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p38 alpha in the preoptic area inhibits brown adipose tissue thermogenesis
Wang, J; Wu, SS; Zhan, HD; Bi, WK; Xu, Y; Liang, YX; Ge, YP; Peng, L; Jin, XC; Lu, KK; Zhao, JJ; Gao, L; He, Z
OBESITY 2022年 30卷11期 页码:2242-
无关键词信息
Objective Elevation of energy expenditure through an increase of brown adipose tissue (BAT) thermogenesis is regarded as one of the most promising ways to prevent obesity development. The preoptic area (POA) of the hypothalamus is a critical area for control of BAT thermogenesis. However, the intracellular signaling cascades in the POA for regulation of BAT thermogenesis are poorly understood. Methods Phosphorylation proteomics (phosphoproteomics) and bioinformatics approaches were used to disclose numerous hypothalamic signaling pathways involved in the regulation of BAT thermogenesis. Conditional manipulation of the p38 alpha gene in mouse POA was performed by stereotaxic injection of adeno-associated virus 9 vector to explore the role of p38 alpha in BAT thermogenesis. Results Multiple hypothalamic signaling pathways were triggered by cold exposure, especially the mitogen-activated protein kinase (MAPK) signaling pathway. The p38 alpha activation, but not extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun NH2-terminal kinase (JNK), in the hypothalamus was significantly decreased during cold exposure. p38 alpha deficiency in the POA dramatically elevated energy expenditure owing to a marked increase in BAT thermogenesis, resulting in significantly decreased body weight gain and fat mass. Overexpression of p38 alpha in the POA led to a dramatic increase in weight gain. Conclusions These results demonstrate that p38 alpha in the POA exacerbates obesity development, at least in part owing to a decrease in BAT thermogenesis.
Association between metabolic obesity phenotypes and multiple myeloma hospitalization burden: A national retrospective study
Zhang, Y; Fan, XD; Zhao, CH; Yuan, ZN; Cheng, YP; Wu, YF; Han, JM; Yuan, ZS; Zhao, YF; Lu, KK
FRONTIERS IN ONCOLOGY 2023年 13卷 页码:-null
无关键词信息
Background & purposeObesity and metabolic disorders were associated with increased risk of MM, a disease characterized by high risk of relapsing and require frequent hospitalizations. In this study, we conducted a retrospective cohort study to explore the association of metabolic obesity phenotypes with the readmission risk of MM. Patients & methodsWe analyzed 34,852 patients diagnosed with MM from the Nationwide Readmissions Database (NRD), a nationally representative database from US. Hospitalization diagnosis of patients were obtained using ICD-10 diagnosis codes. According to obesity and metabolic status, the population was divided into four phenotypes: metabolically healthy non-obese (MHNO), metabolically unhealthy non-obese (MUNO), metabolically healthy obese (MHO), and metabolically unhealthy obese (MUO). The patients with different phenotypes were observed for hospital readmission at days 30-day, 60-day, 90-day and 180-day. Multivariate cox regression model was used to estimate the relationship between obesity metabolic phenotypes and readmissions risk. ResultsThere were 5,400 (15.5%), 7,255 (22.4%), 8,025 (27.0%) and 7,839 (35.6%) unplanned readmissions within 30-day, 60-day, 90-day and 180-day follow-up, respectively. For 90-day and 180-day follow-up, compared with patients with the MHNO phenotype, those with metabolic unhealthy phenotypes MUNO (90-day: P = 0.004; 180-day: P = < 0.001) and MUO (90-day: P = 0.049; 180-day: P = 0.004) showed higher risk of readmission, while patients with only obesity phenotypes MHO (90-day: P = 0.170; 180-day: P = 0.090) experienced no higher risk. However, similar associations were not observed for 30-day and 60-day. Further analysis in 90-day follow-up revealed that, readmission risk elevated with the increase of the combined factor numbers, with aHR of 1.068 (CI: 1.002-1.137, P = 0.043, with one metabolic risk factor), 1.109 (CI: 1.038-1.184, P = 0.002, with two metabolic risk factors) and 1.125 (95% CI: 1.04-1.216, P = 0.003, with three metabolic risk factors), respectively. ConclusionMetabolic disorders, rather than obesity, were independently associated with higher readmission risk in patients with MM, whereas the risk elevated with the increase of the number of combined metabolic factors. However, the effect of metabolic disorders on MM readmission seems to be time-dependent. For MM patient combined with metabolic disorders, more attention should be paid to advance directives to reduce readmission rate and hospitalization burden.
