P2Y13 receptor deficiency favors adipose tissue lipolysis and worsens insulin resistance and fatty liver disease.

Excessive lipolysis in white adipose tissue (WAT) leads to insulin resistance (IR) and ectopic fat accumulation in insulin-sensitive tissues. However, the impact of Gi-coupled receptors in restraining adipocyte lipolysis through inhibition of cAMP production remained poorly elucidated. Given that the Gi-coupled P2Y13 receptor (P2Y13-R) is a purinergic receptor expressed in WAT, we investigated its role in adipocyte lipolysis and its effect on IR and metabolic dysfunction-associated steatotic liver disease (MASLD). In humans, mRNA expression of P2Y13-R in WAT was negatively correlated to adipocyte lipolysis. In mice, adipocytes lacking P2Y13-R displayed higher intracellular cAMP levels, indicating impaired Gi signaling. Consistently, the absence of P2Y13-R was linked to increased lipolysis in adipocytes and WAT explants via hormone-sensitive lipase activation. Metabolic studies indicated that mice lacking P2Y13-R showed a greater susceptibility to diet-induced IR, systemic inflammation, and MASLD compared with their wild-type counterparts. Assays conducted on precision-cut liver slices exposed to WAT conditioned medium and on liver-specific P2Y13-R-knockdown mice suggested that P2Y13-R activity in WAT protects from hepatic steatosis, independently of liver P2Y13-R expression. In conclusion, our findings support the idea that targeting adipose P2Y13-R activity may represent a pharmacological strategy to prevent obesity-associated disorders, including type 2 diabetes and MASLD.

Common mouse models of chronic kidney disease are not associated with cachexia.

The 5/6 nephrectomy and adenine-induced nephropathy mouse models have been extensively used to study Chronic Kidney Disease (CKD)-related cachexia. One common caveat of these CKD models is the cross-sectional nature of comparisons made versus controls. We here performed a comprehensive longitudinal assessment of body composition and energy metabolism in both models. The most striking finding is that weight loss is largely driven by reduced food intake which promotes rapid loss of lean and fat mass. However, in both models, mice catch up weight and lean mass a few days after the surgery or when they are switched back to standard chow diet. Muscle force and mass are fully recovered and no sign of cachexia is observed. Our data demonstrate that the time-course of kidney failure and weight loss are unrelated in these common CKD models. These data highlight the need to reconsider the relative contribution of direct and indirect mechanisms to muscle wasting observed in CKD.

Bitumen fumes and PAHs in asphalt road paving: Emission characteristics, determinants of exposure and environmental impact.

BACKGROUND: Asphalt road paving and its subsequent complex airborne emissions have raised concerns about occupational exposures and environmental impacts. Although several studies described bitumen fumes or Polycyclic Aromatic Hydrocarbons (PAH) emissions at specific worksites, no comprehensive studies have characterised road paving emissions and identified the main determinants of exposure. METHODS: A 10-year study from 2012 to 2022 was performed to examine the pollutants resulting from bitumen fume emissions and covering the main processes used in road paving (asphalt production, mechanical rolled asphalt paving, manual paving, mastic asphalt paving, emulsion paving, and coal-tar asphalt milling). A total of 623 air samples were collected at 63 worksites (on 290 workers, in the environment and near emission sources), and bitumen fumes, PAHs, aldehydes and volatile organic compounds were analysed. Biomonitoring campaigns were performed on 130 workers to assess internal exposure to PAHs. RESULTS: Fume emissions revealed complex mixtures of C10-C30 compounds, including linear saturated hydrocarbons (C6-C12), alicyclic hydrocarbons and aliphatic ketones. PAHs were dominated by 2-3 aromatic ring compounds (naphthalene, fluorene, and phenanthrene), and C1-C13 aldehydes were identified. Binder proportion, paving temperature, outdoor temperature, workload and job category influenced airborne concentrations. A significant temporal trend was observed over the time period of the study, with decreasing BF and PAH exposures. PAH biomonitoring was consistent with air samples, and urinary metabolites of 2-3 ring PAHs dominated over 4-5 ring PAHs. Occupational exposures were generally far lower than exposure limits, except coal-tar asphalt milling activities. Very low environmental concentrations were measured, which highlights a negligible contribution of paving emissions to global environmental pollution. CONCLUSION: The present study confirmed the complex nature of bitumen fumes and characterised the main determinants of exposure. The results highlight the need to reduce the paving temperature and binder proportion. Recycled asphalt pavement use was not associated with higher emissions. The impact of paving activities on environmental airborne pollution was deemed negligible.

