Adipose tissue cysteine dioxygenase type 1 is associated with an anti-inflammatory profile, impacting on systemic metabolic traits.

BACKGROUND: Adipose tissue is a source of multiple factors that modulate systemic insulin sensitivity and cardiovascular risk. Taurine is obtained from the diet but it is less known that it is endogenously synthesized by cysteine dioxygenase type 1 (CDO1). CDO1 exerts a role in adipose tissue from rodent models, but the potential translational value in humans is not available in the literature. METHODS: CDO1 gene expression was analysed in visceral and subcutaneous adipose tissue samples in association with metabolic traits in participants with different degrees of obesity in four independent cohorts. CDO1 was also evaluated in isolated human adipocytes in vitro. Mechanistically, CDO1gene knockdown (KD) of human preadipocytes and adipose-derived mesenchymal stem cells (ASC52telo) (using lentiviral particles) was also evaluated. Mitochondrial respiratory function of adipocytes was evaluated using Seahorse. FINDINGS: Both visceral (VAT) and subcutaneous adipose tissue (SAT) CDO1 mRNA was associated with gene expression markers of adipose tissue function in the four cohorts. Higher CDO1 expression was linked to decreased fasting triglycerides and blood HbA1c even after adjusting by age, BMI and sex. In addition, CDO1 mRNA positively correlated with the expression of genes involved in adipogenesis and negatively with different inflammatory markers. Both VAT and SAT CDO1 mRNA was mainly expressed in adipocytes and significantly increased during adipocyte differentiation, but attenuated under inflammatory conditions. Mechanistically, CDO1 gene KD reduced taurine biosynthesis, evidencing lower CDO1 activity. In both human preadipocytes and ASC52telo cells, CDO1 gene KD resulted in decreased gene expression markers of adipogenesis (ADIPOQ, FABP4, FASN, SLC2A4, CEBPA) and increased inflammatory genes (TNF and IL6) during adipocyte differentiation. Of note, CDO1 gene KD led to decreased mitochondrial respiratory function in parallel to decreased expression of mitochondrial function-, but not biogenesis-related genes. INTERPRETATION: Current findings show the relevance of CDO1 in adipose tissue physiology, suggesting its contribution to an improved systemic metabolic profile. FUNDING: This work was partially supported by research grants PI16/01173, PI19/01712, PI20/01090 and PI21/01361 from the Instituto de Salud Carlos III from Spain, Fondo Europeo de Desarrollo Regional (FEDER) funds, and VII Spanish Diabetes Association grants to Basic Diabetes Research Projects led by young researchers.

Downregulation of hepatic lipopolysaccharide binding protein improves lipogenesis-induced liver lipid accumulation.

Circulating lipopolysaccharide-binding protein (LBP) is increased in individuals with liver steatosis. We aimed to evaluate the possible impact of liver LBP downregulation using lipid nanoparticle-containing chemically modified LBP small interfering RNA (siRNA) (LNP-Lbp UNA-siRNA) on the development of fatty liver. Weekly LNP-Lbp UNA-siRNA was administered to mice fed a standard chow diet, a high-fat and high-sucrose diet, and a methionine- and choline-deficient diet (MCD). In mice fed a high-fat and high-sucrose diet, which displayed induced liver lipogenesis, LBP downregulation led to reduced liver lipid accumulation, lipogenesis (mainly stearoyl-coenzyme A desaturase 1 [Scd1]) and lipid peroxidation-associated oxidative stress markers. LNP-Lbp UNA-siRNA also resulted in significantly decreased blood glucose levels during an insulin tolerance test. In mice fed a standard chow diet or an MCD, in which liver lipogenesis was not induced or was inhibited (especially Scd1 mRNA), liver LBP downregulation did not impact on liver steatosis. The link between hepatocyte LBP and lipogenesis was further confirmed in palmitate-treated Hepa1-6 cells, in primary human hepatocytes, and in subjects with morbid obesity. Altogether, these data indicate that siRNA against liver Lbp mRNA constitutes a potential target therapy for obesity-associated fatty liver through the modulation of hepatic Scd1.

Downregulation of peripheral lipopolysaccharide binding protein impacts on perigonadal adipose tissue only in female mice.

