Expression Of Thermogenesis-related Genes Research Articles

Salt-inducible kinase inhibition promotes the adipocyte thermogenic program and adipose tissue browning

ObjectiveNorepinephrine stimulates the adipose tissue thermogenic program through a β-adrenergic receptor (βAR)–cyclic adenosine monophosphate (cAMP)–protein kinase A (PKA) signaling cascade. We discovered that a noncanonical activation of the mechanistic target of rapamycin complex 1 (mTORC1) by PKA is required for the βAR-stimulation of adipose tissue browning. However, the downstream events triggered by PKA-phosphorylated mTORC1 activation that drive this thermogenic response are not well understood. MethodsWe used a proteomic approach of Stable Isotope Labeling by/with Amino acids in Cell culture (SILAC) to characterize the global protein phosphorylation profile in brown adipocytes treated with the βAR agonist. We identified salt-inducible kinase 3 (SIK3) as a candidate mTORC1 substrate and further tested the effect of SIK3 deficiency or SIK inhibition on the thermogenic gene expression program in brown adipocytes and in mouse adipose tissue. ResultsSIK3 interacts with RAPTOR, the defining component of the mTORC1 complex, and is phosphorylated at Ser884 in a rapamycin-sensitive manner. Pharmacological SIK inhibition by a pan-SIK inhibitor (HG-9-91-01) in brown adipocytes increases basal Ucp1 gene expression and restores its expression upon blockade of either mTORC1 or PKA. Short-hairpin RNA (shRNA) knockdown of Sik3 augments, while overexpression of SIK3 suppresses, Ucp1 gene expression in brown adipocytes. The regulatory PKA phosphorylation domain of SIK3 is essential for its inhibition. CRISPR-mediated Sik3 deletion in brown adipocytes increases type IIa histone deacetylase (HDAC) activity and enhances the expression of genes involved in thermogenesis such as Ucp1, Pgc1α, and mitochondrial OXPHOS complex protein. We further show that HDAC4 interacts with PGC1α after βAR stimulation and reduces lysine acetylation in PGC1α. Finally, a SIK inhibitor well-tolerated in vivo (YKL-05-099) can stimulate the expression of thermogenesis-related genes and browning of mouse subcutaneous adipose tissue. ConclusionsTaken together, our data reveal that SIK3, with the possible contribution of other SIKs, functions as a phosphorylation switch for β-adrenergic activation to drive the adipose tissue thermogenic program and indicates that more work to understand the role of the SIKs is warranted. Our findings also suggest that maneuvers targeting SIKs could be beneficial for obesity and related cardiometabolic disease.

Inhibition of high-fat diet-induced inflammatory responses in adipose tissue by SF1-expressing neurons of the ventromedial hypothalamus

Inflammation and thermogenesis in white adipose tissue (WAT) at different sites influence the overall effects of obesity on metabolic health. In mice fed a high-fat diet (HFD), inflammatory responses are less pronounced in inguinal WAT (ingWAT) than in epididymal WAT (epiWAT). Here we show that ablation and activation of steroidogenic factor 1 (SF1)-expressing neurons in the ventromedial hypothalamus (VMH) oppositely affect the expression of inflammation-related genes and the formation of crown-like structures by infiltrating macrophages in ingWAT, but not in epiWAT, of HFD-fed mice, with these effects being mediated by sympathetic nerves innervating ingWAT. In contrast, SF1 neurons of the VMH preferentially regulated the expression of thermogenesis-related genes in interscapular brown adipose tissue (BAT) of HFD-fed mice. These results suggest that SF1 neurons of the VMH differentially regulate inflammatory responses and thermogenesis among various adipose tissue depots and restrain inflammation associated with diet-induced obesity specifically in ingWAT.