Metabolomics in Diabetic Retinopathy: From Potential Biomarkers to Molecular Basis of Oxidative Stress
Jian, QZ; Wu, YJ; Zhang, F
CELLS 2022年 11卷19期 页码:-null
无关键词信息
Diabetic retinopathy (DR), the leading cause of blindness in working-age adults, is one of the most common complications of diabetes mellitus (DM) featured by metabolic disorders. With the global prevalence of diabetes, the incidence of DR is expected to increase. Prompt detection and the targeting of anti-oxidative stress intervention could effectively reduce visual impairment caused by DR. However, the diagnosis and treatment of DR is often delayed due to the absence of obvious signs of retina imaging. Research progress supports that metabolomics is a powerful tool to discover potential diagnostic biomarkers and therapeutic targets for the causes of oxidative stress through profiling metabolites in diseases, which provides great opportunities for DR with metabolic heterogeneity. Thus, this review summarizes the latest advances in metabolomics in DR, as well as potential diagnostic biomarkers, and predicts molecular targets through the integration of genome-wide association studies (GWAS) with metabolomics. Metabolomics provides potential biomarkers, molecular targets and therapeutic strategies for controlling the progress of DR, especially the interventions at early stages and precise treatments based on individual patient variations.
Polyunsaturated fatty acids promote the rapid fusion of lipid droplets in Caenorhabditis elegans
Wang, YL; Li, CX; Zhang, JJ; Xu, XM; Fu, L; Xu, J; Zhu, H; Hu, Y; Li, CB; Wang, MJ; Wu, YJ; Zou, XJ; Liang, B
JOURNAL OF BIOLOGICAL CHEMISTRY 2022年 298卷8期 页码:-null
无关键词信息
Lipid droplets (LDs) are intracellular organelles that dynamically regulate lipids and energy homeostasis in the cell. LDs can grow through either local lipid synthesis or LD fusion. However, how lipids involving in LD fusion for LD growth is largely unknown. Here, we show that genetic mutation of acox-3 (acyl-CoA oxidase), maoc-1 (enoyl-CoA hydratase), dhs-28 (3-hydroxylacyl-CoA dehydrogenase), and daf-22 (3-ketoacyl-CoA thiolase), all involved in the peroxisomal beta-oxidation pathway in Caenorhabditis elegans, led to rapid fusion of adjacent LDs to form giant LDs (gLDs). Mechanistically, we show that dysfunction of peroxisomal beta-oxidation results in the accumulation of long-chain fatty acid-CoA and phosphocho-line, which may activate the sterol-binding protein 1/sterol regulatory element-binding protein to promote gLD forma-tion. Furthermore, we found that inactivation of either FAT-2 (delta-12 desaturase) or FAT-3 and FAT-1 (delta-15 desaturase and delta-6 desaturase, respectively) to block the biosynthesis of polyunsaturated fatty acids (PUFAs) with three or more double bonds (n >= 3-PUFAs) fully repressed the formation of gLDs; in contrast, dietary supplementation of n >= 3-PUFAs or phosphocholine bearing these PUFAs led to recovery of the formation of gLDs in peroxisomal beta-oxidation-defective worms lacking PUFA biosynthesis. Thus, we conclude that n >= 3-PUFAs, distinct from other well-known lipids and proteins, promote rapid LD fusion leading to LD growth.