BACKGROUND AND AIMS: The sexual dimorphism in fat-mass distribution and circulating leptin and insulin levels is well known, influencing the progression of obesity-associated metabolic disease. Here, we aimed to investigate the possible role of lipopolysaccharide-binding protein (LBP) in this sexual dimorphism. METHODS: The relationship between plasma LBP and fat mass was evaluated in 145 subjects. The effects of Lbp downregulation, using lipid encapsulated unlocked nucleomonomer agent containing chemically modified-siRNA delivery system, were evaluated in mice. RESULTS: Plasma LBP levels were associated with fat mass and leptin levels in women with obesity, but not in men with obesity. In mice, plasma LBP downregulation led to reduced weight, fat mass and leptin gain after a high-fat and high-sucrose diet (HFHS) in females, in parallel to increased expression of adipogenic and thermogenic genes in visceral adipose tissue. This was not observed in males. Plasma LBP downregulation avoided the increase in serum LPS levels in HFHS-fed male and female mice. Serum LPS levels were positively correlated with body weight and fat mass gain, and negatively with markers of adipose tissue function only in female mice. The sexually dimorphic effects were replicated in mice with established obesity. Of note, LBP downregulation led to recovery of estrogen receptor alpha (Esr1) mRNA levels in females but not in males. CONCLUSION: LBP seems to exert a negative feedback on ERα-mediated estrogen action, impacting on genes involved in thermogenesis. The known decreased estrogen action and negative effects of metabolic endotoxemia may be targeted through LBP downregulation.

Specific adipose tissue Lbp gene knockdown prevents diet-induced body weight gain, impacting fat accretion-related gene and protein expression.

Lipopolysaccharide binding protein (Lbp) has been recently identified as a relevant component of innate immunity response associated to adiposity. Here, we aimed to investigate the impact of adipose tissue Lbp on weight gain and white adipose tissue (WAT) in male and female mice fed an obesogenic diet. Specific adipose tissue Lbp gene knockdown was achieved through lentiviral particles containing shRNA-Lbp injected through surgery intervention. In males, WAT Lbp mRNA levels increased in parallel to fat accretion, and specific WAT Lbp gene knockdown led to reduced body weight gain, decreased fat accretion-related gene and protein expression, and increased inguinal WAT basal lipase activity, in parallel to lowered plasma free fatty acids, leptin, triglycerides but higher glycerol levels, resulting in slightly improved insulin action in the insulin tolerance test. In both males and females, inguinal WAT Lbp gene knockdown resulted in increased Ucp1 and Ppargc1a mRNA and Ucp1 protein levels, confirming adipose Lbp as a WAT browning repressor. In perigonadal WAT, Lbp gene knockdown also resulted in increased Ucp1 mRNA levels, but only in female mice, in which it was 500-fold increased. These data suggest specific adipose tissue Lbp gene knockdown as a possible therapeutic approach in the prevention of obesity-associated fat accretion.

Cecal Ligation and Puncture-Induced Sepsis Promotes Brown Adipose Tissue Inflammation Without Any Impact on Expression of Thermogenic-Related Genes.

Background and Aims: The negative effects of chronic low-level inflammation on adipose tissue physiology have been extensively demonstrated, whereas the effects of acute inflammation are less studied. Here, we aimed to investigate the effects of sepsis-induced acute inflammation on gene expression markers of brown and white adipose tissue functionality. Methods: Brown adipose tissue (BAT) and perirenal white adipose tissue (prWAT) gene expression markers were analyzed in cecal ligation and puncture (CLP)-induced sepsis mice model. Results: CLP-induced sepsis attenuated expression of adipogenesis-related genes, in parallel to increased Tnf, Il6, and Ltf gene expression in prWAT. In contrast, CLP-induced sepsis resulted in increased expression of pro-inflammatory genes (Il6, Ltf, and Lbp) in BAT, without affecting expression of genes encoding for thermogenic activity. Conclusion: Sepsis promotes both prWAT and BAT inflammation, associated with reduced adipogenesis-related gene expression in prWAT, without significant effects on BAT thermogenic genes.

The Impact of H2S on Obesity-Associated Metabolic Disturbances.

Over the last several decades, hydrogen sulfide (H2S) has gained attention as a new signaling molecule, with extensive physiological and pathophysiological roles in human disorders affecting vascular biology, immune functions, cellular survival, metabolism, longevity, development, and stress resistance. Apart from its known functions in oxidative stress and inflammation, new evidence has emerged revealing that H2S carries out physiological functions by targeting proteins, enzymes, and transcription factors through a post-translational modification known as persulfidation. This review article provides a critical overview of the current state of the literature addressing the role of H2S in obesity-associated metabolic disturbances, with particular emphasis on its mechanisms of action in obesity, diabetes, non-alcoholic fatty liver disease (NAFLD), and cardiovascular diseases.

