Thioredoxin reductase 1 suppresses adipocyte differentiation and insulin responsiveness

Recently thioredoxin reductase 1 (TrxR1), encoded by Txnrd1, was suggested to modulate glucose and lipid metabolism in mice. Here we discovered that TrxR1 suppresses insulin responsiveness, anabolic metabolism and adipocyte differentiation. Immortalized mouse embryonic fibroblasts (MEFs) lacking Txnrd1 (Txnrd1−/−) displayed increased metabolic flux, glycogen storage, lipogenesis and adipogenesis. This phenotype coincided with upregulated PPARγ expression, promotion of mitotic clonal expansion and downregulation of p27 and p53. Enhanced Akt activation also contributed to augmented adipogenesis and insulin sensitivity. Knockdown of TXNRD1 transcripts accelerated adipocyte differentiation also in human primary preadipocytes. Furthermore, TXNRD1 transcript levels in subcutaneous adipose tissue from 56 women were inversely associated with insulin sensitivity in vivo and lipogenesis in their isolated adipocytes. These results suggest that TrxR1 suppresses anabolic metabolism and adipogenesis by inhibition of intracellular signaling pathways downstream of insulin stimulationThis study was supported by funding to ESJA from Karolinska Institutet, The Swedish Research Council, The Swedish Cancer Society, to MR from the Strategic Research Program in Diabetes and to ACG from Diabetesfonden and a “Ramón y Cajal” fellowship (RYC-2014-15792) from Spanish Ministerio de Economía y Competitivida

Adipocyte Turnover: Relevance to Human Adipose Tissue Morphology

International audienceOBJECTIVE: Adipose tissue may contain few large adipocytes (hypertrophy) or many small adipocytes (hyperplasia). We investigated factors of putative importance for adipose tissue morphology. RESEARCH DESIGN AND METHODS: Subcutaneous adipocyte size and total fat mass were compared in 764 subjects with BMI 18-60 kg/m(2). A morphology value was defined as the difference between the measured adipocyte volume and the expected volume given by a curved-line fit for a given body fat mass and was related to insulin values. In 35 subjects, in vivo adipocyte turnover was measured by exploiting incorporation of atmospheric (14)C into DNA. RESULTS: Occurrence of hyperplasia (negative morphology value) or hypertrophy (positive morphology value) was independent of sex and body weight but correlated with fasting plasma insulin levels and insulin sensitivity, independent of adipocyte volume (beta-coefficient = 0.3, P < 0.0001). Total adipocyte number and morphology were negatively related (r = -0.66); i.e., the total adipocyte number was greatest in pronounced hyperplasia and smallest in pronounced hypertrophy. The absolute number of new adipocytes generated each year was 70% lower (P < 0.001) in hypertrophy than in hyperplasia, and individual values for adipocyte generation and morphology were strongly related (r = 0.7, P < 0.001). The relative death rate (approximately 10% per year) or mean age of adipocytes (approximately 10 years) was not correlated with morphology. CONCLUSIONS: Adipose tissue morphology correlates with insulin measures and is linked to the total adipocyte number independently of sex and body fat level. Low generation rates of adipocytes associate with adipose tissue hypertrophy, whereas high generation rates associate with adipose hyperplasia