Anti-Obesity Effects of Multi-Strain Probiotics in Mice with High-Carbohydrate Diet-Induced Obesity and the Underlying Molecular Mechanisms

Overconsumption of highly refined carbohydrates contributes significantly to the current obesity pandemics. Probiotic administration protects against weight gain in animals fed a high-fat diet (HFD). Nonetheless, the anti-obesity effects of probiotics in a high-carbohydrate diet (HCD)-induced obesity models are not well elucidated. Herein, C57BL/6N male mice were fed an HCD (70% kcal carbohydrate) for 12 weeks and were orally treated with multi-strain probiotics (MSPs) at 1010 CFU or saline every day for 6 weeks. MSPs contained Lactobacillus acidophilus DSM 24936, Lactiplantibacillus plantarum DSM 24937, and Limosilactobacillus reuteri DSM 25175. MSPs treatment not only ameliorated weight gain but also modulated the body fat composition altered by HCD. The MSPs also attenuated the expression of adipogenesis- and lipogenesis-related genes in HCD-fed mice. In addition, MSPs promoted the expression of lipolysis- and fatty acid oxidation-promoting factors in HCD-fed mice. Furthermore, MSPs modulated the expression of thermogenesis-related genes and the serum levels of obesity-related hormones altered by HCD. Treatment with MSPs positively reversed the Firmicutes/Bacteroidetes ratio, which is associated with a risk of obesity. Hence, this study explores the multifaceted anti-obesity mechanisms of MSPs and highlights their potential to be used as effective weight-management products.

The armadillo-repeat containing X-linked protein 3, ARMCX3, is a negative regulator of the browning of adipose tissue associated with obesity.

To determine the role of armadillo repeat-containing X-linked protein 3 (ARMCX3) in the thermogenic plasticity of adipose tissue. Adipose tissues were characterized in Armcx3-KO male mice. Armcx3 gene expression was analyzed in adipose tissue from mice exposed to thermogenic inducers (cold, β3-adenergic stimulus) and in differentiating brown and beige cells in culture. Analyses encompassed circulating metabolite and hormonal profiling, tissue characterization, histology, gene expression patterns, and immunoblot assays. Armcx3 gene expression was assessed in subcutaneous adipose tissue from lean individuals and individuals with obesity and was correlated with expression of marker genes of adipose browning. The effects of adenoviral-mediated overexpression of ARMCX3 on differentiating brown adipocyte gene expression and respiratory activity were determined. Male mice lacking ARMCX3 showed significant induction of white adipose tissue browning. In humans, ARMCX3 expression in subcutaneous adipose tissue was inversely correlated with the expression of marker genes of thermogenic activity, including CIDEA, mitochondrial transcripts, and creatine kinase-B. Armcx3 expression in adipose tissues was repressed by thermogenic activation (cold or β3-adrenergic stimulation) and was upregulated by obesity in mice and humans. Experimentally-induced increases in Armcx3 caused down-regulation of thermogenesis-related genes and reduced mitochondrial oxidative activity of adipocytes in culture, whereas siRNA-mediated Armcx3 knocking-down enhanced expression of thermogenesis-related genes. ARMCX3 is a novel player in the control of thermogenic adipose tissue plasticity that acts to repress acquisition of the browning phenotype and shows a direct association with indicators of obesity in mice and humans.

SOX4 promotes beige adipocyte-mediated adaptive thermogenesis by facilitating PRDM16-PPARγ complex.

Brown and beige fat protect against cold environments and obesity by catabolizing stored energy to generate heat. This process is achieved by controlling thermogenesis-related gene expression and the development of brown/beige fat through the induction of transcription factors, most notably PPARγ. However, the cofactors that induce the expression of thermogenic genes with PPARγ are still not well understood. In this study, we explored the role of SOX4 in adaptive thermogenesis and its relationship with PPARγ. Methods: Whole transcriptome deep sequencing (RNA-seq) analysis of inguinal subcutaneous white adipose tissue (iWAT) after cold stimulation was performed to identify genes with differential expression in mice. Indirect calorimetry detected oxygen consumption rate and heat generation. mRNA levels were analyzed by qPCR assays. Proteins were detected by immunoblotting and immunofluorescence. Interaction of proteins was detected by endogenous and exogenous Co-IP. ChIP-qPCR, FAIRE assay and luciferase reporter assays were used to investigate transcriptional regulation. Results: SOX4 was identified as the main transcriptional effector of thermogenesis. Mice with either adipocyte-specific or UCP1+ cells deletion of SOX4 exhibited significant cold intolerance, decreased energy expenditure, and beige adipocyte formation, which was attributed to decreased thermogenic gene expression. In addition, these mice developed obesity on a high-fat diet, with severe hepatic steatosis, insulin resistance, and inflammation. At the cell level, loss of SOX4 from preadipocytes inhibited the development of beige adipocytes, and loss of SOX4 from mature beige adipocytes reduced the expression of thermogenesis-related genes and energy metabolism. Mechanistically, SOX4 stimulated the transcriptional activity of Ucp1 by binding to PPARγ and activating its transcriptional function. These actions of SOX4 were, at least partly, mediated by recruiting PRDM16 to PPARγ, thus forming a transcriptional complex to elevate the expression of thermogenic genes. Conclusion: SOX4, as a coactivator of PPARγ, drives the thermogenic gene expression program and thermogenesis of beige fat, promoting energy expenditure. It has important physiological significance in resisting cold and obesity.

