Publications by authors named "Yu-Hua Tseng"

107 Publications

Cold-induction of afadin in brown fat supports its thermogenic capacity.

Sci Rep 2021 May 7;11(1):9794. Epub 2021 May 7.

Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

The profound energy-expending nature of brown adipose tissue (BAT) thermogenesis makes it an attractive target tissue to combat obesity-associated metabolic disorders. While cold exposure is the strongest inducer of BAT activity, the temporal mechanisms tuning BAT adaptation during this activation process are incompletely understood. Here we show that the scaffold protein Afadin is dynamically regulated by cold in BAT, and participates in cold acclimation. Cold exposure acutely increases Afadin protein levels and its phosphorylation in BAT. Knockdown of Afadin in brown pre-adipocytes does not alter adipogenesis but restricts β-adrenegic induction of thermogenic genes expression and HSL phosphorylation in mature brown adipocytes. Consistent with a defect in thermogenesis, an impaired cold tolerance was observed in fat-specific Afadin knockout mice. However, while Afadin depletion led to reduced Ucp1 mRNA induction by cold, stimulation of Ucp1 protein was conserved. Transcriptomic analysis revealed that fat-specific ablation of Afadin led to decreased functional enrichment of gene sets controlling essential metabolic functions at thermoneutrality in BAT, whereas it led to an altered reprogramming in response to cold, with enhanced enrichment of different pathways related to metabolism and remodeling. Collectively, we demonstrate a role for Afadin in supporting the adrenergic response in brown adipocytes and BAT function.
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http://dx.doi.org/10.1038/s41598-021-89207-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105362PMC
May 2021

Challenges in tackling energy expenditure as obesity therapy: From preclinical models to clinical application.

Mol Metab 2021 Apr 18;51:101237. Epub 2021 Apr 18.

Cardio Metabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany. Electronic address:

Background: A chronic imbalance of energy intake and energy expenditure results in excess fat storage. The obesity often caused by this overweight is detrimental to the health of millions of people. Understanding both sides of the energy balance equation and their counter-regulatory mechanisms is critical to the development of effective therapies to treat this epidemic.

Scope Of Review: Behaviors surrounding ingestion have been reviewed extensively. This review focuses more specifically on energy expenditure regarding bodyweight control, with a particular emphasis on the organs and attractive metabolic processes known to reduce bodyweight. Moreover, previous and current attempts at anti-obesity strategies focusing on energy expenditure are highlighted. Precise measurements of energy expenditure, which consist of cellular, animal, and human models, as well as measurements of their translatability, are required to provide the most effective therapies.

Major Conclusions: A precise understanding of the components surrounding energy expenditure, including tailored approaches based on genetic, biomarker, or physical characteristics, must be integrated into future anti-obesity treatments. Further comprehensive investigations are required to define suitable treatments, especially because the complex nature of the human perspective remains poorly understood.
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http://dx.doi.org/10.1016/j.molmet.2021.101237DOI Listing
April 2021

Defining the lineage of thermogenic perivascular adipose tissue.

Nat Metab 2021 04 12;3(4):469-484. Epub 2021 Apr 12.

Institute for Diabetes, Obesity & Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

Brown adipose tissue can expend large amounts of energy, and therefore increasing its size or activity is a promising therapeutic approach to combat metabolic disease. In humans, major deposits of brown fat cells are found intimately associated with large blood vessels, corresponding to perivascular adipose tissue (PVAT). However, the cellular origins of PVAT are poorly understood. Here, we determine the identity of perivascular adipocyte progenitors in mice and humans. In mice, thoracic PVAT develops from a fibroblastic lineage, consisting of progenitor cells (Pdgfra, Ly6a and Pparg) and preadipocytes (Pdgfra, Ly6a and Pparg), which share transcriptional similarity with analogous cell types in white adipose tissue. Interestingly, the aortic adventitia of adult animals contains a population of adipogenic smooth muscle cells (Myh11, Pdgfra and Pparg) that contribute to perivascular adipocyte formation. Similarly, human PVAT contains presumptive fibroblastic and smooth muscle-like adipocyte progenitor cells, as revealed by single-nucleus RNA sequencing. Together, these studies define distinct populations of progenitor cells for thermogenic PVAT, providing a foundation for developing strategies to augment brown fat activity.
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http://dx.doi.org/10.1038/s42255-021-00380-0DOI Listing
April 2021

Vascular smooth muscle-derived Trpv1 progenitors are a source of cold-induced thermogenic adipocytes.

Nat Metab 2021 04 12;3(4):485-495. Epub 2021 Apr 12.

Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA.

Brown adipose tissue (BAT) and beige fat function in energy expenditure in part due to their role in thermoregulation, making these tissues attractive targets for treating obesity and metabolic disorders. While prolonged cold exposure promotes de novo recruitment of brown adipocytes, the exact sources of cold-induced thermogenic adipocytes are not completely understood. Here, we identify transient receptor potential cation channel subfamily V member 1 (Trpv1) vascular smooth muscle (VSM) cells as previously unidentified thermogenic adipocyte progenitors. Single-cell RNA sequencing analysis of interscapular brown adipose depots reveals, in addition to the previously known platelet-derived growth factor receptor (Pdgfr)α-expressing mesenchymal progenitors, a population of VSM-derived adipocyte progenitor cells (VSM-APC) expressing the temperature-sensitive cation channel Trpv1. We demonstrate that cold exposure induces the proliferation of Trpv1 VSM-APCs and enahnces their differentiation to highly thermogenic adipocytes. Together, these findings illustrate the landscape of the thermogenic adipose niche at single-cell resolution and identify a new cellular origin for the development of brown and beige adipocytes.
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http://dx.doi.org/10.1038/s42255-021-00373-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076094PMC
April 2021

Endogenous Fatty Acid Synthesis Drives Brown Adipose Tissue Involution.

Cell Rep 2021 Jan;34(2):108624

Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address:

Thermoneutral conditions typical for standard human living environments result in brown adipose tissue (BAT) involution, characterized by decreased mitochondrial mass and increased lipid deposition. Low BAT activity is associated with poor metabolic health, and BAT reactivation may confer therapeutic potential. However, the molecular drivers of this BAT adaptive process in response to thermoneutrality remain enigmatic. Using metabolic and lipidomic approaches, we show that endogenous fatty acid synthesis, regulated by carbohydrate-response element-binding protein (ChREBP), is the central regulator of BAT involution. By transcriptional control of lipogenesis-related enzymes, ChREBP determines the abundance and composition of both storage and membrane lipids known to regulate organelle turnover and function. Notably, ChREBP deficiency and pharmacological inhibition of lipogenesis during thermoneutral adaptation preserved mitochondrial mass and thermogenic capacity of BAT independently of mitochondrial biogenesis. In conclusion, we establish lipogenesis as a potential therapeutic target to prevent loss of BAT thermogenic capacity as seen in adult humans.
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http://dx.doi.org/10.1016/j.celrep.2020.108624DOI Listing
January 2021

Adipocyte Microenvironment: Everybody in the Neighborhood Talks about the Temperature.

Cell Metab 2021 Jan;33(1):4-6

Joslin Diabetes Center, Section on Integrative Physiology and Metabolism, Harvard Medical School, Boston, MA, USA. Electronic address:

Adipose tissue is composed of a variety of cells distributed in different depots and playing various metabolic roles. In a recent issue of Nature, Sun et al. (2020) use snRNA-seq and functional studies to identify a population of adipocytes that can suppress the thermogenic activity of neighboring adipocytes by secretion of acetate.
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http://dx.doi.org/10.1016/j.cmet.2020.12.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955659PMC
January 2021

The involvement of neuroimmune cells in adipose innervation.

Mol Med 2020 12 9;26(1):126. Epub 2020 Dec 9.

School of Biology and Ecology, University of Maine, Orono, ME, USA.

Background: Innervation of adipose tissue is essential for the proper function of this critical metabolic organ. Numerous surgical and chemical denervation studies have demonstrated how maintenance of brain-adipose communication through both sympathetic efferent and sensory afferent nerves helps regulate adipocyte size, cell number, lipolysis, and 'browning' of white adipose tissue. Neurotrophic factors are growth factors that promote neuron survival, regeneration, and plasticity, including neurite outgrowth and synapse formation. Peripheral immune cells have been shown to be a source of neurotrophic factors in humans and mice. Although a number of immune cells reside in the adipose stromal vascular fraction (SVF), it has remained unclear what roles they play in adipose innervation. We previously demonstrated that adipose SVF secretes brain derived neurotrophic factor (BDNF).

Methods: We now show that deletion of this neurotrophic factor from the myeloid lineage of immune cells led to a 'genetic denervation' of inguinal subcutaneous white adipose tissue (scWAT), thereby causing decreased energy expenditure, increased adipose mass, and a blunted UCP1 response to cold stimulation.