Effects of selected bioactive food compounds on human white adipocyte function

Background: Previous studies suggest that intake of specific bioactive compounds may have beneficial clinical effects on adipose tissue partly due to their anti-inflammatory and insulin-sensitizing properties. With the overall aim to contribute to better understanding of the mechanisms of selected bioactive nutrients on fat metabolism, we investigated their role on human white adipocyte function. Methods: The influence of the omega-3-fatty acid docosahexaenoic acid (DHA), the anthocyanin (AC) cyanidin-3-glucoside and its metabolite protocatechuic acid, and the beta-glucan metabolite propionic acid (PI) on adipokine secretion, fatty acid metabolism (lipolysis/lipogenesis) and adipocyte differentiation (lipid accumulation) was studied in human fat cells differentiated in vitro. To investigate possible synergistic, additive or antagonistic effects, DHA was also combined with AC or PI. Results: Each compound, alone or together with DHA, suppressed basal adipocyte lipolysis compared to control treated cells. DHA alone attenuated the secretion of pro-inflammatory adipokines such as chemerin, interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1/CCL2), whereas AC suppressed only the latter two. Treatment with PI decreased IL-6, tumour necrosis factor alpha (TNFα) and adiponectin secretion. A combination of DHA and AC decreased TNFα secretion and increased insulin-stimulated lipogenesis. No effect was found on adipocyte differentiation. At the selected concentrations, none of the compounds was found to be cytotoxic. Conclusion: The studied bioactive food compounds or their metabolites have beneficial effects in human primary fat cells measured as decreased basal lipolytic activity and secretion of inflammatory markers. A minor effect was also observed on insulin-stimulated glucose uptake albeit only with the combination of DHA and AC. Taken together, our results may link the reported health benefits of the selected bioactives on metabolic disorders such as insulin resistance, hypertension and dyslipidemia to effects on white adipocytes

A Novel Type I Receptor Serine-Threonine Kinase Predominantly Expressed in the Adult Central Nervous System*

Receptor serine-threonine kinases (RSTK) mediate inhibitory as well as stimulatory signals for growth and differentiation by binding to members of the transforming growth factor-beta (TGF-beta) superfamily. Over 12 different RSTKs have been isolated so far, displaying wide expression in peripheral tissues and in the nervous system. Here we report the isolation and characterization of a novel type I RSTK termed activin receptor-like kinase-7 (ALK-7) that, unlike other members of this receptor family, is predominantly expressed in the adult central nervous system. The ALK-7 gene encodes a 55-kDa cell-surface protein that exhibits up to 78% amino acid sequence identity in the kinase domain to previously isolated type I receptors for TGF-beta and activin. In the extracellular domain, however, ALK-7 is more divergent, displaying comparable similarities with all members of the ALK subfamily. RNase protection and in situ hybridization studies demonstrated a highly specific mRNA distribution restricted to neurons in several regions of the adult rat central nervous system, including cerebellum, hippocampus, and nuclei of the brainstem. Receptor reconstitution and cross-linking experiments indicated that ALK-7 can form complexes with type II RSTKs for TGF-beta and activin in a ligand-dependent manner, although direct binding of ALK-7 to ligand in these complexes could not be demonstrated. The specific expression pattern of ALK-7, restricted to the postnatal central nervous system, indicates that this receptor may play an important role in the maturation and maintenance of several neuronal subpopulations

Transforming Growth Factor-β3 Regulates Adipocyte Number in Subcutaneous White Adipose Tissue.

White adipose tissue (WAT) mass is determined by adipocyte size and number. While adipocytes are continuously turned over, the mechanisms controlling fat cell number in WAT upon weight changes are unclear. Herein, prospective studies of human subcutaneous WAT demonstrate that weight gain increases both adipocyte size and number, but the latter remains unaltered after weight loss. Transcriptome analyses associate changes in adipocyte number with the expression of 79 genes. This gene set is enriched for growth factors, out of which one, transforming growth factor-β3 (TGFβ3), stimulates adipocyte progenitor proliferation, resulting in a higher number of cells undergoing differentiation in vitro. The relevance of these observations was corroborated in vivo where Tgfb3+/- mice, in comparison with wild-type littermates, display lower subcutaneous adipocyte progenitor proliferation, WAT hypertrophy, and glucose intolerance. TGFβ3 is therefore a regulator of subcutaneous adipocyte number and may link WAT morphology to glucose metabolism

Disrupted circadian oscillations in type 2 diabetes are linked to altered rhythmic mitochondrial metabolism in skeletal muscle