Acute Interval and Continuous Moderate Intensity Exercise Enhanced Circadian Thermogenic Activity through Browning related Genes in Obese Adolescent Female

Thermogenesis is associated with oxidation activity in muscle and fat tissue, the target of non-pharmacological therapy in preventing the increase in obesity. This research was designed to reveal the circadian profile of thermogenic gene expression after the acute interval and continuous moderate-intensity exercise. The subjects were 22 randomly selected obese adolescent females who met the predetermined inclusion criteria. The study subjects were then divided into three groups: control group (CG), acute interval moderate-intensity exercise group (AIMIE), and acute continuous moderate-intensity exercise group (ACMIE). Acute interval and continuous exercise were performed by running on a treadmill for 40-45 minutes, while moderate-intensity was defined as 60%-70% of the maximum heart rate (HRmax). The blood samples were collected initially (pre-exercise), followed by 10 minutes, 6 hours, and 24 hours post-acute interval and continuous moderate-intensity exercise treatment. Measurement of peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) and fibronectin type III domain 5 (FNDC-5) expressions in protein level were confirmed by enzyme-linked immunosorbent assay (ELISA) method. Data were analyzed using one way-ANOVA and two way-ANOVA with a significant level of 5%. The findings suggest a substantial increase in the expression of PGC-1α and FNDC-5 after exercise compared to before the workout. A significant difference in PGC-1α and FNDC-5 expressions between the control group compared to AIMIE and ACMIE (p ≤ 0.05) has been observed. However, there is no significant difference in PGC-1α and FNDC-5 expressions after exercise between AIMIE and ACMIE (p ≥ 0.05). In conclusion, acute interval and continuous moderate-intensity exercise increase the expression of thermogenesis-related genes. Hence, acute interval and continuous moderate-intensity exercise might be potential non-pharmacological therapy to prevent, reduce, and control the increasing prevalence of obesity.

IRX3 Overexpression Enhances Ucp1 Expression In Vivo.

ObjectiveThe Iroquois homeobox 3 (IRX3) gene was recently reported to be a functional downstream target of a common polymorphism in the FTO gene, which encodes an obesity-associated protein; however, the role of IRX3 in energy expenditure remains unclear. Studies have revealed that the overexpression of a dominant–negative form of IRX3 in the mouse hypothalamus and adipose tissue promoted energy expenditure by enhancing brown/browning activities. Meanwhile, we and others recently demonstrated that IRX3 knockdown impaired the browning program of primary preadipocytes in vitro. In this study, we aimed to further clarify the effects of overexpressing human IRX3 (hIRX3) on brown/beige adipose tissues in vivo.MethodsBrown/beige adipocyte-specific hIRX3-overexpressing mice were generated and the browning program of white adipose tissues was induced by both chronic cold stimulation and CL316,243 injection. Body weight, fat mass, lean mass, and energy expenditure were measured, while morphological changes and the expression of thermogenesis-related genes in adipose tissue were analyzed. Moreover, the browning capacity of primary preadipocytes derived from hIRX3-overexpressing mice was assessed. RNA sequencing was also employed to investigate the effect of hIRX3 on the expression of thermogenesis-related genes.ResultshIRX3 overexpression in embryonic brown/beige adipose tissues (Rosa26 h IRX3;Ucp1-Cre) led to increased energy expenditure, decreased fat mass, and a lean body phenotype. After acute cold exposure or CL316,243 stimulation, brown/beige tissue hIRX3-overexpressing mice showed an increase in Ucp1 expression. Consistent with this, induced hIRX3 overexpression in adult mice (Rosa26 h IRX3;Ucp1-CreERT2) also promoted a moderate increase in Ucp1 expression. Ex vitro experiments further revealed that hIRX3 overexpression induced by Ucp1-driven Cre recombinase activity upregulated brown/beige adipocytes Ucp1 expression and oxygen consumption rate (OCR). RNA sequencing analyses indicated that hIRX3 overexpression in brown adipocytes enhanced brown fat cell differentiation, glycolysis, and gluconeogenesis.ConclusionConsistent with the in vitro findings, brown/beige adipocyte-specific overexpression of hIRX3 promoted Ucp1 expression and thermogenesis, while reducing fat mass.