Activation of Endogenous H2S Biosynthesis or Supplementation with Exogenous H2S Enhances Adipose Tissue Adipogenesis and Preserves Adipocyte Physiology in Humans.

Aims: To investigate the impact of exogenous hydrogen sulfide (H2S) and its endogenous biosynthesis on human adipocytes and adipose tissue in the context of obesity and insulin resistance. Results: Experiments in human adipose tissue explants and in isolated preadipocytes demonstrated that exogenous H2S or the activation of endogenous H2S biosynthesis resulted in increased adipogenesis, insulin action, sirtuin deacetylase, and PPARγ transcriptional activity, whereas chemical inhibition and gene knockdown of each enzyme generating H2S (CTH, CBS, MPST) led to altered adipocyte differentiation, cellular senescence, and increased inflammation. In agreement with these experimental data, visceral and subcutaneous adipose tissue expression of H2S-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 H2S biosynthesis-related genes. In human preadipocytes, the expression of CTH, CBS, and MPST genes and H2S 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%). Innovation: No previous studies investigated the impact of H2S on human adipose tissue. This study suggests that the potentiation of adipose tissue H2S biosynthesis is a possible therapeutic approach to improve adipose tissue dysfunction in patients with obesity and insulin resistance. Conclusion: Altogether, these data supported the relevance of H2S biosynthesis in the modulation of human adipocyte physiology. Antioxid. Redox Signal. 35, 319-340.

Adipose tissue knockdown of lysozyme reduces local inflammation and improves adipogenesis in high-fat diet-fed mice.

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.

Permanent cystathionine-ß-Synthase gene knockdown promotes inflammation and oxidative stress in immortalized human adipose-derived mesenchymal stem cells, enhancing their adipogenic capacity.

In the present study, we aimed to investigate the impact of permanent cystathionine-ß-Synthase (CBS) gene knockdown in human telomerase reverse transcriptase (hTERT) immortalized human adipose-derived mesenchymal stem cells (ASC52telo) and in their capacity to differentiate into adipocytes. CBS gene KD in ASC52telo cells led to increased cellular inflammation (IL6, CXCL8, TNF) and oxidative stress markers (increased intracellular reactive oxygen species and decreased reduced glutathione levels) in parallel to decreased H2S production and rejuvenation (LC3 and SIRT1)-related gene expression. In addition, CBS gene KD in ASC52telo cells resulted in altered mitochondrial respiratory function, characterised by decreased basal respiration (specifically proton leak) and spare respiratory capacity, without significant effects on cell viability and proliferation. In this context, shCBS-ASC52telo cells displayed enhanced adipogenic (FABP4, ADIPOQ, SLC2A4, CEBPA, PPARG)-, lipogenic (FASN, DGAT1)- and adipocyte (LEP, LBP)-related gene expression markers, decreased expression of proinflammatory cytokines, and increased intracellular lipid accumulation during adipocyte differentiation compared to control ASC52telo cells. Otherwise, the increased adipogenic potential of shCBS-ASC52telo cells was detrimental to the ability to differentiate into osteogenic linage. In conclusion, this study demonstrated that permanent CBS gene KD in ASC52telo cells promotes a cellular senescence phenotype with a very increased adipogenic potential, promoting a non-physiological enhanced adipocyte differentiation with excessive lipid storage.

Morbidly obese subjects show increased serum sulfide in proportion to fat mass.

BACKGROUND AND OBJECTIVES: The importance of hydrogen sulfide is increasingly recognized in the pathophysiology of obesity and type 2 diabetes in animal models. Very few studies have evaluated circulating sulfides in humans, with discrepant results. Here, we aimed to investigate serum sulfide levels according to obesity. SUBJECTS AND METHODS: Serum sulfide levels were analyzed, using a selective fluorescent probe, in two independent cohorts [cross-sectionally in discovery (n = 139) and validation (n = 71) cohorts, and longitudinally in 82 participants from discovery cohort]. In the validation cohort, blood gene expression of enzymes contributing to H2S generation and consumption were also measured. RESULTS: In the discovery cohort, serum sulfide concentration was significantly increased in subjects with morbid obesity at baseline and follow-up, and positively correlated with BMI and fat mass, but negatively with total cholesterol, haemoglobin, serum ferritin, iron and bilirubin after adjusting by age, gender and fat mass. Fat mass (ß = 0.51, t = 3.67, p < 0.0001) contributed independently to age-, gender-, insulin sensitivity- and BMI-adjusted serum sulfide concentration variance. Importantly, receiver operating characteristic analysis demonstrated the relevance of fat mass predicting serum sulfide levels, which was replicated in the validation cohort. In addition, serum sulfide concentration was decreased in morbidly obese subjects with impaired compared to those with normal fasting glucose. Longitudinally, weight gain resulted in increased serum sulfide concentration, whereas weight loss had opposite effects, being the percent change in serum sulfide positively correlated with the percent change in BMI and waist circumference, but negatively with bilirubin. Whole blood CBS, CTH, MPST, SQOR, TST and MPO gene expression was not associated to obesity or serum sulfide concentration. CONCLUSIONS: Altogether these data indicated that serum sulfide concentrations were increased in subjects with morbid obesity in proportion to fat mass and inversely associated with circulating markers of haem degradation.

