The ribosomal protein S6 kinase 1 (S6K1) is a relevant effector downstream of the mammalian target of rapamycin complex 1 (mTORC1), best known for its role in the control of lipid homeostasis. ...Consistent with this, mice lacking the
S6k1
gene have a defect in their ability to induce the commitment of fat precursor cells to the adipogenic lineage, which contributes to a significant reduction of fat mass. Here, we assess the therapeutic blockage of S6K1 in diet-induced obese mice challenged with LY2584702 tosylate, a specific oral S6K1 inhibitor initially developed for the treatment of solid tumors. We show that diminished S6K1 activity hampers fat mass expansion and ameliorates dyslipidemia and hepatic steatosis, while modifying transcriptome-wide gene expression programs relevant for adipose and liver function. Accordingly, decreased mTORC1 signaling in fat (but increased in the liver) segregated with defective epithelial-mesenchymal transition and the impaired expression of Cd36 (coding for a fatty acid translocase) and Lgals1 (Galectin 1) in both tissues. All these factors combined align with reduced adipocyte size and improved lipidomic signatures in the liver, while hepatic steatosis and hypertriglyceridemia were improved in treatments lasting either 3 months or 6 weeks.
Several proteins of the innate immune system are known to be deregulated with insulin resistance. We here aimed to investigate the relationship among circulating lysozyme (both plasma concentration ...and activity) and obesity-associated metabolic disturbances.
Plasma lysozyme concentration was determined cross-sectionally in a discovery (Cohort 1, n = 137) and in a replication cohort (Cohort 2, n = 181), in which plasma lysozyme activity was also analyzed. Plasma lysozyme was also evaluated longitudinally in participants from the replication cohort (n = 93). Leukocyte lysozyme expression (LYZ mRNA) were also investigated in an independent cohort (Cohort 3, n = 76), and adipose tissue (AT) LYZ mRNA (n = 25) and plasma peptidoglycan levels (n = 61) in subcohorts from discovery cohort.
Translocation of peptidoglycan (as inferred from its increased circulating levels) was linked to plasma lysozyme, hyperinsulinemia and dyslipidemia in obese subjects. In both discovery and replication cohorts, plasma lysozyme levels and activity were significantly increased in obesity in direct association with obesity-associated metabolic disturbances and inflammatory parameters, being circulating lysozyme negatively correlated with fasting glucose, HbA1c and insulin resistance (HOMA-IR) in obese subjects. Of note, total cholesterol (p < 0.0001) and LDL cholesterol (p = 0.003) contributed independently to age-, gender- and BMI adjusted plasma lysozyme activity. Longitudinally, changes in HbA1c levels and serum LDL cholesterol were negatively associated with circulating lysozyme antimicrobial activity. On the contrary, the change in glucose infusion rate during the clamp (insulin sensitivity) was positively associated with lysozyme concentration.
Increased plasma lysozyme levels and activity are found in obese subjects. The longitudinal findings suggest that plasma lysozyme might be protective on the development of obesity-associated metabolic disturbances.
Recent studies indicate a possible role of TSH/TSHR signalling axis on adipogenesis and adipose tissue physiology. Here, we aimed to investigate the relationship between adipose tissue TSHB and ...adipose tissue physiology-related gene expression.
Subcutaneous and visceral adipose tissue TSHB gene expression was analysed in two independent cohorts Cohort1 (N = 96) and Cohort2 (N = 45) and after bariatric surgery-induced weight loss Cohort3 (N = 22). Adipose tissue TSH protein expression was also analysed in a subgroup of participants from Cohort 1 (N = 16). The effects of recombinant TSH on human subcutaneous preadipocytes and adipocytes were investigated.
In cohort 1, both visceral and subcutaneous adipose tissue TSHB gene expression was positively correlated with the expression of mitochondrial function (PPARGC1A, ISCA2, CISD1, SIRT1, NFE2L2, NRF1) and fatty acid mobilization (CAV1, ENGL1), but not with adipogenic-related genes. Of note, adipose tissue TSH protein levels were also associated with some of these markers of mitochondrial function and fatty acid mobilization. These associations were replicated in cohort 2. Bariatric surgery-induced weight loss resulted in increased subcutaneous adipose tissue TSHB in parallel to increased PPARGC1A. In human subcutaneous adipocytes, rh-TSH administration led to increased mitochondrial respiratory capacity in parallel to increased mitochondrial function- and adipogenic-related gene expression, but no significant effects were observed during differentiation of human preadipocytes.
