Honors & Awards
Finalist in Life Science Research Foundation (LSRF) award, Life Sciences Research Foundation (2022)
Pfizer Research Prize, Pfizer Research Prize Foundation (2022)
SNSF Postdoc Fellowship, Swiss National Science Foundation (2020)
ETH Medal, ETH Zurich (2020)
Chinese government award, China Scholarship Council (2018)
Best poster award, Competence Center Personalized Medicine in Zurich (2018)
Boards, Advisory Committees, Professional Organizations
Clinical board certificates, Changxing Municipal Health Bureau (2014 - Present)
Clinical board certificates, Jiangsu Municipal Health Bureau (2012 - Present)
Doctor of Science, ETH Zurich (2020)
Master of Medicine, Capital Medical University (2014)
Bachelor of Medicine, Xuzhou Medical College (2011)
Identification of a regulatory pathway inhibiting adipogenesis via RSPO2.
Healthy adipose tissue remodeling depends on the balance between de novo adipogenesis from adipogenic progenitor cells and the hypertrophy of adipocytes. De novo adipogenesis has been shown to promote healthy adipose tissue expansion, which confers protection from obesity-associated insulin resistance. Here, we define the role and trajectory of different adipogenic precursor subpopulations and further delineate the mechanism and cellular trajectory of adipogenesis, using single-cell RNA-sequencing datasets of murine adipogenic precursors. We identify Rspo2 as a functional regulator of adipogenesis, which is secreted by a subset of CD142+ cells to inhibit maturation of early progenitors through the receptor Lgr4. Increased circulating RSPO2 in mice leads to adipose tissue hypertrophy and insulin resistance and increased RSPO2 levels in male obese individuals correlate with impaired glucose homeostasis. Taken together, these findings identify a complex cellular crosstalk that inhibits adipogenesis and impairs adipose tissue homeostasis.
View details for DOI 10.1038/s42255-021-00509-1
View details for PubMedID 35027768
Local acetate inhibits brown adipose tissue function.
Proceedings of the National Academy of Sciences of the United States of America
2021; 118 (49)
Brown adipose tissue has been extensively studied in the last decade for its potential to counteract the obesity pandemic. However, the paracrine regulation within brown tissue is largely unknown. Here, we show that local acetate directly inhibits brown fat thermogenesis, without changing acetate levels in the circulation. We demonstrate that modulating acetate within brown tissue at physiological levels blunts its function and systemically decreases energy expenditure. Using a series of transcriptomic analyses, we identified genes related to the tricarboxylic acid cycle and brown adipocyte formation, which are down-regulated upon local acetate administration. Overall, these findings demonstrate that local acetate inhibits brown fat function.
View details for DOI 10.1073/pnas.2116125118
View details for PubMedID 34845033
Cold-induced epigenetic programming of the sperm enhances brown adipose tissue activity in the offspring
2018; 24 (9): 1372-+
Recent research has focused on environmental effects that control tissue functionality and systemic metabolism. However, whether such stimuli affect human thermogenesis and body mass index (BMI) has not been explored. Here we show retrospectively that the presence of brown adipose tissue (BAT) and the season of conception are linked to BMI in humans. In mice, we demonstrate that cold exposure (CE) of males, but not females, before mating results in improved systemic metabolism and protection from diet-induced obesity of the male offspring. Integrated analyses of the DNA methylome and RNA sequencing of the sperm from male mice revealed several clusters of co-regulated differentially methylated regions (DMRs) and differentially expressed genes (DEGs), suggesting that the improved metabolic health of the offspring was due to enhanced BAT formation and increased neurogenesis. The conclusions are supported by cell-autonomous studies in the offspring that demonstrate an enhanced capacity to form mature active brown adipocytes, improved neuronal density and more norepinephrine release in BAT in response to cold stimulation. Taken together, our results indicate that in humans and in mice, seasonal or experimental CE induces an epigenetic programming of the sperm such that the offspring harbor hyperactive BAT and an improved adaptation to overnutrition and hypothermia.