Results: We and others have previously shown that noradrenergic stimulation via cold exposure increases adipose innervation in the inguinal depot. Here we have identified a subset of myeloid cells that home to scWAT upon cold exposure and are Ly6C CCR2 Cx3CR1 monocytes/macrophages that express noradrenergic receptors and BDNF. This subset of myeloid lineage cells also clearly interacted with peripheral nerves in the scWAT and were therefore considered neuroimmune cells.

Conclusions: We propose that these myeloid lineage, cold induced neuroimmune cells (CINCs) are key players in maintaining adipose innervation as well as promoting adipose nerve remodeling under noradrenergic stimulation, such as cold exposure.
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http://dx.doi.org/10.1186/s10020-020-00254-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727151PMC
December 2020

Brown Fat-Activating Lipokine 12,13-diHOME in Human Milk Is Associated With Infant Adiposity.

J Clin Endocrinol Metab 2021 Jan;106(2):e943-e956

Department of Integrative Physiology and Metabolism, Joslin Diabetes Center, Boston, Massachusetts.

Context: Little is known about the specific breastmilk components responsible for protective effects on infant obesity. Whether 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME), an oxidized linoleic acid metabolite and activator of brown fat metabolism, is present in human milk, or linked to infant adiposity, is unknown.

Objective: To examine associations between concentrations of 12,13-diHOME in human milk and infant adiposity.

Design: Prospective cohort study from 2015 to 2019, following participants from birth to 6 months of age.

Setting: Academic medical centers.

Participants: Volunteer sample of 58 exclusively breastfeeding mother-infant pairs; exclusion criteria included smoking, gestational diabetes, and health conditions with the potential to influence maternal or infant weight gain.

Main Outcome Measures: Infant anthropometric measures including weight, length, body mass index (BMI), and body composition at birth and at 1, 3, and 6 months postpartum.

Results: We report for the first time that 12,13-diHOME is present in human milk. Higher milk 12,13-diHOME level was associated with increased weight-for-length Z-score at birth (β = 0.5742, P = 0.0008), lower infant fat mass at 1 month (P = 0.021), and reduced gain in BMI Z-score from 0 to 6 months (β = -0.3997, P = 0.025). We observed similar associations between infant adiposity and milk abundance of related oxidized linoleic acid metabolites 12,13-Epoxy-9(Z)-octadecenoic acid (12,13-epOME) and 9,10-Dihydroxy-12-octadecenoic acid (9,10-diHOME), and metabolites linked to thermogenesis including succinate and lyso-phosphatidylglycerol 18:0. Milk abundance of 12,13-diHOME was not associated with maternal BMI, but was positively associated with maternal height, milk glucose concentration, and was significantly increased after a bout of moderate exercise.

Conclusions: We report novel associations between milk abundance of 12,13-diHOME and adiposity during infancy.
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http://dx.doi.org/10.1210/clinem/dgaa799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823229PMC
January 2021

CRISPR-engineered human brown-like adipocytes prevent diet-induced obesity and ameliorate metabolic syndrome in mice.

Sci Transl Med 2020 08;12(558)

Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.

Brown and brown-like beige/brite adipocytes dissipate energy and have been proposed as therapeutic targets to combat metabolic disorders. However, the therapeutic effects of cell-based therapy in humans remain unclear. Here, we created human brown-like (HUMBLE) cells by engineering human white preadipocytes using CRISPR-Cas9-SAM-gRNA to activate endogenous uncoupling protein 1 expression. Obese mice that received HUMBLE cell transplants showed a sustained improvement in glucose tolerance and insulin sensitivity, as well as increased energy expenditure. Mechanistically, increased arginine/nitric oxide (NO) metabolism in HUMBLE adipocytes promoted the production of NO that was carried by -nitrosothiols and nitrite in red blood cells to activate endogenous brown fat and improved glucose homeostasis in recipient animals. Together, these data demonstrate the utility of using CRISPR-Cas9 technology to engineer human white adipocytes to display brown fat-like phenotypes and may open up cell-based therapeutic opportunities to combat obesity and diabetes.
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http://dx.doi.org/10.1126/scitranslmed.aaz8664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704293PMC
August 2020

Lipidomics of brown and white adipose tissue: Implications for energy metabolism.

Biochim Biophys Acta Mol Cell Biol Lipids 2020 10 4;1865(10):158788. Epub 2020 Aug 4.