Metabolism of benzo[a]pyrene after low-dose subchronic exposure to an industrial mixture of carcinogenic polycyclic aromatic hydrocarbons in rats: a cocktail effect study.

Polycyclic aromatic hydrocarbons (PAHs) are interesting environmental pollutants for understanding cocktail effects. High-molecular-weight-PAHs (HMW-PAHs) are classified as probable or possible carcinogens; only benzo[a]pyrene (B[a]P) is a certain carcinogen in humans. Their toxicity depends on their metabolic activation. While 3-hydroxybenzo[a]pyrene (3-OHB[a]P) represents its detoxification pathway, trans-anti-7,8,9,10-tetrahydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene (tetrol-B[a]P) represents the carcinogenicity pathway. The objective was to study the metabolism of B[a]P and HMW-PAHs during chronic low-dose exposure to B[a]P or a PAH mixture. Rats were exposed orally 5 times/week for 10 weeks to low-levels of B[a]P (0.02 and 0.2 mg.kg-1.d-1) or to an industrial mixture extracted from coal tar pitch (CTP) adjusted to 0.2 mg.kg-1.d-1 B[a]P. Urinary levels of monohydroxy-, diol-, and tetrol-PAH were measured during weeks 1 and 10 by HPLC-fluorescence and GC‒MS/MS. After 1 week, the percentages of B[a]P eliminated as 3-OHB[a]P and tetrol-B[a]P were not different depending on the dose of B[a]P, whereas they were reduced by half in the CTP group. Repeated exposure led to an increase in the percentages of the 2 metabolites for the 0.02-B[a]P group. Moreover, the percentage of B[a]P eliminated as 3-OHB[a]P was equal in the 0.2-B[a]P and CTP groups, whereas it remained halved for tetrol-B[a]P in the CTP group. The percent elimination of HMW-PAH metabolites did not vary between weeks 1 and 10. Thus, dose, duration of exposure and chemical composition of the mixture have a major influence on PAH metabolism that goes beyond a simple additive effect. This work contributes to the reflection on determination of limit values and risk assessments in a context of poly-exposures.

Adipose tissue is a source of regenerative cells that augment the repair of skeletal muscle after injury.

Fibro-adipogenic progenitors (FAPs) play a crucial role in skeletal muscle regeneration, as they generate a favorable niche that allows satellite cells to perform efficient muscle regeneration. After muscle injury, FAP content increases rapidly within the injured muscle, the origin of which has been attributed to their proliferation within the muscle itself. However, recent single-cell RNAseq approaches have revealed phenotype and functional heterogeneity in FAPs, raising the question of how this differentiation of regenerative subtypes occurs. Here we report that FAP-like cells residing in subcutaneous adipose tissue (ScAT), the adipose stromal cells (ASCs), are rapidly released from ScAT in response to muscle injury. Additionally, we find that released ASCs infiltrate the damaged muscle, via a platelet-dependent mechanism and thus contribute to the FAP heterogeneity. Moreover, we show that either blocking ASCs infiltration or removing ASCs tissue source impair muscle regeneration. Collectively, our data reveal that ScAT is an unsuspected physiological reservoir of regenerative cells that support skeletal muscle regeneration, underlining a beneficial relationship between muscle and fat.

Remote Assessment of Quality of Life and Functional Exercise Capacity in a Cohort of COVID-19 Patients One Year after Hospitalization (TELECOVID).