View details for DOI 10.1038/s41591-018-0102-y
View details for Web of Science ID 000444174100018
View details for PubMedID 29988127
A stromal cell population that inhibits adipogenesis in mammalian fat depots
2018; 559 (7712): 103-+
Adipocyte development and differentiation have an important role in the aetiology of obesity and its co-morbidities1,2. Although multiple studies have investigated the adipogenic stem and precursor cells that give rise to mature adipocytes3-14, our understanding of their in vivo origin and properties is incomplete2,15,16. This is partially due to the highly heterogeneous and unstructured nature of adipose tissue depots17, which has proven difficult to molecularly dissect using classical approaches such as fluorescence-activated cell sorting and Cre-lox lines based on candidate marker genes16,18. Here, using the resolving power of single-cell transcriptomics19 in a mouse model, we reveal distinct subpopulations of adipose stem and precursor cells in the stromal vascular fraction of subcutaneous adipose tissue. We identify one of these subpopulations as CD142+ adipogenesis-regulatory cells, which can suppress adipocyte formation in vivo and in vitro in a paracrine manner. We show that adipogenesis-regulatory cells are refractory to adipogenesis and that they are functionally conserved in humans. Our findings point to a potentially critical role for adipogenesis-regulatory cells in modulating adipose tissue plasticity, which is linked to metabolic control, differential insulin sensitivity and type 2 diabetes.
View details for DOI 10.1038/s41586-018-0226-8
View details for Web of Science ID 000437267400048
View details for PubMedID 29925944
GPR180 is a component of TGF beta signalling that promotes thermogenic adipocyte function and mediates the metabolic effects of the adipocyte-secreted factor CTHRC1
2021; 12 (1): 7144
Activation of thermogenic brown and beige adipocytes is considered as a strategy to improve metabolic control. Here, we identify GPR180 as a receptor regulating brown and beige adipocyte function and whole-body glucose homeostasis, whose expression in humans is associated with improved metabolic control. We demonstrate that GPR180 is not a GPCR but a component of the TGFβ signalling pathway and regulates the activity of the TGFβ receptor complex through SMAD3 phosphorylation. In addition, using genetic and pharmacological tools, we provide evidence that GPR180 is required to manifest Collagen triple helix repeat containing 1 (CTHRC1) action to regulate brown and beige adipocyte activity and glucose homeostasis. In this work, we show that CTHRC1/GPR180 signalling integrates into the TGFβ signalling as an alternative axis to fine-tune and achieve low-grade activation of the pathway to prevent pathophysiological response while contributing to control of glucose and energy metabolism.
View details for DOI 10.1038/s41467-021-27442-x
View details for Web of Science ID 000728313100027
View details for PubMedID 34880217
SORLA is required for insulin-induced expansion of the adipocyte precursor pool in visceral fat
JOURNAL OF CELL BIOLOGY
2021; 220 (12)
Visceral adipose tissue shows remarkable plasticity, constantly replacing mature adipocytes from an inherent pool of adipocyte precursors. The number of precursors is set in the juvenile organism and remains constant in adult life. Which signals drive precursor pool expansion in juveniles and why they operate in visceral but not in subcutaneous white adipose tissue (WAT) are unclear. Using mouse models, we identified the insulin-sensitizing receptor SORLA as a molecular factor explaining the distinct proliferative capacity of visceral WAT. High levels of SORLA activity in precursors of juvenile visceral WAT prime these cells for nutritional stimuli provided through insulin, promoting mitotic expansion of the visceral precursor cell pool in overfed juvenile mice. SORLA activity is low in subcutaneous precursors, blunting their response to insulin and preventing diet-induced proliferation of this cell type. Our findings provide a molecular explanation for the unique proliferative properties of juvenile visceral WAT, and for the genetic association of SORLA with visceral obesity in humans.
View details for DOI 10.1083/jcb.202006058
View details for Web of Science ID 000719912800001
View details for PubMedID 34779857
View details for PubMedCentralID PMC8598079
Lipolysis drives expression of the constitutively active receptor GPR3 to induce adipose thermogenesis
2021; 184 (13): 3502-+
Thermogenic adipocytes possess a therapeutically appealing, energy-expending capacity, which is canonically cold-induced by ligand-dependent activation of β-adrenergic G protein-coupled receptors (GPCRs). Here, we uncover an alternate paradigm of GPCR-mediated adipose thermogenesis through the constitutively active receptor, GPR3. We show that the N terminus of GPR3 confers intrinsic signaling activity, resulting in continuous Gs-coupling and cAMP production without an exogenous ligand. Thus, transcriptional induction of Gpr3 represents the regulatory parallel to ligand-binding of conventional GPCRs. Consequently, increasing Gpr3 expression in thermogenic adipocytes is alone sufficient to drive energy expenditure and counteract metabolic disease in mice. Gpr3 transcription is cold-stimulated by a lipolytic signal, and dietary fat potentiates GPR3-dependent thermogenesis to amplify the response to caloric excess. Moreover, we find GPR3 to be an essential, adrenergic-independent regulator of human brown adipocytes. Taken together, our findings reveal a noncanonical mechanism of GPCR control and thermogenic activation through the lipolysis-induced expression of constitutively active GPR3.