Lysozyme is a component of the innate immune system linked to obesity associated-chronic low-grade inflammation and altered glucose tolerance.

BACKGROUND & AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Compounds that modulate AMPK activity and hepatic steatosis impact the biosynthesis of microRNAs required to maintain lipid homeostasis in hepatocytes.

BACKGROUND: While the impact of metformin in hepatocytes leads to fatty acid (FA) oxidation and decreased lipogenesis, hepatic microRNAs (miRNAs) have been associated with fat overload and impaired metabolism, contributing to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). METHODS: We investigated the expression of hundreds of miRNAs in primary hepatocytes challenged by compounds modulating steatosis, palmitic acid and compound C (as inducers), and metformin (as an inhibitor). Then, additional hepatocyte and rodent models were evaluated, together with transient mimic miRNAs transfection, lipid droplet staining, thin-layer chromatography, quantitative lipidomes, and mitochondrial activity, while human samples outlined the translational significance of this work. FINDINGS: Our results show that treatments triggering fat accumulation and AMPK disruption may compromise the biosynthesis of hepatic miRNAs, while the knockdown of the miRNA-processing enzyme DICER in human hepatocytes exhibited increased lipid deposition. In this context, the ectopic recovery of miR-30b and miR-30c led to significant changes in genes related to FA metabolism, consistent reduction of ceramides, higher mitochondrial activity, and enabled ß-oxidation, redirecting FA metabolism from energy storage to expenditure. INTERPRETATION: Current findings unravel the biosynthesis of hepatic miR-30b and miR-30c in tackling inadequate FA accumulation, offering a potential avenue for the treatment of NAFLD. FUNDING: Instituto de Salud Carlos III (ISCIII), Govern de la Generalitat (PERIS2016), Associació Catalana de Diabetis (ACD), Sociedad Española de Diabetes (SED), Fondo Europeo de Desarrollo Regional (FEDER), Xunta de Galicia, Ministerio de Economía y Competitividad (MINECO), "La Caixa" Foundation, and CIBER de la Fisiopatología de la Obesidad y Nutrición (CIBEROBN).

Circulating Irisin and Myostatin as Markers of Muscle Strength and Physical Condition in Elderly Subjects.

BACKGROUND AND OBJECTIVE: Aging is a physiological process known to produce changes in body composition, affecting the musculature and leading to decreased muscle strength. Muscle in response to exercise acts as an endocrine organ, producing and releasing myokines such as irisin and myostatin that modulate muscular growth. Here, we aimed to evaluate the effects of low intensity resistance exercise, with or without protein supplementation, on body composition, anthropometric parameters and circulating irisin and myostatin in elderly subjects. METHODS: This is a prospective and controlled clinical trial in which subjects were randomized into 3 groups: (1) control group (n = 20), (2) low intensity resistance exercise group (RE) (n = 14), and (3) low intensity resistance exercise and nutritional support group (RENS) (n = 9). Participants, aged 60-75 years, were studied at baseline and 16 weeks thereafter. Body composition was evaluated through bioelectric impedance. Serum irisin and myostatin was measured using ELISA. RESULTS: At follow-up, RENS resulted in a significant increase in fat free mass (47.4 ± 7.4 vs. 46.5 ± 7.4, p = 0.046), the calf muscle circumference (36.4 ± 1.3 vs. 32.3 ± 4.3, p = 0.025), and circulating irisin (3 ± 1.1 vs. 2.6 ± 1.3, p = 0.030) compared to baseline. RE resulted in a significant increase in grip strength (17.2 ± 4.6 vs. 15.3 ± 4.6, p = 0.011) and irisin (3.1 ± 0.8 vs. 2.4 ± 0.3, p = 0.011) and decreased walking speed at different distance (p < 0.02). Opposite findings in these parameters were observed in control intervention. In line with these findings, the percent change of calf muscle circumference (p = 0.003) and fat free mass (p < 0.0001) were significantly increased in RENS compared to control, whereas fat mass (p = 0.033) was decreased. Interestingly, in this group, strength was positively correlated with fat free mass (r = 0.782, p = 0.008), and circulating irisin was significantly decreased in those participants with strength loss at the end of the study (p = 0.002). No significant correlation between circulating irisin and myostatin in any group was observed. CONCLUSION: Circulating irisin, but not myostatin, constitutes a marker for improved muscular performance in elderly subjects.