Studies have reported persistent symptoms in patients hospitalized for COVID-19 up to 6 months post-discharge; however, sequalae beyond 6 months are unknown. This study aimed to investigate the clinical status of COVID-19 patients one year after hospital discharge and describe the factors related to poor outcomes. We conducted a single-center, prospective, cohort study of patients in Le Havre hospital (France) between 1 March 2020 and 11 May 2020. Baseline characteristics were collected from medical charts (including KATZ index and Clinical Frailty scale (CFS)), and a remote assessment was conducted 12 months after discharge. The main outcomes were the scores of the physical and mental components (PCS and MCS) of the Short-Form 36 (SF-36) and performance on the one-minute sit-to-stand test (STST1'). Scores <50% of the predicted values were considered as poor, and univariate and multivariate analyses were undertaken to investigate factors related to poor outcomes. Remote assessment was performed for 128 of the 157 (82%) eligible patients. Twenty-two patients were admitted to the intensive care unit (ICU), 45 to the intermediate care unit (IU), and 61 to the general ward (GW). Patients who spent time in ICU were more independent and younger. A large proportion of the sample had poor physical (30%) and mental health (27%) and a poor functional exercise capacity (33%) at the remote assessment. Higher levels of frailty at admission and hospital discharge were, respectively, associated with a higher risk of poor functional exercise capacity (StdOR 3.64 (95%CI 1.39-10.72); p = 0.01) and a higher risk of poor mental health (StdOR 2.81 (95%CI 1.17-7.45); p = 0.03). Long-term outcomes following hospitalization for COVID-19 infection may be negative for at least one year after discharge. Remote follow-up assessment could be highly beneficial for COVID-19 patients.

ChREBPß is dispensable for the control of glucose homeostasis and energy balance.

Impaired glucose metabolism is observed in obesity and type 2 diabetes. Glucose controls gene expression through the transcription factor ChREBP in liver and adipose tissues. Mlxipl encodes 2 isoforms: ChREBPα, the full-length form (translocation into the nucleus is under the control of glucose), and ChREBPß, a constitutively nuclear shorter form. ChREBPß gene expression in white adipose tissue is strongly associated with insulin sensitivity. Here, we investigated the consequences of ChREBPß deficiency on insulin action and energy balance. ChREBPß-deficient male and female C57BL6/J and FVB/N mice were produced using CRISPR/Cas9-mediated gene editing. Unlike global ChREBP deficiency, lack of ChREBPß showed modest effects on gene expression in adipose tissues and the liver, with variations chiefly observed in brown adipose tissue. In mice fed chow and 2 types of high-fat diets, lack of ChREBPß had moderate effects on body composition and insulin sensitivity. At thermoneutrality, ChREBPß deficiency did not prevent the whitening of brown adipose tissue previously reported in total ChREBP-KO mice. These findings revealed that ChREBPß is dispensable for metabolic adaptations to nutritional and thermic challenges.

Simultaneous analysis of PAH urinary mono- and dihydroxylated metabolites by GC-MS-MS following SPE and two-stage derivatization.

A new gas chromatography-tandem mass spectrometry method for the determination of mono- and dihydroxylated polycyclic aromatic hydrocarbon metabolites (OH-PAHs and diol-PAHs) in urine was developed and validated. Various sample preparation procedures were compared, namely liquid-liquid extraction (LLE), dispersive solid-phase extraction (dSPE), and SPE, alone or combined. A novel two-stage derivatization approach using 2 silylation reagents was developed, and an experimental procedure design was used to optimize the programmed temperature vaporization-solvent vent injection (PTV-SV) GC parameters. The method focused on 11 target compounds resulting from four- to five-ring suspected carcinogenic PAHs. SPE was identified as an acceptable and more convenient extraction method for all tested metabolites, with extraction rates ranging from 63 to 86% and relative standard deviations lower than 20%. The two-stage derivatization approach successfully allowed first the derivatization of OH-PAHs by MTBSTFA (N-tert-butyldimethylsilyl-N-methyltrifluoroacetamide) and then diol-PAHs by BSTFA (N,O-bis(trimethylsilyl)trifluoroacetamide) in a single run. The limits of quantification were in the range of 0.01-0.02 µg l-1 for OH-PAHs and 0.02-0.2 µg l-1 for diol-PAHs. The intra- and interday precisions were lower than 10%. The method was applied to determine PAH metabolites in urine collected at the beginning and at the end of the working week from 6 workers involved in aluminum production. The mean diol-PAH levels at the end of the week were 10 to 20 times higher (0.86-2.34 µg g-1 creatinine) than those of OH-PAHs (0.03-0.30 µg g-1). These results confirmed the usefulness of this new analytical technique for detecting and characterizing metabolic patterns of PAHs in urine and assessing carcinogenic occupational exposures.

Metabolic and cardiovascular adaptations to an 8-wk lifestyle weight loss intervention in younger and older obese men.