The association of the adipokine zinc-alpha2-glycoprotein with non-alcoholic fatty liver disease and related risk factors: A comprehensive systematic review.

The adipokine zinc-alpha2-glycoprotein (ZAG), a multidisciplinary protein, is involved in lipid metabolism, glucose homeostasis and energy balance. Accumulating evidence demonstrates that the expression of ZAG is mainly downregulated in obesity and obesity-related conditions. In the present study, we assessed the association of ZAG with non-alcoholic fatty liver disease (NAFLD) and the related risk factors including obesity, metabolic factors and inflammatory parameters, with emphasis on potential mechanisms underlying these associations. PRISMA guidelines were followed in this review. Systematic searches were performed using the PubMed/Medline, ScienceDirect, Scopus, EMBASE, ProQuest and Google Scholar databases, up to August 2020 for all relevant published papers. Out of 362 records screened, 34 articles were included in the final analysis. According to the studies reviewed here, ZAG appears to exert a protective effect against NAFLD by enhancing mRNA expression levels of peroxisome proliferator-activated receptor α (PPARα) and PPARγ, promoting mRNA expression levels of the lipolysis-related genes, reducing mRNA expression levels of the lipogenesis-related genes, increasing hepatic fatty acid oxidation, ameliorating hepatic steatosis, promoting the activity of brown adipose tissue and the expression of thermogenesis-related genes, modulating energy balance and glucose homeostasis, and elevating plasma levels of healthy adipokines such as adiponectin. ZAG can also be involved in the regulation of inflammatory responses by attenuation of the expression of pro-inflammatory and pro-fibrotic mediators. According to the studies reviewed here, ZAG is suggested to be a promising therapeutic target for NAFLD. However, the favourable effects of ZAG need to be confirmed in prospective cohort studies.

Leukotriene A4 hydrolase deficiency protects mice from diet-induced obesity by increasing energy expenditure through neuroendocrine axis.

Obesity is a health problem worldwide, and brown adipose tissue (BAT) is important for energy expenditure. Here, we explored the role of leukotriene A4 hydrolase (LTA4 H), a key enzyme in the synthesis of the lipid mediator leukotriene B4 (LTB4 ), in diet-induced obesity. LTA4 H-deficient (LTA4 H-KO) mice fed a high-fat diet (HFD) showed a lean phenotype, and bone-marrow transplantation studies revealed that LTA4 H-deficiency in non-hematopoietic cells was responsible for this lean phenotype. LTA4 H-KO mice exhibited greater energy expenditure, but similar food intake and fecal energy loss. LTA4 H-KO BAT showed higher expression of thermogenesis-related genes. In addition, the plasma thyroid-stimulating hormone and thyroid hormone concentrations, as well as HFD-induced catecholamine secretion, were higher in LTA4 H-KO mice. In contrast, LTB4 receptor (BLT1)-deficient mice did not show a lean phenotype, implying that the phenotype of LTA4 H-KO mice is independent of the LTB4 /BLT1 axis. These results indicate that LTA4 H mediates the diet-induced obesity by reducing catecholamine and thyroid hormone secretion.

Eriocitrin Improves Adiposity and Related Metabolic Disorders in High-Fat Diet-Induced Obese Mice

Eriocitrin (EC) is an abundant flavonoid in lemons, which is known as a strong antioxidant agent. This study investigated the biological and molecular mechanisms underlying the anti-obesity effect of EC in high-fat diet (HFD)-fed obese mice. C57BL/6N mice were fed an HFD (40 kcal% fat) with or without 0.005% (w/w) EC for 16 weeks. Dietary EC improved adiposity by increasing adipocyte fatty acid (FA) oxidation, energy expenditure, and mRNA expression of thermogenesis-related genes in brown adipose tissue (BAT) and skeletal muscle, whereas it also decreased lipogenesis-related gene expression in white adipose tissue. In addition to adiposity, EC prevented hepatic steatosis by diminishing lipogenesis while enhancing FA oxidation in the liver and fecal lipid excretion, which was linked to attenuation of hyperlipidemia. Moreover, EC improved insulin sensitivity by decreasing hepatic gluconeogenesis and proinflammatory responses. These findings indicate that EC may protect against diet-induced adiposity and related metabolic disorders by controlling thermogenesis of BAT and skeletal muscle, FA oxidation, lipogenesis, fecal lipid excretion, glucose utilization, and gluconeogenesis.