View details for DOI 10.1016/j.cell.2021.04.037
View details for Web of Science ID 000665547300015
View details for PubMedID 34048700
View details for PubMedCentralID PMC8238500
Plasticity and heterogeneity of thermogenic adipose tissue
2021; 3 (6): 751-761
The perception of adipose tissue, both in the scientific community and in the general population, has changed dramatically in the past 20 years. While adipose tissue was thought for a long time to be a rather simple lipid storage entity, it is now recognized as a highly heterogeneous organ and a critical regulator of systemic metabolism, composed of many different subtypes of cells, with important endocrine functions. Additionally, adipose tissue is nowadays recognized to contribute to energy turnover, due to the presence of specialized thermogenic adipocytes, which can be found in many adipose depots. This review discusses the unprecedented insights that we have gained into the heterogeneity of thermogenic adipocytes and their respective precursors due to the technical developments in single-cell and nucleus technologies. These methodological advances have increased our understanding of how adipose tissue catabolic function is influenced by developmental and intercellular communication events.
View details for DOI 10.1038/s42255-021-00417-4
View details for Web of Science ID 000665078900005
View details for PubMedID 34158657
Lysosomal lipoprotein processing in endothelial cells stimulates adipose tissue thermogenic adaptation.
2021; 33 (3): 547-564.e7
In response to cold exposure, thermogenic adipocytes internalize large amounts of fatty acids after lipoprotein lipase-mediated hydrolysis of triglyceride-rich lipoproteins (TRL) in the capillary lumen of brown adipose tissue (BAT) and white adipose tissue (WAT). Here, we show that in cold-exposed mice, vascular endothelial cells in adipose tissues endocytose substantial amounts of entire TRL particles. These lipoproteins subsequently follow the endosomal-lysosomal pathway, where they undergo lysosomal acid lipase (LAL)-mediated processing. Endothelial cell-specific LAL deficiency results in impaired thermogenic capacity as a consequence of reduced recruitment of brown and brite/beige adipocytes. Mechanistically, TRL processing by LAL induces proliferation of endothelial cells and adipocyte precursors via beta-oxidation-dependent production of reactive oxygen species, which in turn stimulates hypoxia-inducible factor-1α-dependent proliferative responses. In conclusion, this study demonstrates a physiological role for TRL particle uptake into BAT and WAT and establishes endothelial lipoprotein processing as an important determinant of adipose tissue remodeling during thermogenic adaptation.
View details for DOI 10.1016/j.cmet.2020.12.001
View details for PubMedID 33357458
snRNA-seq reveals a subpopulation of adipocytes that regulates thermogenesis
2020; 587 (7832): 98-+
Adipose tissue is usually classified on the basis of its function as white, brown or beige (brite)1. It is an important regulator of systemic metabolism, as shown by the fact that dysfunctional adipose tissue in obesity leads to a variety of secondary metabolic complications2,3. In addition, adipose tissue functions as a signalling hub that regulates systemic metabolism through paracrine and endocrine signals4. Here we use single-nucleus RNA-sequencing (snRNA-seq) analysis in mice and humans to characterize adipocyte heterogeneity. We identify a rare subpopulation of adipocytes in mice that increases in abundance at higher temperatures, and we show that this subpopulation regulates the activity of neighbouring adipocytes through acetate-mediated modulation of their thermogenic capacity. Human adipose tissue contains higher numbers of cells of this subpopulation, which could explain the lower thermogenic activity of human compared to mouse adipose tissue and suggests that targeting this pathway could be used to restore thermogenic activity.
