Honors & Awards
ETH Medal for outstanding doctoral theses, ETH Zurich (2020)
Award for Outstanding Self-Financed Students Abroad, Ministry of Education of China (2019)
Doctor of Philosophy, ETH Zurich (2020)
Master of Science, Columbia University (2014)
Bachelor of Science, China Pharmaceutical University (2010)
Stephen Quake, Postdoctoral Faculty Sponsor
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
Quantification of adipocyte numbers following adipose tissue remodeling
2021; 35 (4): 109023
To analyze the capacity of white and brown adipose tissue remodeling, we developed two mouse lines to label, quantitatively trace, and ablate white, brown, and brite/beige adipocytes at different ambient temperatures. We show here that the brown adipocytes are recruited first and reach a peak after 1 week of cold stimulation followed by a decline during prolonged cold exposure. On the contrary, brite/beige cell numbers plateau after 3 weeks of cold exposure. At thermoneutrality, brown adipose tissue, in spite of being masked by a white-like morphology, retains its brown-like physiology, as Ucp1+ cells can be recovered immediately upon beta3-adrenergic stimulation. We further demonstrate that the recruitment of Ucp1+ cells in response to cold is driven by existing adipocytes. In contrast, the regeneration of the interscapular brown adipose tissue following ablation of Ucp1+ cells is driven by de novo differentiation.
View details for DOI 10.1016/j.celrep.2021.109023
View details for Web of Science ID 000644709600003
View details for PubMedID 33909996
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
ESRRG and PERM1 Govern Mitochondrial Conversion in Brite/Beige Adipocyte Formation
FRONTIERS IN ENDOCRINOLOGY
2020; 11: 387
When exposed to cold temperatures, mice increase their thermogenic capacity by an expansion of brown adipose tissue mass and the formation of brite/beige adipocytes in white adipose tissue depots. However, the process of the transcriptional changes underlying the conversion of a phenotypic white to brite/beige adipocytes is only poorly understood. By analyzing transcriptome profiles of inguinal adipocytes during cold exposure and in mouse models with a different propensity to form brite/beige adipocytes, we identified ESRRG and PERM1 as modulators of this process. The production of heat by mitochondrial uncoupled respiration is a key feature of brite/beige compared to white adipocytes and we show here that both candidates are involved in PGC1α transcriptional network to positively regulate mitochondrial capacity. Moreover, we show that an increased expression of ESRRG or PERM1 supports the formation of brown or brite/beige adipocytes in vitro and in vivo. These results reveal that ESRRG and PERM1 are early induced in and important regulators of brite/beige adipocyte formation.
View details for DOI 10.3389/fendo.2020.00387
View details for Web of Science ID 000543841400001
View details for PubMedID 32595605
View details for PubMedCentralID PMC7304443
A Genetic Model to Study the Contribution of Brown and Brite Adipocytes to Metabolism
2020; 30 (10): 3424-+
UCP1-dependent thermogenesis is studied to define new strategies to ameliorate obesity and type 2 diabetes; however, animal models are mostly limited to germline mutations of UCP1, which can effect adaptive changes in UCP1-independent pathways. We develop an inducible mouse model for the sequential ablation of UCP1+ brown and brite/beige adipocytes in adult mice. We demonstrate that activated brown adipocytes can increase systemic energy expenditure (EE) by 30%, while the contribution of brite/beige UCP1+ cells is <5%. Notably, UCP1+ adipocytes do not contribute to circulating FGF21 levels, either at room temperature or after cold exposure. We demonstrate that the FGF21-mediated effects on EE and glucose homeostasis are partially dependent on the presence of UCP1+ cells, while the effect on weight loss is not. In conclusion, acute UCP1+ cell deletion may be a useful model to study the impact of brown and brite/beige adipocytes on metabolism.