The number of older obese adults is increasing worldwide. Whether obese adults show similar health benefits in response to lifestyle interventions at different ages is unknown. The study enrolled 25 obese men (body mass index: 31-39 kg/m2) in two arms according to age (30-40 and 60-70 yr old). Participants underwent an 8-wk intervention with moderate calorie restriction (∼20% below individual energy requirements) and supervised endurance training resulting in ∼5% weight loss. Body composition was measured using dual energy X-ray absorptiometry. Insulin sensitivity was assessed during a hypersinsulinemic-euglycemic clamp. Cardiometabolic profile was derived from blood parameters. Subcutaneous fat and vastus lateralis muscle biopsies were used for ex vivo analyses. Two-way repeated-measure ANOVA and linear mixed models were used to evaluate the response to lifestyle intervention and comparison between the two groups. Fat mass was decreased and bone mass was preserved in the two groups after intervention. Muscle mass decreased significantly in older obese men. Cardiovascular risk (Framingham risk score, plasma triglyceride, and cholesterol) and insulin sensitivity were greatly improved to a similar extent in the two age groups after intervention. Changes in adipose tissue and skeletal muscle transcriptomes were marginal. Analysis of the differential response to the lifestyle intervention showed tenuous differences between age groups. These data suggest that lifestyle intervention combining calorie restriction and exercise shows similar beneficial effects on cardiometabolic risk and insulin sensitivity in younger and older obese men. However, attention must be paid to potential loss of muscle mass in response to weight loss in older obese men.NEW & NOTEWORTHY Rise in obesity and aging worldwide are major trends of critical importance in public health. This study addresses a current challenge in obesity management. Do older obese adults respond differently to a lifestyle intervention composed of moderate calorie restriction and supervised physical activity than younger ones? The main conclusion of the study is that older and younger obese men similarly benefit from the intervention in terms of cardiometabolic risk.

3D Adipose Tissue Culture Links the Organotypic Microenvironment to Improved Adipogenesis.

Obesity and type 2 diabetes are strongly associated with adipose tissue dysfunction and impaired adipogenesis. Understanding the molecular underpinnings that control adipogenesis is thus of fundamental importance for the development of novel therapeutics against metabolic disorders. However, translational approaches are hampered as current models do not accurately recapitulate adipogenesis. Here, a scaffold-free versatile 3D adipocyte culture platform with chemically defined conditions is presented in which primary human preadipocytes accurately recapitulate adipogenesis. Following differentiation, multi-omics profiling and functional tests demonstrate that 3D adipocyte cultures feature mature molecular and cellular phenotypes similar to freshly isolated mature adipocytes. Spheroids exhibit physiologically relevant gene expression signatures with 4704 differentially expressed genes compared to conventional 2D cultures (false discovery rate < 0.05), including the concerted expression of factors shaping the adipogenic niche. Furthermore, lipid profiles of >1000 lipid species closely resemble patterns of the corresponding isogenic mature adipocytes in vivo (R2 = 0.97). Integration of multi-omics signatures with analyses of the activity profiles of 503 transcription factors using global promoter motif inference reveals a complex signaling network, involving YAP, Hedgehog, and TGFß signaling, that links the organotypic microenvironment in 3D culture to the activation and reinforcement of PPARγ and CEBP activity resulting in improved adipogenesis.

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.

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.

Towards a recommended biomonitoring strategy for assessing the occupational exposure of roofers to PAHs.

The aims of this work were to assess the PAH exposure among roofers and to identify relevant biomarkers for monitoring occupational exposure. Several campaigns were conducted between 2004 and 2017, with 28 individual air samples and 240 urinary samples collected from 73 roofers. Seventeen parent PAHs and 14 urinary biomarkers, metabolites of pyrene (1-OHP), benzo(a)pyrene (3-OHBaP and TetraolBaP), naphthalene (1- and 2-naphtols), fluorene (1- 2- 3- 9-fluorenols) and phenanthrene (1- 2- 3- 4- 9-phenanthrols), were analysed. Three exposure groups were considered: soft-applied roofing using polymer-modified bitumen ("PMB"), hot-applied roofing using oxidized bitumen ("OB") and the tearing off of old roof coatings containing coal tar ("CT"). The PAHs containing 2-3 rings were much more abundant, and the highest airborne levels were observed in the "CT" group. The biomonitoring results were consistent with these results, with a large predominance of 2-3 ring PAH metabolites. 1-OHP, 3-fluorenol and 2-phenanthrol were better correlated with airborne levels and less influenced by smoking than the other metabolites. Conversely, 1-/2-naphtol levels were heavily influenced by smoking and not correlated with airborne naphthalene levels. Moreover, 3-OHBaP and TetraolBaP levels were very low when applying bitumen membranes, and much higher exposures were observed during tear-off activities. In this context, the recommended strategy for roofer biomonitoring should include 1-OHP, fluorenols and phenanthrols, as well as carcinogenic BaP metabolites (3-OHBaP or TetraolBaP) when evaluating the occupational exposure of roofers that are tearing off old roof coatings.