Funding: The authors are supported by grants from the AstraZeneca SciLifeLab Research Programme, Novo Nordisk Foundation (NNF14OC0011493, and NNF17OC0030088), Swedish Diabetes Foundation (DIA2018-357), Swedish Research Council (2015-00165 and 2018-02389), the Knut and Alice Wallenberg Foundation (2018-0094), the Strategic Research Programme in Diabetes at Karolinska Institutet (2009-1068), the Stockholm County Council (SLL20170159), and the Swedish Research Council for Sport Science (P2019-0140). B.M.G. was supported by fellowships from the Novo Nordisk Foundation (NNF19OC0055072), the Wenner-Gren Foundation, an Albert Renold Travel Fellowship from the European Foundation for the Study of Diabetes, and an Eric Reid Fund for Methodology from the Biochemical Society. N.J.P. and L.S.-P. were supported by an Individual Fellowship from the Marie Skłodowska-Curie Actions (European Commission: 704978 and 675610). X.Z. and K.A.E. were supported by NIH R01AR066082. N.J.P. was supported by grants from the Sigurd och Elsa Goljes Minne and Lars Hierta Memorial Foundations (Sweden). We acknowledge the Beta Cell in-vivo Imaging/Extracellular Flux Analysis core facility supported by the Strategic Research Program in Diabetes for the usage of the Seahorse flux analyzer. Additional support was received from the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen (NNF18CC0034900). The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent research center at the University of Copenhagen, partially funded by an unrestricted donation from the Novo Nordisk Foundation. We acknowledge the Single-Cell Omics platform at the Novo Nordisk Foundation Center for Basic Metabolic Research for technical and computational expertise and support. Schematics are created with BioRender.com.Peer reviewedPublisher PD

Ceruloplasmin is a novel adipokine which is overexpressed in adipose tissue of obese subjects and in obesity-associated cancer cells

Obesity confers an increased risk of developing specific cancer forms. Although the mechanisms are unclear, increased fat cell secretion of specific proteins (adipokines) may promote/facilitate development of malignant tumors in obesity via cross-talk between adipose tissue(s) and the tissues prone to develop cancer among obese. We searched for novel adipokines that were overexpressed in adipose tissue of obese subjects as well as in tumor cells derived from cancers commonly associated with obesity. For this purpose expression data from human adipose tissue of obese and non-obese as well as from a large panel of human cancer cell lines and corresponding primary cells and tissues were explored. We found expression of ceruloplasmin to be the most enriched in obesity-associated cancer cells. This gene was also significantly up-regulated in adipose tissue of obese subjects. Ceruloplasmin is the body's main copper carrier and is involved in angiogenesis. We demonstrate that ceruloplasmin is a novel adipokine, which is produced and secreted at increased rates in obesity. In the obese state, adipose tissue contributed markedly (up to 22%) to the total circulating protein level. In summary, we have through bioinformatic screening identified ceruloplasmin as a novel adipokine with increased expression in adipose tissue of obese subjects as well as in cells from obesity-associated cancers. Whether there is a causal relationship between adipose overexpression of ceruloplasmin and cancer development in obesity cannot be answered by these cross-sectional comparisons

Role of Receptor-Interacting Protein 140 in human fat cells

<p>Abstract</p> <p>Background</p> <p>Mice lacking <it>Receptor-interacting protein 140 (RIP140) </it>have reduced body fat which at least partly is mediated through increased lipid and glucose metabolism in adipose tissue. In humans, <it>RIP140 </it>is lower expressed in visceral white adipose tissue (WAT) of obese versus lean subjects. We investigated the role of <it>RIP140 </it>in human subcutaneous WAT, which is the major fat depot of the body.</p> <p>Methods</p> <p>Messenger RNA levels of <it>RIP140 </it>were measured in samples of subcutaneous WAT from women with a wide variation in BMI and in different human WAT preparations. <it>RIP140 </it>mRNA was knocked down with siRNA in <it>in vitro </it>differentiated adipocytes and the impact on glucose transport and mRNA levels of target genes determined.</p> <p>Results</p> <p><it>RIP140 </it>mRNA levels in subcutaneous WAT were decreased among obese compared to lean women and increased by weight-loss, but did not associate with mitochondrial DNA copy number. <it>RIP140 </it>expression increased during adipocyte differentiation <it>in vitro </it>and was higher in isolated adipocytes compared to corresponding pieces of WAT. Knock down of <it>RIP140 </it>increased basal glucose transport and mRNA levels of <it>glucose transporter 4 </it>and <it>uncoupling protein-1</it>.</p> <p>Conclusions</p> <p>Human <it>RIP140 </it>inhibits glucose uptake and the expression of genes promoting energy expenditure in the same fashion as the murine orthologue. Increased levels of human <it>RIP140 </it>in subcutaneous WAT of lean subjects may contribute to economize on energy stores. By contrast, the function and expression pattern does not support that <it>RIP140 </it>regulate human obesity.</p