Microalgae oil from Schizochytrium sp. alleviates obesity and modulates gut microbiota in high-fat diet-fed mice
Ran, LY; Yu, JH; Ma, R; Yao, Q; Wang, MJ; Bi, YP; Yu, ZC; Wu, YJ
FOOD & FUNCTION 2022年 13卷24期 页码:12799-
无关键词信息
Omega-3 PUFAs rich in fish oil are believed to prevent obesity by improving lipid metabolism and regulating gut microbiota. Microalgae oil is considered as an alternative source of omega-3 PUFAs owing to diminishing fish resources. Schizochytrium microalgae oil (SMO), with a high DHA proportion, is a promising source for commercial DHA production. However, its weight-loss and gut microbiota-regulating properties are not well studied. Here we compared the obesity reducing effects of SMO, commercial fish oil (FO) and a weight-loss drug, Orlistat (OL), in a high-fat diet (HFD) induced obesity mouse model. We found that SMO is comparable to commercial FO and OL with regard to weight loss, and it even exhibits the weight-loss effects earlier than FO and OL. It can efficiently inhibit the expression of lipogenesis-related genes and induce the expression of lipolysis-related genes. Moreover, SMO has different gut microbiota modulating effects from those of FO and OL. It does not influence the diversity of bacterial community, but does increase the abundance of several beneficial SCFAs-producing bacteria and inhibits obesity-promoting Desulfovibrio and several pathogens. We also found that SMO recovers the HFD-disturbed metabolic capability of gut microbiota. It can increase the abundance of several metabolism-related pathways, such as those of amino acids, SCFAs and bile acid, and decrease the level of the LPS biosynthesis pathway, which probably contributes to an improvement of lipid metabolism and restoration of the colonic mucosal barrier impaired by HFD. Our data suggest that SMO can be used as a superior dietary supplement for alleviating obesity.
Ajuba functions as a co-activator of C/EBP beta to induce expression of PPAR gamma and C/EBP alpha during adipogenesis
Yan, H; Li, Q; Li, MY; Zou, XQ; Bai, NN; Yu, ZC; Zhang, J; Zhang, D; Zhang, Q; Wang, JM; Jia, H; Wu, YJ; Hou, ZY
MOLECULAR AND CELLULAR ENDOCRINOLOGY 2022年 MOL CELL ENDOCRINOL卷Mol. Cell. Endocrinol.期 页码:-null
无关键词信息
Adipogenesis is regulated by a complicated network of transcription factors among which PPAR gamma and C/EBP family members are the major regulators. During adipogenesis, C/EBP beta is induced early and then transactivates PPAR gamma and C/EBP alpha, which cooperatively induce genes whose expressions give rise to the mature adipocyte phenotype. Identifying the factors that influence the expression and activity of C/EBP beta should provide additional insight into the mechanisms regulating adipogenesis. Here, we demonstrate that depletion of Ajuba in 3T3-L1 cells significantly decreases mRNA and protein levels of PPAR gamma and C/EBP alpha and impairs adipocyte differentiation, while overexpression increases expression of these genes and promotes adipocyte differentiation. Moreover, restoration of C/EBP alpha or PPAR gamma expression in Ajuba-deficient 3T3-L1 cells improves the impaired lipid accumulation. Mechanistically, Ajuba interacts with C/EBP beta and recruits CBP to facilitate the binding of C/EBP beta to the promoter of PPAR gamma and C/EBP alpha, resulting in increased H3 histone acetylation and target gene expression. Collectively, these data indicate that Ajuba functions as a co-activator of C/EBP beta, and may be an important therapeutic target for combating obesity-related diseases.
GATA zinc finger protein p66 & beta; promotes breast cancer cell migration by acting as a co-activator of Snail
Zou, XQ; Ma, L; Zhang, YH; Zhang, Q; Xu, C; Zhang, D; Chu, YM; Zhang, J; Li, MY; Zhang, H; Wang, JM; Peng, CC; Wei, G; Wu, YJ; Hou, ZY; Jia, H
CELL DEATH & DISEASE 2023年 14卷6期 页码:-null
无关键词信息
The transcriptional repressor Snail induces EMT during embryonic development and tumor metastasis. Growing evidence indicates that Snail functions as a trans-activator to induce gene expression; however, the underlying mechanism remains elusive. Here, we report that Snail cooperates with GATA zinc finger protein p66 & beta; to transactivate genes in breast cancer cells. Biologically, depletion of p66 & beta; reduces cell migration and lung metastasis in BALB/c mice. Mechanistically, Snail interacts with p66 & beta; and cooperatively induces gene transcription. Notably, a group of genes induced by Snail harbor conserved G-rich cis-elements (5 & PRIME;-GGGAGG-3 & PRIME;, designated as G-box) in their proximal promoter regions. Snail directly binds to G-box via its zinc fingers and transactivates the G-box-containing promoters. p66 & beta; enhances Snail binding affinity to G-box, whereas depletion of p66 & beta; results in a decreased binding affinity of Snail to the endogenous promoters and concomitantly reduces the transcription of Snail-induced genes. Taken together, these data demonstrated that p66 & beta; is critical for Snail-mediated cell migration by acting as a co-activator of Snail to induce genes containing G-box elements in the promoters.