Pyruvate kinase M2 represses thermogenic gene expression in brown adipocytes.

Utilizing the thermogenic capacity of brown adipose tissue is a potential anti-obesity strategy; therefore, the mechanisms controlling expression of thermogenesis-related genes are of interest. Pyruvate kinase (PK) catalyzes the last step of glycolysis and exists as four isoenzymes: PK, liver, PK, red blood cell, PK, muscle (PKM1 and PKM2). PKM2 has both glycolytic and nuclear functions. Here, we report that PKM2 is enriched in brown adipose compared with white adipose tissue. Specific knockdown of PKM2 in mature brown adipocytes demonstrates that silencing of PKM2 does not lead to a decrease in PK activity, but causes a robust upregulation of thermogenic uncoupling protein 1 (Ucp1) and fibroblast growth factor 21 (Fgf21) gene expression. This increase is not mediated by any of the known mechanisms for PKM2-regulated gene expression, thus implying the existence of a novel mechanism for PKM2-dependent effects on gene expression.

Neonatal Resveratrol and Nicotinamide Riboside Supplementations Sex-Dependently Affect Beige Transcriptional Programming of Preadipocytes in Mouse Adipose Tissue.

Nutritional programming of the thermogenic and fuel oxidation capacity of white adipose tissue (WAT) through dietary interventions in early life is a potential strategy to enhance future metabolic health. We previously showed that mild neonatal supplementations with the polyphenol resveratrol (RSV) and the vitamin B3 form nicotinamide riboside (NR) have sex-dependent, long-term effects on the thermogenic/oxidative phenotype of WAT of mice in adulthood, enhancing this phenotype selectively in male animals. Here, we tested the hypothesis that these dietary interventions may impact the commitment of progenitor cells resident in the developing WAT toward brown-like (beige) adipogenesis. NMRI mice received orally from postnatal day 2–20 (P2–20) a mild dose of RSV or NR, in independent experiments; control littermates received the vehicle. Sex-separated primary cultures were established at P35 from the stromovascular fraction of inguinal WAT (iWAT) and of brown adipose tissue (BAT). Expression of genes related to thermogenesis and oxidative metabolism was assessed in the differentiated cultures, and in vivo in the iWAT depot of young (P35) animals. Neonatal RSV and NR treatments had little impact on the animals’ growth during early postnatal life and the expression of thermogenesis- and oxidative metabolism-related genes in the iWAT depot of young mice. However, the expression of brown/beige adipocyte marker genes was upregulated in the iWAT primary cultures from RSV supplemented and NR supplemented male mice, and downregulated in those from supplemented female mice, as compared to cultures derived from sex-matched control littermates. RSV supplementation had similar sex-dependent effects on the expression of thermogenesis-related genes in the BAT primary cultures. A link between the sex-dependent short-term effects of neonatal RSV and NR supplementations on primary iWAT preadipocyte differentiation observed herein and their previously reported sex-dependent long-term effects on the thermogenic/oxidative capacity of adult iWAT is suggested. The results provide proof-of-concept that the fate of preadipocytes resident in WAT of young animals toward the beige adipogenesis transcriptional program can be modulated by specific food bioactives/micronutrients received in early postnatal life.

Kiwifruit seed oil prevents obesity by regulating inflammation, thermogenesis, and gut microbiota in high-fat diet-induced obese C57BL/6 mice