Role of the Neutral Amino Acid Transporter SLC7A10 in Adipocyte Lipid Storage, Obesity and Insulin Resistance

Elucidation of mechanisms that govern lipid storage, oxidative stress, and insulin resistance may lead to improved therapeutic options for type 2 diabetes and other obesity-related diseases. Here, we find that adipose expression of the small neutral amino acid transporter SLC7A10, also known as alanine-serine-cysteine transporter-1 (ASC-1), shows strong inverse correlates with visceral adiposity, insulin resistance, and adipocyte hypertrophy across multiple cohorts. Concordantly, loss of Slc7a10 function in zebrafish in vivo accelerates diet-induced body weight gain and adipocyte enlargement. Mechanistically, SLC7A10 inhibition in human and murine adipocytes decreases adipocyte serine uptake and total glutathione levels and promotes reactive oxygen species (ROS) generation. Conversely, SLC7A10 overexpression decreases ROS generation and increases mitochondrial respiratory capacity. RNA sequencing revealed consistent changes in gene expression between human adipocytes and zebrafish visceral adipose tissue following loss of SLC7A10, e.g., upregulation of SCD (lipid storage) and downregulation of CPT1A (lipid oxidation). Interestingly, ROS scavenger reduced lipid accumulation and attenuated the lipid-storing effect of SLC7A10 inhibition. These data uncover adipocyte SLC7A10 as a novel important regulator of adipocyte resilience to nutrient and oxidative stress, in part by enhancing glutathione levels and mitochondrial respiration, conducive to decreased ROS generation, lipid accumulation, adipocyte hypertrophy, insulin resistance, and type 2 diabetes.acceptedVersio

ApoB100-LDL Acts as a Metabolic Signal from Liver to Peripheral Fat Causing Inhibition of Lipolysis in Adipocytes

International audienceBACKGROUND: Free fatty acids released from adipose tissue affect the synthesis of apolipoprotein B-containing lipoproteins and glucose metabolism in the liver. Whether there also exists a reciprocal metabolic arm affecting energy metabolism in white adipose tissue is unknown. METHODS AND FINDINGS: We investigated the effects of apoB-containing lipoproteins on catecholamine-induced lipolysis in adipocytes from subcutaneous fat cells of obese but otherwise healthy men, fat pads from mice with plasma lipoproteins containing high or intermediate levels of apoB100 or no apoB100, primary cultured adipocytes, and 3T3-L1 cells. In subcutaneous fat cells, the rate of lipolysis was inversely related to plasma apoB levels. In human primary adipocytes, LDL inhibited lipolysis in a concentration-dependent fashion. In contrast, VLDL had no effect. Lipolysis was increased in fat pads from mice lacking plasma apoB100, reduced in apoB100-only mice, and intermediate in wild-type mice. Mice lacking apoB100 also had higher oxygen consumption and lipid oxidation. In 3T3-L1 cells, apoB100-containing lipoproteins inhibited lipolysis in a dose-dependent fashion, but lipoproteins containing apoB48 had no effect. ApoB100-LDL mediated inhibition of lipolysis was abolished in fat pads of mice deficient in the LDL receptor (Ldlr(-/-)Apob(100/100)). CONCLUSIONS: Our results show that the binding of apoB100-LDL to adipocytes via the LDL receptor inhibits intracellular noradrenaline-induced lipolysis in adipocytes. Thus, apoB100-LDL is a novel signaling molecule from the liver to peripheral fat deposits that may be an important link between atherogenic dyslipidemias and facets of the metabolic syndrome