Branched-Chain Amino Acids Metabolism and Their Roles in Retinopathy: From Relevance to Mechanism
Zhang, XA; Xia, MX; Wu, YJ; Zhang, F
NUTRIENTS 2023年 15卷9期 页码:-null 影响因子:3.759
无关键词信息
Retinopathy is one of the leading causes of irreversible blindness and vision loss worldwide. Imbalanced nutrients play important roles in the pathogenesis and pathophysiology of retinal diseases. Branched-Chain Amino Acids (BCAAs), as essential amino acids, perform a variety of biological functions, including protein synthesis, glucose metabolism, lipid metabolism, inflammation, and oxidative stress in metabolic tissues of diabetes and aging-related diseases. Recently, it has been shown that BCAAs are highly related to neuroprotection, oxidative stress, inflammatory and glutamate toxicity in the retina of retinopathy. Therefore, this review summarizes the alterations of BCAA levels in retinopathy, especially diabetic retinopathy and aging-related macular disease, and the genetics, functions, and mechanisms of BCAAs in the retina as well as other metabolic tissues for reference. All of these efforts aim to provide fundamental knowledge of BCAAs for further discoveries and research on retina health based on the sensing and signaling of essential amino acids.
Oxysterol-Binding Protein: new insights into lipid transport functions and human diseases
Lin, YN; Ran, LY; Du, XM; Yang, HY; Wu, YJ
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS 2023年 1868卷9期 页码:-null
无关键词信息
Oxysterol-binding protein (OSBP) mediates lipid exchange between organelles at membrane contact sites, thereby regulating lipid dynamics and homeostasis. How OSBP's lipid transfer function impacts health and disease remain to be elucidated. In this review, we first summarize the structural characteristics and lipid transport functions of OSBP, and then focus on recent progresses linking OSBP with fatty liver disease, diabetes, lysosome-related diseases, cancer and viral infections, with the aim of discovering novel therapeutic strategies for common human diseases.
重组人生长激素对棕榈酸诱导的HepG2细胞脂质沉积的影响
张芳;冉丽媛;张金金;吴英杰;
山东第一医科大学(山东省医学科学院)学报 2023年 44卷09期 页码:641-646
重组人生长激素;;脂肪肝细胞模型;;棕榈酸;;脂质代谢
目的 探讨重组人生长激素(recombinant human growth hormone,rhGH)对体外诱导的脂肪肝细胞模型脂质代谢的影响,为进一步拓广rhGH在临床中的应用提供理论支撑。方法 利用棕榈酸(palmitic acid,PA)诱导HepG2细胞脂质积累,构建脂肪肝细胞模型,对细胞模型给予不同浓度的rhGH处理,利用CCK8实验检测不同浓度PA和rhGH对HepG2细胞存活率的影响,通过油红O染色评估HepG2细胞中的脂质积累水平,采用实时荧光定量PCR(real-time fluorescence quantitative PCR,RT-qPCR)和Western blot评估HepG2细胞系内脂质代谢相关基因和蛋白表达水平。结果 利用0.2 mmol/L PA,成功诱导了脂肪肝细胞模型,该模型表现为细胞质内脂滴显著积聚。经rhGH刺激后,胞内脂滴积聚随rhGH浓度升高而降低,40μg/L的rhGH给药浓度可达到显著降脂效果。RT-qPCR和Western blot结果显示,rhGH处理后细胞内脂质合成相关基因和蛋白表达显著下调,脂质分解相关基因和蛋白表达无明显变化。结论 rhGH可通过抑制脂肪酸从头合成途径来减轻PA诱导的HepG2细胞中的脂质沉积。
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