Obesity is considered as a chronic disease which seriously affecting people's health and daily life. Kiwifruit (Actinidia chinensis Planch) seed oil (KSO), as a by-product of kiwifruit processing, is rich in fatty acids. Conventional wisdom holds that KSO has many health benefits, but there is no scientific basis. Here, the relieving effects of KSO on obesity and its potential mechanism were investigated in high-fat diet (HFD)-induced C57BL/6 mice. Mice were divided into four groups: ND (normal diet); HFD; L-KSO and H-KSO (HFD supplemented with 1.0 and 3.0 mL/kg·bw of KSO per day, respectively). Results showed that continuous supplementation KSO for 12 weeks significantly decreased bodyweight, inguinal fat tissue weight, blood glucose, and HOMA-IR index and ameliorated serum lipids accumulation (TC, TG, HDL-C, and LDL-C). Relative mRNA expression of inflammatory cytokines (TNF-α, IL-6, IL-1β, COX-2, and iNOS) was down-regulated and expression of thermogenesis-related genes (PPAR-γ, UCP1, PGC1-α, and PRDM16) was up-regulated in the inguinal fat tissue of KSO treated mice. Principal component analysis showed that the microbial community compositions of four groups were different. KSO supplementation dramatically decreased the Firmicutes-to-Bacteroidetes ratio. Together, our findings demonstrated that long-term supplementation KSO ameliorates obesity by reducing inflammation, adipose thermogenesis and gut microbiota dysbiosis.

GQ-16, a TZD-Derived Partial PPARγ Agonist, Induces the Expression of Thermogenesis-Related Genes in Brown Fat and Visceral White Fat and Decreases Visceral Adiposity in Obese and Hyperglycemic Mice.

BackgroundBeige adipocytes comprise a unique thermogenic cell type in the white adipose tissue (WAT) of rodents and humans, and play a critical role in energy homeostasis. In this scenario, recruitment of beige cells has been an important focus of interest for the development of novel therapeutic strategies to treat obesity. PPARγ activation by full agonists (thiazolidinediones, TZDs) drives the appearance of beige cells, a process so-called browning of WAT. However, this does not translate into increased energy expenditure, and TZDs are associated with weight gain. Partial PPARγ agonists, on the other hand, do not induce weight gain, but have not been shown to drive WAT browning. The present study was designed to investigate the effects of GQ-16 on BAT and on browning of WAT in obese mice.MethodsMale Swiss mice with obesity and hyperglycemia induced by high fat diet were treated with vehicle, rosiglitazone (4 mg/kg/d) or the TZD-derived partial PPARγ agonist GQ-16 (40 mg/kg/d) for 14 days. Fasting blood glucose, aspartate aminotransferase, alanine aminotransferase and lipid profile were measured. WAT and brown adipose tissue (BAT) depots were excised for determination of adiposity, relative expression of Ucp-1, Cidea, Prdm16, Cd40 and Tmem26 by RT-qPCR, histological analysis, and UCP-1 protein expression analysis by immunohistochemistry. Liver samples were also removed for histological analysis and determination of hepatic triglyceride content.ResultsGQ-16 treatment reduced high fat diet-induced weight gain in mice despite increasing energy intake. This was accompanied by reduced epididymal fat mass, reduced liver triglyceride content, morphological signs of increased BAT activity, increased expression of thermogenesis-related genes in interscapular BAT and epididymal WAT, and increased UCP-1 protein expression in interscapular BAT and in epididymal and inguinal WAT.ConclusionThis study suggests for the first time that a partial PPARγ agonist may increase BAT activity and induce the expression of thermogenesis-related genes in visceral WAT.General SignificanceThese findings suggest that PPARγ activity might be modulated by partial agonists to induce WAT browning and treat obesity.

CMKLR1 deficiency influences glucose tolerance and thermogenesis in mice on high fat diet

Obesity has become a global epidemic disease, contributing to increases in the prevalence of type 2 diabetes. CMKLR1, one of the receptors for chemerin, has a wide range of functions in physiological and pathological activity, including innate and adaptive immunity, inflammation, metabolism and reproduction. In our study, CMKLR1 deficiency did not influence the gain of body weight but did exacerbate glucose intolerance, increase serum insulin level, and promote insulin resistance in mice on high fat diets. The expression of thermogenesis related genes was examined and indicated to decrease in CMKLR1 knockout (KO) mice in both normal and cold environments, which indicated CMKLR1 influence the thermogenesis process. Cold exposure induced significant body mass decrease and improved glucose tolerance and insulin resistance in wild type HFD mice but had no obvious effect on CMKLR1 KO HFD mice. In vitro, loss of CMKLR1 did not significantly influence the differentiation of stromal vascular fibroblasts (SVFs) derived from adipose tissue, but did suppress the expression of thermogenesis related genes. Collectively, these data demonstrate that CMKLR1 deficiency induces inbalance of glucose metabolism and impairs the cold induced-thermogenesis process in high diet models.