View details for DOI 10.1038/s41586-020-2856-x
View details for Web of Science ID 000582810000003
View details for PubMedID 33116305
Inhibition of Mevalonate Pathway Prevents Adipocyte Browning in Mice and Men by Affecting Protein Prenylation
2019; 29 (4): 901-+
Recent research focusing on brown adipose tissue (BAT) function emphasizes its importance in systemic metabolic homeostasis. We show here that genetic and pharmacological inhibition of the mevalonate pathway leads to reduced human and mouse brown adipocyte function in vitro and impaired adipose tissue browning in vivo. A retrospective analysis of a large patient cohort suggests an inverse correlation between statin use and active BAT in humans, while we show in a prospective clinical trial that fluvastatin reduces thermogenic gene expression in human BAT. We identify geranylgeranyl pyrophosphate as the key mevalonate pathway intermediate driving adipocyte browning in vitro and in vivo, whose effects are mediated by geranylgeranyltransferases (GGTases), enzymes catalyzing geranylgeranylation of small GTP-binding proteins, thereby regulating YAP1/TAZ signaling through F-actin modulation. Conversely, adipocyte-specific ablation of GGTase I leads to impaired adipocyte browning, reduced energy expenditure, and glucose intolerance under obesogenic conditions, highlighting the importance of this pathway in modulating brown adipocyte functionality and systemic metabolism.
View details for DOI 10.1016/j.cmet.2018.11.017
View details for Web of Science ID 000463015800013
View details for PubMedID 30581121
BATLAS: Deconvoluting Brown Adipose Tissue
2018; 25 (3): 784-+
Recruitment and activation of thermogenic adipocytes have received increasing attention as a strategy to improve systemic metabolic control. The analysis of brown and brite adipocytes is complicated by the complexity of adipose tissue biopsies. Here, we provide an in-depth analysis of pure brown, brite, and white adipocyte transcriptomes. By combining mouse and human transcriptome data, we identify a gene signature that can classify brown and white adipocytes in mice and men. Using a machine-learning-based cell deconvolution approach, we develop an algorithm proficient in calculating the brown adipocyte content in complex human and mouse biopsies. Applying this algorithm, we can show in a human weight loss study that brown adipose tissue (BAT) content is associated with energy expenditure and the propensity to lose weight. This online available tool can be used for in-depth characterization of complex adipose tissue samples and may support the development of therapeutic strategies to increase energy expenditure in humans.
View details for DOI 10.1016/j.celrep.2018.09.044
View details for Web of Science ID 000448217500022
View details for PubMedID 30332656
Maternal n-3 polyunsaturated fatty acid deprivation during pregnancy and lactation affects neurogenesis and apoptosis in adult offspring: associated with DNA methylation of brain-derived neurotrophic factor transcripts
2016; 36 (9): 1013-1021
In this study, we hypothesized that n-3 polyunsaturated fatty acid (PUFA) deficiency during pregnancy and lactation will make a lasting impact on brain neurogenesis and apoptosis of the adult offspring and that these harmful effects cannot be reversed by n-3 PUFA supplementation after weaning. Moreover, the underlying mechanisms may be attributable to the epigenetic changes of brain-derived neurotrophic factor (BDNF). C57BL/6J female mice were fed with n-3 PUFA-deficient diet (n-3 def) or n-3 PUFA-adequate diet (n-3 adq) throughout pregnancy and lactation. At postnatal 21 days, equal numbers of male pups from both groups were fed the opposite diet, and the remaining male pups were fed with the same diets as their mothers until 3 months of age. Feeding the n-3 adq diet to pups from the maternal n-3 def group significantly increased the n-3 PUFA concentration but did not change expressions of calretinin, Bcl2, and Bax in the hippocampus. Feeding the n-3 def diet to pups from the maternal n-3 adq group significantly reduced the n-3 PUFA concentration but did not reduce expressions of calretinin and Bcl2. Similarly, BDNF levels, especially mRNA expressions of BDNF transcripts IV and IX, were also reduced by maternal n-3 def and not reversed by n-3 PUFA supplementation after weaning. The decrease in BDNF expression by maternal n-3 def diet was associated with greater DNA methylation at special CpG sites. These results suggested that the maternal n-3 PUFA deficiency during pregnancy and lactation imprints long-term changes of brain development in adult offspring.
