor for cold-induced transcriptional activation of thermogenic genes. We aimed to further characterize this requirement of the ß3-adrenergic receptor as a functional distinction between classical brown and brite/beige adipocytes. However, when comparing wild-type and ß3-adrenergic receptor knockout mice, we observed no differences in cold-induced thermogenic gene expression (Ucp1, Pgc1a, Dio2, and Cidea) in brown or white (brite/beige) adipose tissues. Irrespective of the duration of the cold exposure or the sex of the mice, we observed no effect of the absence of the ß3-adrenergic receptor. Experiments with the ß3-adrenergic receptor agonist CL-316,243 verified the functional absence of ß3-adrenergic signaling in these knockout mice. The ß3-adrenergic receptor knockout model in the present study was maintained on a FVB/N background, whereas earlier reports used C57BL/6 and 129Sv mice. Thus our data imply background-dependent differences in adrenergic signaling mechanisms in response to cold exposure. Nonetheless, the present data indicate that the ß3-adrenergic receptor is dispensable for cold-induced transcriptional activation in both classical brown and, as opposed to earlier studies, brite/beige cells.