Roles of hepatic glucokinase in intertissue metabolic communication: Examination of novel liver-specific glucokinase knockout mice

Glucokinase is expressed principally in pancreatic β-cells and hepatocytes, and catalyzes the phosphorylation of glucose to glucose-6-phosphate, a rate-limiting step of glycolysis. To better understand the roles of hepatic glucokinase, we generated Gck knockout mice by ablating liver-specific exon 1b. The knockout mice exhibited impaired glucose tolerance, decreased hepatic glycogen content, and reduced Pklr and Fas gene expression in the liver, indicating that hepatic glucokinase plays important roles in glucose metabolism. It has also been reported that hepatic glucokinase regulates the expression of thermogenesis-related genes in brown adipose tissue (BAT) and insulin secretion in response to glucose. However, the liver-specific Gck knockout mice displayed neither altered expression of thermogenesis-related genes in BAT nor impaired insulin secretion by β-cells under a normal chow diet. These results suggest that chronic suppression of hepatic glucokinase has a small influence on intertissue (liver-to-BAT as well as liver-to-β-cell) metabolic communication.

Obesity is associated with a decrease in expression but not with the hypermethylation of thermogenesis-related genes in adipose tissues.

BackgroundImpaired thermogenesis can promote obesity. Therefore, the aim of this study was to investigate whether the expression of thermogenesis-related genes is altered in adipose tissues of obese individuals and whether excessive methylation of their promoters is involved in this phenomenon.MethodsThe expression of genes encoding β adrenergic receptors (ADRBs), thyroid hormone receptors (THRs), 5’-iodothyronine deiodinases (DIOs), and uncoupling proteins (UCPs) was measured by real-time PCR in visceral and in subcutaneous adipose tissues of 58 obese (BMI >40 kg/m2) and 50 slim (BMI 20-24.9 kg/m2) individuals. The methylation status of these genes was studied by the methylation-sensitive digestion/real-time PCR method.ResultsThe expression of ADRB2, ADRB3, THRA, THRB, DIO2, UCP2 was significantly lower in the adipose tissues of obese patients than in tissues of normal-weight individuals (P < 0.00001). In the obese, the expression of ADRB2, ADRB3, DIO2 was lower in visceral adipose tissue than in subcutaneous adipose tissue (P = 0.008, P = 0.002, P = 0.001, respectively). However, the mean methylation of CpG islands of these genes was similar in tissues with their high and low expression, and there was no correlation between the level of expression and the level of methylation.ConclusionsDecreased expression of thermogenesis-related genes in adipose tissues of obese patients might result in the reduced reactivity to both hormonal and adrenergic stimuli and therefore in a lower potential to activate thermogenesis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0395-2) contains supplementary material, which is available to authorized users.

脂肪组织转化关键因子的研究进展

脂肪组织科分为褐色脂肪组织(Brown adipose tissue, BAT)和白色脂肪组织(white adipose tissue)。BAT为一种特化的产热组织，是小型哺乳动物非颤抖性产热的主要部位。PRDM16 (PR domain-con- taining 16)锌指蛋白在BAT中特异性表达，可触发BAT细胞中PGC-1α (Peroxisome proliferators-ac- tivated receptor-γcoactivator-1)和解偶联蛋白1基因等的表达，是促进褐色脂肪细胞形成的关键调控因子。BMP7 (Bone morphogenetic proteins 7)也可激活PRDM16和PGC-1α等基因的表达，刺激BAT细胞分化及产热增强。COXII (cyclooxygenase-2)、PPARα (peroxisome proliferator-activated receptor α)、PGC-1α是褐色脂肪细胞分化与代谢中的关键调控因子。在WAT中COXII是肾上腺素信号通路的一个效应分子，对于WAT中诱导形成褐色脂肪细胞是必需的。PPARα在BAT中的表达水平高于WAT，能诱导BAT中的产热相关基因的表达及原代褐色脂肪细胞的生成。PGC-1α也能诱导WAT中褐色脂肪细胞的形成，在褐色脂肪细胞分化的过程中PGC-1α表达量上升。本论文对脂肪转化过程中关键因子进行研究，并且对于小型哺乳动物的脂肪转化研究给出一些展望。 Adipose tissue is divided into brown adipose tissue (BAT) and white adipose tissue (WAT). BAT was a specialized thermogenic tissue, which was the main site of nonshivering thermogenesis in small mammals. PR domain-containing 16 (PRDM16) was a brown adipose determination factor. It was selectively expressed in BAT and induced the expression of α subunit of peroxisome proliferators-activated receptor-γcoactivator-1 (PGC-1α) and uncoupling protein 1. BMP7 could stimulate brown adipocyte differentiation and enhance thermogenesis by activating the expression PRDM16 and PGC-1α genes. COXII, PPARα and PGC-1α were the key regulatory factors of differentiation and metabolism in brown adipocyte. COXII was an effector molecule of adrenergic pathway in WAT. It was necessary for the formation of brown adipocytes. PPARα expression level in BAT was higher than WAT. It could induce the expression of thermogenesis related genes and promote the generation of primary brown adipocyte. PGC-1α also could induce the formation of brown adipocytes in WAT. In the process of brown adipocytes differentiation, PGC-1α expression level increased. In this paper, the key factors of transformation of adipose tissue were studied, and some prospects for the study of the fat tissue transformation of small mammals were given.