Metabolism and genotoxicity of polycyclic aromatic hydrocarbons in human skin explants: mixture effects and modulation by sunlight.

Cutaneous exposure to carcinogenic polycyclic aromatic hydrocarbons (PAH) occurs frequently in the industrialized workplace. In the present study, we addressed this topic in a series of experiments using human skin explants and organic extracts of relevant industrial products. PAH mixtures were applied topically in volumes containing either 10 or 1 nmol B[a]P. We first observed that although mixtures were very efficient at inducing expression of CYP450 1A1, 1A2, and 1B1, formation of adducts of PAH metabolites to DNA, like those of benzo[a]pyrene diol epoxide (BPDE), was drastically reduced as the complexity of the surrounding matrix increased. Interestingly, observation of a nonlinear, dose-dependent response with the least complex mixture suggested the existence of a threshold for this inhibitory effect. We then investigated the impact of simulated sunlight (SSL) on the effects of PAH in skin. SSL was found to decrease the expression of CYP450 genes when applied either after or more efficiently before PAH treatment. Accordingly, the level of DNA-BPDE adducts was reduced in skin samples exposed to both PAH and SSL. The main conclusion of our work is that both increasing chemical complexity of the mixtures and co-exposure to UV radiation decreased the production of adducts between DNA and PAH metabolites. Such results must be taken into account in risk management.

Influence of exposure dose, complex mixture, and ultraviolet radiation on skin absorption and bioactivation of polycyclic aromatic hydrocarbons ex vivo.

Combined exposure to complex mixtures of polycyclic aromatic hydrocarbons (PAHs) and ultraviolet radiation (UVR) is suspected to enhance PAH skin permeability and skin cancer risk depending on PAH bioactivation. The impact of PAH mixtures (exposure dose, composition, and complexity) and UVR was assessed for PAH cutaneous absorption and metabolism using realistic exposure conditions and human skin explants. PAH complex mixtures were extracted from the industrial products coal tar pitch (CTP-I) and petroleum coke (PC-I). The synthetic mixture (CTP-S) was identically reconstituted using PAH standards. The applied dose was adjusted to 1 (PC-I, CTP-I) or 10 nmol (CTP-I, CTP-S) of benzo[a]pyrene (B[a]P). Unmetabolized PAHs were recovered from the skin surface, skin and medium, and then quantified by HPLC-fluorescence detection. PAH metabolites were collected from the medium and analyzed by GC-MS/MS. B[a]P and PAH penetration was lower for the highest B[a]P dose, industrial mixtures, and CTP-I compared to PC-I. Skin irradiation increased PAH penetration only for CTP-I. PAH uptake was poorly influenced by the different experimental conditions. PAH metabolism markedly decreased in the application of mixtures, leading to unmetabolized PAH accumulation in human skin. PAH metabolism was similar between CTP-I and PC-I, but was lower for the highest dose and the industrial mixtures, suggesting a saturation of xenobiotic metabolizing enzymes, as confirmed in a time-course study. UVR strongly inhibited all PAH metabolism. Altogether, these results underline the necessity to consider the reality of human exposure (PAH complex mixtures and UVR) during in vitro experiments to properly estimate skin absorption and metabolism.

Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids.