View details for DOI 10.1016/j.nutres.2016.06.005
View details for Web of Science ID 000383924000015
View details for PubMedID 27632922
Dietary ratios of n-6/n-3 polyunsaturated fatty acids during maternal pregnancy affect hippocampal neurogenesis and apoptosis in mouse offspring
2015; 32 (3): 1170-1179
although n-3 polyunsaturated fatty acids (PUFAs) play crucial roles in brain development and function, neither the optimal level of n-3 PUFAs nor the optimal ratio of n-6/n-3 PUFAs in the maternal diet are well defined. In this study, we investigated the effects of dietary n-6/n-3 PUFA ratios during pregnancy on neurogenesis and apoptosis in the brains of mouse offspring. Metods: female C57BL/6J mice were fed one of three diets with high, medium and low ratios of n-6/n-3 PUFAs (15.7:1, 6.3:1, 1.6:1), as well as a high fish oil diet with a n-6/n-3 ratio of 1:5.7; an n-3 PUFA-deficient diet served as control. The feeding regimens began two months before mouse conception and continued for the duration of the pregnancy. The neurogenesis and apoptosis of hippocampal CA3 area in the offspring were detected.compared to the n-3 PUFA-deficient diet, n-3 PUFA-containing diets, particularly those with n-6/n-3 PUFA ratios of 6.3:1 and 1.6:1, significantly increased both phosphorylation of histone H3 at ser 10 (p-H3ser10) and calretinin-positive cells in hippocampus CA3 of the offspring. Furthermore, increased expression of Bcl2 protein, decreased expression of Bax protein, and reduced caspase 3 activity and numbers of TUNEL apoptotic cells were found in the three diets with high, medium and low n-6/n-3 PUFA ratios. However, there were no differences in any of these parameters between the high fish oil diet group and the n-3 PUFA-deficient diet group.these data suggest that a higher intake of n-3 PUFAs with a lower ratio of n-6/n-3 PUFAs of between about 6:1 to 1:1, supplied to mothers during pregnancy, may benefit brain neurogenesis and apoptosis in offspring. However, excessive maternal intake of n-3 PUFAs may exert a negative influence on brain development in the offspring.
View details for DOI 10.3305/nh.2015.32.3.9259
View details for Web of Science ID 000362925300028
View details for PubMedID 26319835
Particle size determines effects of lipoprotein lipase on the catabolism of n-3 triglyceride-rich particles
2015; 34 (4): 767-774
The catabolic pathways of n-3 triglyceride (TG) rich particles (n-3 TGRP) have not been clearly elucidated. In this study, we investigated the effects of lipoprotein lipase (LPL) on the catabolism of n-3 TGRP compared to n-6 TGRP in vivo and in vitro, and we determined whether particle size affects the biological functions of LPL in n-3 TGRP catabolism.Four types of lipid emulsions, chylomicron (CM)-sized n-3 TG and n-6 TG emulsions, and very low density lipoprotein (VLDL)-sized n-3 TG and n-6 TG emulsions, were labeled with 1,1'-dioctadecy1-3,3,3',3'-tetramethylindo-carbocyanine perchlorate (DiI) and administered via a bolus injection to LPL gene knockout (LPL+/-) mice in vivo and were added to cultured LPL miRNA-transfected 3T3-L1 adipocytes in vitro.With CM-sized emulsions, a reduction in LPL expression in LPL+/- mice had almost no effect on tissue uptake of n-3 TG emulsions with smaller changes in their initial blood clearance; however, greater effects were observed for VLDL-sized n-3 TG emulsions with respect to tissue uptake with greater changes in their initial blood clearance, compared to n-6 TG emulsions with the same size. In vitro, LPL miRNA transfection had smaller effects on CM-sized and greater effects on VLDL-sized n-3 TG emulsions, with respect to particle uptake, cell TG mass, particle-cell binding and particle lipolysis.These results suggested that LPL is more important for catabolism of n-3 TGRP of smaller size; whereas it is essential for catabolism of all sizes of n-6 TGRP.