GQ‐16, a novel partial PPARγ ligand, decreases visceral adiposity and induces the expression of thermogenesis‐related genes in mice with obesity and insulin resistance induced by diet (1160.8)

Thiazolidinediones are used for the treatment of type 2 diabetes (T2DM) and their therapeutic actions are mediated via activation of PPARγ. Despite their efficacy, their use is limited by side effects such as weight gain. We have previously identified a novel PPARγ ligand with similar anti‐diabetic efficacy as rosiglitazone (RSG), but without weight gain.Objective: To evaluate the effects of different doses of GQ‐16 on adiposity and gene expression in mice with insulin resistance and obesity induced by diet.Methods: Mice were fed normal‐fat (NFD) or high‐fat (HFD) diet since weaning. At the age of 16 wk, they received GQ‐16 (5, 10 or 20mg/kg/d), RSG (4mg/kg/d) or vehicle by gavage. White adipose tissue (WAT) pads were excised for determination of adiposity and gene expression by qPCR.Results (P&lt;0.05, 4 mice/group): In HFD‐treated mice, weight gain was reduced by treatment with 5, 10 and 20 mg/kg/d of GQ‐16, but increased by RSG. GQ‐16 (10 and 20 mg/kg/d) decreased blood glucose similarly to RSG. In addition, GQ‐16 treatment (20 mg/kg/d) reduced WAT pads, whereas RSG treatment increased them. Brown fat‐selective genes were upregulated in WAT in response to GQ‐16.Conclusions: Lower doses of GQ‐16 decreased blood glucose and visceral adiposity. This latter finding might possibly reflect increased thermogenesis, since GQ‐16 induced the expression of thermogenesis‐related genes, and reinforces the potential of GQ‐16 as a new strategy to treat obese patients with T2DM.Grant Funding Source: CNPq

Brown fat like gene expression in the epicardial fat depot correlates with circulating HDL-cholesterol and triglycerides in patients with coronary artery disease

BackgroundRecent evidence indicates that epicardial adipose tissue (EAT) expresses uncoupling protein-1 (UCP1), a marker of brown adipocytes. However, the putative effects of the presence of brown adipocytes in EAT remain unknown. MethodsThe mRNA expression of genes related to brown adipocyte-mediated thermogenesis was measured in the fat samples collected from the epicardial-, mediastinal- and subcutaneous-depots of patients undergoing coronary artery bypass grafting. Both univariate and multivariate analyses were then utilized to determine any association between gene expression and the anthropometrics and fasting blood chemistries of these patients. ResultsEAT exhibited significantly higher expression of UCP1 and cytochrome c oxidase subunit-IV (COX-IV) compared to mediastinal- and subcutaneous-fat depots (P≤0.05). EAT expression of UCP1 (r=0.50), COX-IV (r=0.37) and lipoprotein lipase (LPL) (r=0.58) positively associated with circulating levels of HDL-cholesterol (P≤0.05). In addition, EAT expression of LPL, acyl coA dehydrogenase-short, -medium and -long chain genes associated negatively with circulating TG levels (P≤0.05). ConclusionsAbundance of UCP-1 in the EAT relative to other fat depots confirms the presence of brown adipocytes in human EAT. Furthermore, the correlations among the EAT expression of thermogenesis-related genes with the circulating HDL and TG levels indicate that presence of active brown adipocytes shares a functional association with the circulating plasma lipids in humans.