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1.
Cell ; 185(6): 949-966.e19, 2022 03 17.
Article in English | MEDLINE | ID: mdl-35247329

ABSTRACT

Beige fat plays key roles in the regulation of systemic energy homeostasis; however, detailed mechanisms and safe strategy for its activation remain elusive. In this study, we discovered that local hyperthermia therapy (LHT) targeting beige fat promoted its activation in humans and mice. LHT achieved using a hydrogel-based photothermal therapy activated beige fat, preventing and treating obesity in mice without adverse effects. HSF1 is required for the effects since HSF1 deficiency blunted the metabolic benefits of LHT. HSF1 regulates Hnrnpa2b1 (A2b1) transcription, leading to increased mRNA stability of key metabolic genes. Importantly, analysis of human association studies followed by functional analysis revealed that the HSF1 gain-of-function variant p.P365T is associated with improved metabolic performance in humans and increased A2b1 transcription in mice and cells. Overall, we demonstrate that LHT offers a promising strategy against obesity by inducing beige fat activation via HSF1-A2B1 transcriptional axis.


Subject(s)
Adipose Tissue, Beige , Adipose Tissue, White , Hyperthermia, Induced , Obesity/therapy , Adipose Tissue, Beige/metabolism , Adipose Tissue, Brown/metabolism , Adipose Tissue, White/metabolism , Animals , Mice , Mice, Inbred C57BL , Obesity/metabolism
2.
Adv Sci (Weinh) ; 10(25): e2300436, 2023 09.
Article in English | MEDLINE | ID: mdl-37407508

ABSTRACT

N6-methyladenosine (m6 A) modification has been implicated in the progression of obesity and metabolic diseases. However, its impact on beige fat biology is not well understood. Here, via m6 A-sequencing and RNA-sequencing, this work reports that upon beige adipocytes activation, glycolytic genes undergo major events of m6 A modification and transcriptional activation. Genetic ablation of m6 A writer Mettl3 in fat tissues reveals that Mettl3 deficiency in mature beige adipocytes leads to suppressed glycolytic capability and thermogenesis, as well as reduced preadipocytes proliferation via glycolytic product lactate. In addition, specific modulation of Mettl3 in beige fat via AAV delivery demonstrates consistently Mettl3's role in glucose metabolism, thermogenesis, and beige fat hyperplasia. Mechanistically, Mettl3 and m6 A reader Igf2bp2 control mRNA stability of key glycolytic genes in beige adipocytes. Overall, these findings highlight the significance of m6 A on fat biology and systemic energy homeostasis.


Subject(s)
Adipose Tissue, Beige , Glycolysis , Methylation , Adipose Tissue, Beige/metabolism , Glycolysis/genetics , Homeostasis/genetics , RNA/metabolism
3.
Front Physiol ; 12: 667698, 2021.
Article in English | MEDLINE | ID: mdl-34017267

ABSTRACT

Beige adipocytes are newly identified thermogenic-poised adipocytes that could be activated by cold or ß3-adrenergic receptor (ß3-AR) signaling and offer therapeutic potential for treating obesity and metabolic diseases. Here we applied RNA-sequencing analysis in the beige fat of mice under cold exposure or ß3-AR agonist CL316,243 (CL) treatment to provide a comparative and comprehensive analysis for the similarity and heterogeneity of these two stimulants. Importantly, via KEGG analysis, we found that cold and CL commonly induced oxidative phosphorylation. Meanwhile, cold increased glycerolipid and amino acids metabolism while CL treatment triggered a broader spectrum of metabolic responses including carbohydrate metabolism. Besides, cold or CL treatment featured greater heterogeneity in downregulated gene programs. Of note, the top changed genes in each category were confirmed by qPCR analysis. Overall, our analysis provided a better understanding of the heterogeneity of differential models for beige adipocytes activation and a possible clue for optimizing ß3-AR agonists in the future.

4.
Oncogene ; 39(4): 833-848, 2020 01.
Article in English | MEDLINE | ID: mdl-31562393

ABSTRACT

Cancer cells undergo significant lipid metabolic reprogramming to ensure sufficient energy supply for survival and progression. However, how cancer cells integrate lipid metabolic signaling with cancer progression is not well understood. In the present study, we demonstrated that C/EBPδ, a critical lipid metabolic regulator, is a TGF-ß1 downstream gene and promotes lung adenocarcinoma metastasis. Importantly, C/EBPδ caused significant oscillations in both lipid metabolic and epithelial to mesenchymal transition (EMT) gene networks. Mechanistically, we demonstrated that C/EBPδ recruited oncogene NCOA3 to transcriptionally activate Slug, a canonical EMT transcription factor, which in turn induced oxLDL receptor-1 (Lox1) expression and enhanced oxLDL uptake to promote cancer metastasis, which could be blocked with LOX1 neutralizing antibody. In summary, our results unveiled a previously unappreciated interplay between lipid metabolic and metastatic program, as well as the existence of a pivotal C/EBPδ-Slug-Lox1 transcription axis to promote oxLDL levels and cancer metastasis.


Subject(s)
Adenocarcinoma of Lung/secondary , CCAAT-Enhancer-Binding Protein-delta/metabolism , Lipoproteins, LDL/metabolism , Lung Neoplasms/pathology , Neoplastic Cells, Circulating/pathology , Scavenger Receptors, Class E/metabolism , Snail Family Transcription Factors/metabolism , Adenocarcinoma of Lung/genetics , Adenocarcinoma of Lung/metabolism , Animals , Cell Line, Tumor , Cell Movement , Cell Survival , Databases, Genetic , Epithelial-Mesenchymal Transition , Female , Gene Expression Regulation, Neoplastic , Humans , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Mice , Mice, Inbred BALB C , Mice, Nude , Neoplasm Metastasis , Neoplastic Cells, Circulating/metabolism , Nuclear Receptor Coactivator 3/metabolism , Signal Transduction , Transforming Growth Factor beta/metabolism , Xenograft Model Antitumor Assays
5.
Aging Cell ; 19(11): e13267, 2020 11.
Article in English | MEDLINE | ID: mdl-33219735

ABSTRACT

Aging leads to a number of disorders caused by cellular senescence, tissue damage, and organ dysfunction. It has been reported that anti-inflammatory and insulin-sensitizing compounds delay, or reverse, the aging process and prevent metabolic disorders, neurodegenerative disease, and muscle atrophy, improving healthspan and extending lifespan. Here we investigated the effects of PPARγ agonists in preventing aging and increasing longevity, given their known properties in lowering inflammation and decreasing glycemia. Our molecular and physiological studies show that long-term treatment of mice at 14 months of age with low doses of the PPARγ ligand rosiglitazone (Rosi) improved glucose metabolism and mitochondrial functionality. These effects were associated with decreased inflammation and reduced tissue atrophy, improved cognitive function, and diminished anxiety- and depression-like conditions, without any adverse effects on cardiac and skeletal functionality. Furthermore, Rosi treatment of mice started when they were 14 months old was associated with lifespan extension. A retrospective analysis of the effects of the PPARγ agonist pioglitazone (Pio) on longevity showed decreased mortality in patients receiving Pio compared to those receiving a PPARγ-independent insulin secretagogue glimepiride. Taken together, these data suggest the possibility of using PPARγ agonists to promote healthy aging and extend lifespan.


Subject(s)
Aging/pathology , Longevity/drug effects , Metabolic Diseases/drug therapy , PPAR gamma/therapeutic use , Animals , Humans , Male , Metabolic Diseases/mortality , Mice , PPAR gamma/pharmacology , Retrospective Studies , Survival Analysis
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