View details for DOI 10.1016/j.clnu.2014.07.006
View details for Web of Science ID 000357241900031
View details for PubMedID 25048714
Genome-wide screen of DNA methylation identifies novel markers in childhood obesity
2015; 566 (1): 74-83
Epigenetic modifications have been highlighted in chronic non-communicable diseases. The aim of this study was to investigate genome-wide DNA methylation for the identification of methylation markers in obesity. With obese Chinese preschool children, we performed comprehensive DNA methylation profiling of gene promoters and CpG islands to determine the differentially methylated genes using methylated DNA immunoprecipitation followed by hybridization to the NimbleGen Human DNA Methylation 385K Promoter Plus CpG Island Microarray. We found that compared to lean children, 251 promoters and 575 CGIs were demethylated, and 141 promoters and 277 CGIs were hypermethylated in obese children, and their distribution on chromosomes was imbalanced, showing more promoters and CGIs with demethylation on chromosomes 3, 16, 17 and 19 and more differentially methylated promoters and CGIs on chromosome X compared with chromosome Y. Further analysis indicated that aberrant methylations occurred mostly in HCP promoters and promoter CGIs. Among the top 80 promoters and CGIs that had differentiated methylation between obese and lean children, nearly half have been previously studied, and almost all of them are involved in the pathogenesis of cancers that are associated with many organs. Furthermore, four genes (FZD7, PRLHR, EXOSC4, and EIF6) with differential promoter methylation were validated, and their associations with obesity must be clarified. In conclusion, this study represents the first effort to determine methylation markers in obese Chinese children, which has potential relevance for identifying markers that are useful in elucidating the mechanisms of obesity pathogenesis and its complications.
View details for DOI 10.1016/j.gene.2015.04.032
View details for Web of Science ID 000355711500012
View details for PubMedID 25871514
Genome-wide screen of promoter methylation identifies novel markers in diet-induced obese mice
2014; 30 (1): 42-52
To investigate the genome-wide promoter methylation and gene expression for the identification of methylation markers in obesity.Using a high-fat, diet-induced obese mouse model, we performed comprehensive DNA methylation profiling of gene promoters to determine the differentially methylated genes using methylated DNA immunoprecipitation followed by hybridization to the NimbleGen MM8 CpG plus Promoter Microarray. We further integrated epigenomics data with gene expression profiling to identify promoters exhibiting an association between methylation status and the expression of downstream genes.A total of 24 hypermethylated promoters and 42 hypomethylated promoters in epididymal fat were selected as methylation markers, which were associated with downregulated and upregulated gene expression, respectively. The promoter methylation and differential gene expression of three markers (Mmp2, Foxj3 and Ube2q2) in the fat were validated by sequencing bisulfitemodified DNA and real-time reverse transcriptase PCR. The genes with these differentially methylated promoters and the associated transcriptional expression in the fat were primarily involved in biological activities in lipid metabolism and storage, cellular differentiation, immunity and the pathogenesis of obesity-related complications.This study represents the first effort to determine methylation markers in obese mice that may regulate gene transcription in obesity. Our approach has potential relevance for clinical applications by identifying markers useful in elucidating the mechanisms of obesity pathogenesis and its complications.
View details for DOI 10.3305/nh.2014.30.1.7521
View details for Web of Science ID 000340864700006
View details for PubMedID 25137261
Epigenetic Modification of the Leptin Promoter in Diet-Induced Obese Mice and the Effects of N-3 Polyunsaturated Fatty Acids
2014; 4: 5282
We report evidence of a detailed epigenetic modification of the leptin promoter and the effects of n-3 polyunsaturated fatty acids (n-3 PUFAs), which is closely associated with the leptin gene transcription in obesity. In the adipose tissue of diet induced obese (DIO) mice, methylation of the CpG island and the binding of methyl-CpG-binding domain protein 2 (MBD2) and DNA methyltransferases (DNMTs) at the leptin promoter are increased and RNA Pol II is decreased. Additionally, histones H3 and H4 are hypoacetylated, lysine 4 of histone H3 (H3K4) is hypomethylated and the binding of histone deacetylases (HDACs) 1, 2 and 6 is increased at the leptin promoter in the DIO mice. These modifications may serve a feedback role to maintain leptin concentrations within a normal range. The regulation of leptin transcriptional expression by n-3 PUFAs is mediated, at least in part, by epigenetic targets, such as MBD2 and histone modifications.
View details for DOI 10.1038/srep05282
View details for Web of Science ID 000337339800005
View details for PubMedID 24923522
View details for PubMedCentralID PMC5381469