Hydrogen sulfide impacts on inflammation-induced adipocyte dysfunction.

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.

Neuregulin 4 Is a Novel Marker of Beige Adipocyte Precursor Cells in Human Adipose Tissue.

Background: Nrg4 expression has been linked to brown adipose tissue activity and browning of white adipocytes in mice. Here, we aimed to investigate whether these observations could be translated to humans by investigating NRG4 mRNA and markers of brown/beige adipocytes in human visceral (VAT) and subcutaneous adipose tissue (SAT). We also studied the possible association of NRG4 with insulin action. Methods: SAT and VAT NRG4 and markers of brown/beige (UCP1, UCP3, and TMEM26)-related gene expression were analyzed in two independent cohorts (n = 331 and n = 59). Insulin resistance/sensitivity was measured using HOMAIR and glucose infusion rate during euglycemic hyperinsulinemic clamp. Results: In both cohort 1 and cohort 2, NRG4 and thermogenic/beige-related gene expression were significantly increased in VAT compared to SAT. Adipogenic-related genes followed an opposite pattern. In cohort 1, VAT NRG4 gene expression was positively correlated with BMI and expression of UCP1, UCP3, TMEM26, and negatively with adipogenic (FASN, PPARG, and SLC2A4)- and inflammatory (IL6 and IL8)-related genes. In SAT, NRG4 gene expression was negatively correlated with HOMAIR and positively with UCP1 and TMEM26 gene expression. Multiple linear regression analysis revealed that expression of TMEM26 gene was the best predictor of NRG4 gene expression in both VAT and SAT. Specifically, NRG4 and TMEM26 gene expression was significantly increased in VAT, but not in SAT stromal vascular fraction cells (p < 0.001). In cohort 2, the significant association between NRG4 and TMEM26 gene expression in both VAT and SAT was confirmed, and SAT NRG4 gene expression also was positively correlated with insulin action and the expression of UCP1. Conclusion: Current findings suggest NRG4 gene expression as a novel marker of beige adipocytes in human adipose tissue.

Adipose tissue TSH as a new modulator of human adipocyte mitochondrial function.

BACKGROUND/OBJECTIVES: 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. SUBJECTS/METHODS: 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. RESULTS: 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. CONCLUSION: These data point to a possible role of adipose tissue TSH in the maintenance of adipocyte mitochondrial function.

Adipose TSHB in Humans and Serum TSH in Hypothyroid Rats Inform About Cellular Senescence.

BACKGROUND/AIMS: Thyroid hormones have been recently linked to senescence and longevity. Given the recent description of TSHB mRNA in human adipose tissue (AT), we aimed to investigate the relationship between local AT TSH and adipose tissue senescence. METHODS: TSHB mRNA (measured by real-time PCR) and markers of adipose tissue senescence [BAX, DBC1, TP53, TNF (real-time PCR), telomere length (Telo TAGGG Telomere Length Assay) and lipidomics (liquid chromatography mass spectrometry)] were analysed in subcutaneous (SAT) and visceral (VAT) AT from euthyroid subjects. The chronic effects of TSH were also investigated in AT from hypothyroid rats and after recombinant human TSH (rhTSH) administration in human adipocytes. RESULTS: Both VAT and SAT TSHB gene expression negatively correlated with markers of AT cellular senescence (BAX, DBC1, TP53, TNF gene expression and specific glucosylceramides) and positively associated with telomere length. Supporting these observations, both rhTSH administration in human adipocytes and increased TSH in hypothyroid rats resulted in decreased markers of cellular senescence (Bax and Tp53 mRNA) in both gonadal and subcutaneous white adipose tissue. CONCLUSION: These data point to a possible role of TSH in AT cellular senescence.