Epidemiological studies indicate that insulin resistance (IR), a hallmark of type 2 diabetes, is associated with an increased risk of major depression. Here, we demonstrated that male mice fed a high-fat diet (HFD) exhibited peripheral metabolic impairments reminiscent of IR accompanied by elevated circulating levels of branched-chain amino acids (BCAAs), whereas both parameters were normalized by chronic treatment with metformin (Met). Given the role of BCAAs in the regulation of tryptophan influx into the brain, we then explored the activity of the serotonin (5-HT) system. Our results indicated that HFD-fed mice displayed impairment in the electrical activity of dorsal raphe 5-HT neurons, attenuated hippocampal extracellular 5-HT concentrations and anxiety, one of the most visible and early symptoms of depression. On the contrary, Met stimulated 5-HT neurons excitability and 5-HT neurotransmission while hindering HFD-induced anxiety. Met also promoted antidepressant-like activities as observed with fluoxetine. In light of these data, we designed a modified HFD in which BCAA dietary supply was reduced by half. Deficiency in BCAAs failed to reverse HFD-induced metabolic impairments while producing antidepressant-like activity and enhancing the behavioral response to fluoxetine. Our results suggest that Met may act by decreasing circulating BCAAs levels to favor serotonergic neurotransmission in the hippocampus and promote antidepressant-like effects in mice fed an HFD. These findings also lead us to envision that a diet poor in BCAAs, provided either alone or as add-on therapy to conventional antidepressant drugs, could help to relieve depressive symptoms in patients with metabolic comorbidities.SIGNIFICANCE STATEMENT Insulin resistance in humans is associated with increased risk of anxiodepressive disorders. Such a relationship has been also found in rodents fed a high-fat diet (HFD). To determine whether insulin-sensitizing strategies induce anxiolytic- and/or antidepressant-like activities and to investigate the underlying mechanisms, we tested the effects of metformin, an oral antidiabetic drug, in mice fed an HFD. Metformin reduced levels of circulating branched-chain amino acids, which regulate tryptophan uptake within the brain. Moreover, metformin increased hippocampal serotonergic neurotransmission while promoting anxiolytic- and antidepressant-like effects. Moreover, a diet poor in these amino acids produced similar beneficial behavioral property. Collectively, these results suggest that metformin could be used as add-on therapy to a conventional antidepressant for the comorbidity between metabolic and mental disorders.

Apolipoprotein M: a novel adipokine decreasing with obesity and upregulated by calorie restriction.

BACKGROUND: The adipose tissue (AT) is a secretory organ producing a wide variety of factors that participate in the genesis of metabolic disorders linked to excess fat mass. Weight loss improves obesity-related disorders. OBJECTIVES: Transcriptomic studies on human AT, and a combination of analyses of transcriptome and proteome profiling of conditioned media from adipocytes and stromal cells isolated from human AT, have led to the identification of apolipoprotein M (apoM) as a putative adipokine. We aimed to validate apoM as novel adipokine, investigate the relation of AT APOM expression with metabolic syndrome and insulin sensitivity, and study the regulation of its expression in AT and secretion during calorie restriction-induced weight loss. METHODS: We examined APOM mRNA level and secretion in AT from 485 individuals enrolled in 5 independent clinical trials, and in vitro in human multipotent adipose-derived stem cell adipocytes. APOM expression and secretion were measured during dieting. RESULTS: APOM was expressed in human subcutaneous and visceral AT, mainly by adipocytes. ApoM was released into circulation from AT, and plasma apoM concentrations correlate with AT APOM mRNA levels. In AT, APOM expression inversely correlated with adipocyte size, was lower in obese compared to lean individuals, and reduced in subjects with metabolic syndrome and type 2 diabetes. Regardless of fat depot, there was a positive relation between AT APOM expression and systemic insulin sensitivity, independently of fat mass and plasma HDL cholesterol. In human multipotent adipose-derived stem cell adipocytes, APOM expression was enhanced by insulin-sensitizing peroxisome proliferator-activated receptor agonists and inhibited by tumor necrosis factor α, a cytokine that causes insulin resistance. In obese individuals, calorie restriction increased AT APOM expression and secretion. CONCLUSIONS: ApoM is a novel adipokine, the expression of which is a hallmark of healthy AT and is upregulated by calorie restriction. AT apoM deserves further investigation as a potential biomarker of risk for diabetes and cardiovascular diseases.

Interaction between hormone-sensitive lipase and ChREBP in fat cells controls insulin sensitivity.