These data point to a possible role of adipose tissue TSH in the maintenance of adipocyte mitochondrial function.
To investigate the impact of exogenous hydrogen sulfide (H
S) and its endogenous biosynthesis on human adipocytes and adipose tissue in the context of obesity and insulin resistance.
Experiments in ...human adipose tissue explants and in isolated preadipocytes demonstrated that exogenous H
S or the activation of endogenous H
S biosynthesis resulted in increased adipogenesis, insulin action, sirtuin deacetylase, and PPARγ transcriptional activity, whereas chemical inhibition and gene knockdown of each enzyme generating H
S (
,
,
) led to altered adipocyte differentiation, cellular senescence, and increased inflammation. In agreement with these experimental data, visceral and subcutaneous adipose tissue expression of H
S-synthesising enzymes was significantly reduced in morbidly obese subjects in association with attenuated adipogenesis and increased markers of adipose tissue inflammation and senescence. Interestingly, weight-loss interventions (including bariatric surgery or diet/exercise) improved the expression of H
S biosynthesis-related genes. In human preadipocytes, the expression of
,
, and
genes and H
S production were dramatically increased during adipocyte differentiation. More importantly, the adipocyte proteome exhibiting persulfidation was characterized, disclosing that different proteins involved in fatty acid and lipid metabolism, the citrate cycle, insulin signaling, several adipokines, and PPAR, experienced the most dramatic persulfidation (85-98%).
No previous studies investigated the impact of H
S on human adipose tissue. This study suggests that the potentiation of adipose tissue H
S biosynthesis is a possible therapeutic approach to improve adipose tissue dysfunction in patients with obesity and insulin resistance.
Altogether, these data supported the relevance of H
S biosynthesis in the modulation of human adipocyte physiology.
. 35, 319-340.
Chronic systemic low-level inflammation in metabolic disease is known to affect adipose tissue biology. Lysozyme (LYZ) is a major innate immune protein but its role in adipose tissue has not been ...investigated. Here, we aimed to investigate LYZ in human and rodents fat depots, and its possible role in obesity-associated adipose tissue dysfunction. LYZ mRNA and protein were identified to be highly expressed in adipose tissue from subjects with obesity and linked to systemic chronic-low grade inflammation, adipose tissue inflammation and metabolic disturbances, including hyperglycemia, dyslipidemia and decreased markers of adipose tissue adipogenesis. These findings were confirmed in experimental models after a high-fat diet in mice and rats and also in ob/ob mice. Importantly, specific inguinal and perigonadal white adipose tissue lysozyme (Lyz2) gene knockdown in high-fat diet-fed mice resulted in improved adipose tissue inflammation in parallel to reduced lysozyme activity. Of note, Lyz2 gene knockdown restored adipogenesis and reduced weight gain in this model. In conclusion, altogether these observations point to lysozyme as a new actor in obesity-associated adipose tissue dysfunction. The therapeutic targeting of lysozyme production might contribute to improve adipose tissue metabolic homeostasis.
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•Lysozyme gene is highly expressed in human and mice subcutaneous and visceral adipose tissue in association to obesity.•Adipose tissue lysozyme expression is linked to adipose tissue inflammation and obesity-associated metabolic disturbances.•Specific adipose tissue lysozyme gene knockdown reduces adipose tissue inflammation and restores adipogenesis.
Membrane-derived extracellular vesicles (EVs) are released to the circulation by cells found in adipose tissue, transferring microRNAs (miRNAs) that may mediate the adaptive response of recipient ...cells. This study investigated plasma EVs from obese vs. nonobese women and their functional impact in adipocytes.
Plasma EVs were isolated by differential centrifugation. Concentration and size were examined by nanoparticle tracking analysis (NanoSight). RNA was purified from plasma and plasma EVs of 45 women (47 ± 12 years, 58% of obesity) and profiles of mature miRNAs were assessed. Functional analyses were performed in human adipocytes.