View details for DOI 10.1016/j.celrep.2020.02.055
View details for Web of Science ID 000519189700019
View details for PubMedID 32160547
Antioxidants protect against diabetes by improving glucose homeostasis in mouse models of inducible insulin resistance and obesity
2019; 62 (11): 2094-2105
In the context of diabetes, the health benefit of antioxidant treatment has been widely debated. In this study, we investigated the effect of antioxidant treatment during the development of insulin resistance and hyperphagia in obesity and partial lipodystrophy.We studied the role of antioxidants in the regulation of insulin resistance using the tamoxifen-inducible fat-specific insulin receptor knockout (iFIRKO) mouse model, which allowed us to analyse the antioxidant's effect in a time-resolved manner. In addition, leptin-deficient ob/ob mice were used as a hyperphagic, chronically obese and diabetic mouse model to validate the beneficial effect of antioxidants on metabolism.Acute induction of insulin receptor knockout in adipocytes changed the substrate preference to fat before induction of a diabetic phenotype including hyperinsulinaemia and hyperglycaemia. In healthy chow-fed animals as well as in morbidly obese mice, this diabetic phase could be reversed within a few weeks. Furthermore, after the induction of insulin receptor knockout in mature adipocytes, iFIRKO mice were protected from subsequent obesity development through high-fat diet feeding. By genetic tracing we show that the persistent fat mass loss in mice after insulin receptor knockout in adipocytes is not caused by the depletion of adipocytes. Treatment of iFIRKO mice with antioxidants postponed and reduced hyperglycaemia by increasing insulin sensitivity. In ob/ob mice, antioxidants rescued both hyperglycaemia and hyperphagia.We conclude that fat mass reduction through insulin resistance in adipocytes is not reversible. Furthermore, it seems unlikely that adipocytes undergo apoptosis during the process of extreme lipolysis, as a consequence of insulin resistance. Antioxidants have a beneficial health effect not only during the acute phase of diabetes development, but also in a temporary fashion once chronic obesity and diabetes have been established.
View details for DOI 10.1007/s00125-019-4937-7
View details for Web of Science ID 000491944900014
View details for PubMedID 31309261
View details for PubMedCentralID PMC6805816
Human brown adipose tissue is phenocopied by classical brown adipose tissue in physiologically humanized mice
2019; 1 (8): 830-843
Human and rodent brown adipose tissues (BAT) appear morphologically and molecularly different. Here we compare human BAT with both classical brown and brite/beige adipose tissues of 'physiologically humanized' mice: middle-aged mice living under conditions approaching human thermal and nutritional conditions, that is, prolonged exposure to thermoneutral temperature (approximately 30 °C) and to an energy-rich (high-fat, high-sugar) diet. We find that the morphological, cellular and molecular characteristics (both marker and adipose-selective gene expression) of classical brown fat, but not of brite/beige fat, of these physiologically humanized mice are notably similar to human BAT. We also demonstrate, both in silico and experimentally, that in physiologically humanized mice only classical BAT possesses a high thermogenic potential. These observations suggest that classical rodent BAT is the tissue of choice for translational studies aimed at recruiting human BAT to counteract the development of obesity and its comorbidities.
View details for DOI 10.1038/s42255-019-0101-4
View details for Web of Science ID 000500745300010
View details for PubMedID 32694768
Environmental and Nutritional Effects Regulating Adipose Tissue Function and Metabolism Across Generations
2019; 6 (11): 1900275
The unabated rise in obesity prevalence during the last 40 years has spurred substantial interest in understanding the reasons for this epidemic. Studies in mice and humans have demonstrated that obesity is a highly heritable disease; however genetic variations within specific populations have so far not been able to explain this phenomenon to its full extent. Recent work has demonstrated that environmental cues can be sensed by an organism to elicit lasting changes, which in turn can affect systemic energy metabolism by different epigenetic mechanisms such as changes in small noncoding RNA expression, DNA methylation patterns, as well as histone modifications. These changes can directly modulate cellular function in response to environmental cues, however research during the last decade has demonstrated that some of these modifications might be transmitted to subsequent generations, thus modulating energy metabolism of the progeny in an inter- as well as transgenerational manner. In this context, adipose tissue has become a focus of research due to its plasticity, which allows the formation of energy storing (white) as well as energy wasting (brown/brite/beige) cells within the same depot. In this Review, the effects of environmental induced obesity with a particular focus on adipose tissue are discussed.