Impaired adipose tissue insulin signalling is a critical feature of insulin resistance. Here we identify a pathway linking the lipolytic enzyme hormone-sensitive lipase (HSL) to insulin action via the glucose-responsive transcription factor ChREBP and its target, the fatty acid elongase ELOVL6. Genetic inhibition of HSL in human adipocytes and mouse adipose tissue results in enhanced insulin sensitivity and induction of ELOVL6. ELOVL6 promotes an increase in phospholipid oleic acid, which modifies plasma membrane fluidity and enhances insulin signalling. HSL deficiency-mediated effects are suppressed by gene silencing of ChREBP and ELOVL6. Mechanistically, physical interaction between HSL, independent of lipase activity, and the isoform activated by glucose metabolism ChREBPα impairs ChREBPα translocation into the nucleus and induction of ChREBPß, the isoform with high transcriptional activity that is strongly associated with whole-body insulin sensitivity. Targeting the HSL-ChREBP interaction may allow therapeutic strategies for the restoration of insulin sensitivity.

A realistic human skin model to study benzo[a]pyrene cutaneous absorption in order to determine the most relevant biomarker for carcinogenic exposure.

Polycyclic aromatic hydrocarbons (PAH) are ubiquitous pollutants, among which benzo[a]pyrene (B[a]P) is the only compound classified carcinogenic to humans. Besides pulmonary uptake, skin is the major route of PAH absorption during occupational exposure. Health risk due to PAH exposure is commonly assessed among workers using biomonitoring. A realistic human ex vivo skin model was developed to explore B[a]P diffusion and metabolism to determine the most relevant biomarker following dermal exposure. Three realistic doses (0.88, 8.85 and 22.11 nmol/cm2) were topically applied for 8, 24, and 48 h. B[a]P and its metabolites were quantified by liquid chromatography coupled with fluorimetric detection. The impact of time, applied dose, and donor age were estimated using a linear mixed-effects model. B[a]P vastly penetrated the skin within 8 h. The major metabolites were 3-hydroxybenzo[a]pyrene (3-OHB[a]P) and 7,8,9,10-tetrahydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene (B[a]P-tetrol). This latter predominantly derives from the most carcinogenic metabolite of B[a]P, benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE), as well as benzo[a]pyrene-9,10-diol-7,8-epoxide (reverse-BPDE). Benzo[a]pyrene-trans-7,8-dihydrodiol (B[a]P-7,8-diol) was a minor metabolite, and benzo[a]pyrene-trans-4,5-dihydrodiol (B[a]P-4,5-diol) was never quantified. Unmetabolized B[a]P bioavailability was limited following dermal exposure since less than 3% of the applied dose could be measured in the culture medium. B[a]P was continuously absorbed and metabolized by human skin over 48 h. B[a]P-tetrol production became saturated as the applied dose increased, while no effect was measured on the other metabolic pathways. Age had a slight positive effect on B[a]P absorption and metabolism. This work supports the relevance of B[a]P-tetrol to assess occupational exposure and carcinogenic risk after cutaneous absorption of B[a]P.

Niacin induces miR-502-3p expression which impairs insulin sensitivity in human adipocytes.

MicroRNAs have been involved in insulin resistance (IR). As the mechanism whereby niacin, an anti-dyslipidemic agent, leads to IR remains elusive, we sought to identify differentially expressed microRNAs in adipose tissue (AT) of individuals receiving niacin and to explore the link between microRNAs, niacin and IR in human adipocytes.In a double-blind controlled study, 22 obese men received extended-release niacin or placebo over 8 weeks. Bioclinical data and subcutaneous AT biopsies were obtained before and after treatment. AT microRNA expression profiles were determined using RTqPCR for 758 human-specific microRNAs. hMADS adipocytes were treated with niacin, or acipimox (a niacin-like drug without effect on IR), or transfected with miR-502-3p. Glucose uptake and Western blotting were performed.In obese men, insulin sensitivity decreased after niacin treatment. In AT, the expression of 6 microRNAs including miR-502-3p was up-regulated. Treatment of hMADS adipocytes with niacin specifically increased miR-502-3p expression. Acipimox had no effect. Overexpression of miR-502-3p in adipocytes led to reduced insulin-induced glucose uptake and lower insulin-stimulated AKT phosphorylation.Long term niacin treatment altered microRNA expression levels in human AT. Increased miR-502-3p expression may play a role in the mediation of IR due to niacin in adipocytes.The study is registered in Clinical Trials NCT01083329 and EudraCT 2009-012124-85.