Smaller plasma EVs were found in obese when compared to nonobese women. Positive associations were identified between circulating EVs numbers and parameters of impaired glucose tolerance. Almost 40% of plasma cell-free miRNAs were also found in isolated plasma EVs, defined as Ct values < 37 in ≥75% of samples. BMI together with parameters of insulin resistance were major contributors to EVs-contained miRNA patterns. Treatments of cultured human adipocytes with EVs from obese women led to a significant reduction of genes involved in lipid biosynthesis, while increasing the expression of IRS1 (12.3%, p = 0.002).
Interpretation: Size, concentration and the miRNA cargo of plasma EVs are associated with obesity and parameters of insulin resistance. Plasma EVs may mediate intercellular communication relevant to metabolism in adipocytes.
A dual role of hydrogen sulfide (H2S) in inflammation is well-reported and recent studies demonstrated adipogenic effects of H2S in 3T3-L1 cells. Here, we aimed to investigate the effects of H2S on ...adipocyte differentiation and inflammation. H2S concentration in 3T3-L1 culture media was increased during adipocyte differentiation in parallel to adipogenic and Cth gene expression, and its inhibition using DL-Propargyl Glycine (PPG) impaired 3T3-L1 differentiation. GYY4137 and Na2S administration only in the first or in the last stage of adipocyte differentiation resulted in a significant increased expression of adipogenic genes. However, when GYY4137 or Na2S were administrated during all process no significant effects on adipogenic gene expression were found, suggesting that excessive H2S administration might exert negative effects on adipogenesis. In fact, continuous addition of Na2S, which resulted in Na2S excess, inhibited adipogenesis, whereas time-expired Na2S had no effect. In inflammatory conditions, GYY4137, but not Na2S, administration attenuated the negative effects of inflammation on adipogenesis and insulin signaling-related gene expression during adipocyte differentiation. In inflamed adipocytes, Na2S administration enhanced the negative effects of inflammatory process. Altogether these data showed that slow-releasing H2S improved adipocyte differentiation in inflammatory conditions, and that H2S proadipogenic effects depend on dose, donor and exposure time.
•H2S releasing donors administration in the first or in the last stage of adipocyte differentiation has adipogenic effects.•H2S excess administration inhibited adipocyte differentiation.•Administration of a slow-releasing H2S donor attenuated the negative effects of inflammation on adipogenesis.
ABSTRACT
During adipogenesis, preadipocytes' cytoskeleton reorganizes in parallel with lipid accumulation. Failure to do so may impact the ability of adipose tissue (AT) to shift between lipid ...storage and mobilization. Here, we identify cytoskeletal transgelin 2 (TAGLN2) as a protein expressed in AT and associated with obesity and inflammation, being normalized upon weight loss. TAGLN2 was primarily found in the adipose stromovascular cell fraction, but inflammation, TGF‐β, and estradiol also prompted increased expression in human adipocytes. Tagln2 knockdown revealed a key functional role, being required for proliferation and differentiation of fat cells, whereas transgenic mice overexpressing Tagln2 using the adipocyte protein 2 promoter disclosed remarkable sex‐dependent variations, in which females displayed “healthy” obesity and hypertrophied adipocytes but preserved insulin sensitivity, and males exhibited physiologic changes suggestive of defective AT expandability, including increased number of small adipocytes, activation of immune cells, mitochondrial dysfunction, and impaired metabolism together with decreased insulin sensitivity. The metabolic relevance and sexual dimorphism of TAGLN2 was also outlined by genetic variants that may modulate its expression and are associated with obesity and the risk of ischemic heart disease in men. Collectively, current findings highlight the contribution of cytoskeletal TAGLN2 to the obese phenotype in a gender‐dependent manner.—Ortega, F. J., Moreno‐Navarrete, J. M., Mercader, J. M., Gómez‐Serrano, M., García‐Santos, E., Latorre, J., Lluch, A., Sabater, M., Caballano‐Infantes, E., Guzmán, R., Macías‐González, M., Buxo, M., Gironés, J., Vilallonga, R., Naon, D., Botas, P., Delgado, E., Corella, D., Burcelin, R., Frühbeck, G., Ricart, W., Simó, R., Castrillon‐Rodríguez, I., Tinahones, F. J., Bosch, F., Vidal‐Puig, A., Malagón, M. M., Peral, B., Zorzano, A., Fernández‐Real, J. M. Cytoskeletal transgelin 2 contributes to gender‐dependent adipose tissue expandability and immune function. FASEB J. 33, 9656–9671 (2019). www.fasebj.org
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