View details for DOI 10.1002/advs.201900275
View details for Web of Science ID 000470189500025
View details for PubMedID 31179229
View details for PubMedCentralID PMC6548959
Maternal overnutrition programs hedonic and metabolic phenotypes across generations through sperm tsRNAs
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2019; 116 (21): 10547-10556
There is a growing body of evidence linking maternal overnutrition to obesity and psychopathology that can be conserved across multiple generations. Recently, we demonstrated in a maternal high-fat diet (HFD; MHFD) mouse model that MHFD induced enhanced hedonic behaviors and obesogenic phenotypes that were conserved across three generations via the paternal lineage, which was independent of sperm methylome changes. Here, we show that sperm tRNA-derived small RNAs (tsRNAs) partly contribute to the transmission of such phenotypes. We observe increased expression of sperm tsRNAs in the F1 male offspring born to HFD-exposed dams. Microinjection of sperm tsRNAs from the F1-HFD male into normal zygotes reproduces obesogenic phenotypes and addictive-like behaviors, such as increased preference of palatable foods and enhanced sensitivity to drugs of abuse in the resultant offspring. The expression of several of the differentially expressed sperm tsRNAs predicted targets such as CHRNA2 and GRIN3A, which have been implicated in addiction pathology, are altered in the mesolimbic reward brain regions of the F1-HFD father and the resultant HFD-tsRNA offspring. Together, our findings demonstrate that sperm tsRNA is a potential vector that contributes to the transmission of MHFD-induced addictive-like behaviors and obesogenic phenotypes across generations, thereby emphasizing its role in diverse pathological outcomes.
View details for DOI 10.1073/pnas.1820810116
View details for Web of Science ID 000468403400059
View details for PubMedID 31061112
View details for PubMedCentralID PMC6534971
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
- Fat cells with a sweet tooth NATURE 2019; 565 (7738): 167-168
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
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
Peroxisome Proliferator Activated Receptor Gamma Controls Mature Brown Adipocyte Inducibility through Glycerol Kinase
2018; 22 (3): 760-773
Peroxisome proliferator-activated receptors (PPARs) have been suggested as the master regulators of adipose tissue formation. However, their role in regulating brown fat functionality has not been resolved. To address this question, we generated mice with inducible brown fat-specific deletions of PPARα, β/δ, and γ, respectively. We found that both PPARα and β/δδ are dispensable for brown fat function. In contrast, we could show that ablation of PPARγ in vitro and in vivo led to a reduced thermogenic capacity accompanied by a loss of inducibility by β-adrenergic signaling, as well as a shift from oxidative fatty acid metabolism to glucose utilization. We identified glycerol kinase (Gyk) as a partial mediator of PPARγ function and could show that Gyk expression correlates with brown fat thermogenic capacity in human brown fat biopsies. Thus, Gyk might constitute the link between PPARγ-mediated regulation of brown fat function and activation by β-adrenergic signaling.
View details for DOI 10.1016/j.celrep.2017.12.067
View details for Web of Science ID 000423449400016
View details for PubMedID 29346772
Bmp4 Promotes a Brown to White-like Adipocyte Shift
2016; 16 (8): 2243-2258
While Bmp4 has a well-established role in the commitment of mesenchymal stem cells into the adipogenic lineage, its role in brown adipocyte formation and activity is not well defined. Here, we show that Bmp4 has a dual function in adipogenesis by inducing adipocyte commitment while inhibiting the acquisition of a brown phenotype during terminal differentiation. Selective brown adipose tissue overexpression of Bmp4 in mice induces a shift from a brown to a white-like adipocyte phenotype. This effect is mediated by Smad signaling and might be in part due to suppression of lipolysis, via regulation of hormone sensitive lipase expression linked to reduced Ppar activity. Given that we observed a strong correlation between BMP4 levels and adipocyte size, as well as insulin sensitivity in humans, we propose that Bmp4 is an important factor in the context of obesity and type 2 diabetes.
View details for DOI 10.1016/j.celrep.2016.07.048
View details for Web of Science ID 000382310100020
View details for PubMedID 27524617
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