Joslin Diabetes Center, Section on Integrative Physiology and Metabolism, Harvard Medical School, Boston, MA, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA. Electronic address:

Adipose tissue exerts multiple vital functions that critically maintain energy balance, including storing and expending energy, as well as secreting factors that systemically modulate nutrient metabolism. Since lipids are the major constituents of the adipocytes, it is unsurprising that the lipid composition of these cells plays a critical role in maintaining their functions and communicating with other organs and cells. In both positive and negative energy balance conditions, lipids and free fatty acids secreted from adipocytes exert either beneficial or detrimental effects in other tissues, such as the liver, pancreas and muscle. The way the adipocytes communicate with other organs tightly depends on the nature of their lipidome composition. Notwithstanding, the lipidome composition of the adipocytes is affected by physiological factors such as adipocyte type, gender and age, but also by environmental cues such as diet composition, thermal stress and physical activity. Here we provide an updated overview on how the adipose tissue lipidome profile is shaped by different physiological and environmental factors and how these changes impact the way the adipocytes regulate whole-body energy metabolism.
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http://dx.doi.org/10.1016/j.bbalip.2020.158788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484152PMC
October 2020

The Link between Stress and IL-6 Is Heating Up.

Cell Metab 2020 08;32(2):152-153

Joslin Diabetes Center, Section on Integrative Physiology and Metabolism, Harvard Medical School, Boston, MA, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA. Electronic address:

Psychological stress has long been known to reduce adaptability to inflammatory challenges, although the precise mechanism has remained elusive. In a recent issue of Cell, Qing et al. (2020) demonstrate that psychological stress induces secretion of IL-6 from brown adipose tissue, which promotes hepatic gluconeogenesis, and reduces host fitness to inflammatory insults.
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http://dx.doi.org/10.1016/j.cmet.2020.07.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071353PMC
August 2020

The Heating Microenvironment: Intercellular Cross Talk Within Thermogenic Adipose Tissue.

Diabetes 2020 08;69(8):1599-1604

Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA

Adipose tissue serves as the body's primary energy storage site; however, findings in recent decades have transformed our understanding of the multifaceted roles of this adaptable organ. The ability of adipose tissue to undergo energy expenditure through heat generation is termed adaptive thermogenesis, a process carried out by thermogenic adipocytes. Adipocytes are the primary parenchymal cell type in adipose tissue, yet these cells are sustained within a rich stromal vascular microenvironment comprised of adipose stem cells and progenitors, immune cells, neuronal cells, fibroblasts, and endothelial cells. Intricate cross talk between these diverse cell types is essential in regulating the activation of thermogenic fat, and the past decade has shed significant light on how this intercellular communication functions. This review will draw upon recent findings and current perspectives on the sophisticated repertoire of cellular and molecular features that comprise the adipose thermogenic milieu.
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http://dx.doi.org/10.2337/db20-0303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372068PMC
August 2020

Cell Types Promoting Goosebumps Form a Niche to Regulate Hair Follicle Stem Cells.

Cell 2020 08 16;182(3):578-593.e19. Epub 2020 Jul 16.

Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA. Electronic address:

Piloerection (goosebumps) requires concerted actions of the hair follicle, the arrector pili muscle (APM), and the sympathetic nerve, providing a model to study interactions across epithelium, mesenchyme, and nerves. Here, we show that APMs and sympathetic nerves form a dual-component niche to modulate hair follicle stem cell (HFSC) activity. Sympathetic nerves form synapse-like structures with HFSCs and regulate HFSCs through norepinephrine, whereas APMs maintain sympathetic innervation to HFSCs. Without norepinephrine signaling, HFSCs enter deep quiescence by down-regulating the cell cycle and metabolism while up-regulating quiescence regulators Foxp1 and Fgf18. During development, HFSC progeny secretes Sonic Hedgehog (SHH) to direct the formation of this APM-sympathetic nerve niche, which in turn controls hair follicle regeneration in adults. Our results reveal a reciprocal interdependence between a regenerative tissue and its niche at different stages and demonstrate sympathetic nerves can modulate stem cells through synapse-like connections and neurotransmitters to couple tissue production with demands.
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http://dx.doi.org/10.1016/j.cell.2020.06.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540726PMC
August 2020

Integrated metabolomics reveals altered lipid metabolism in adipose tissue in a model of extreme longevity.

Geroscience 2020 12 6;42(6):1527-1546. Epub 2020 Jul 6.

Joslin Diabetes Center, Section on Integrative Physiology and Metabolism, Harvard Medical School, Boston, MA, USA.

Adipose tissue plays an essential role in metabolic health. Ames dwarf mice are exceptionally long-lived and display metabolically beneficial phenotypes in their adipose tissue, providing an ideal model for studying the intersection between adipose tissue and longevity. To this end, we assessed the metabolome and lipidome of adipose tissue in Ames dwarf mice. We observed distinct lipid profiles in brown versus white adipose tissue of Ames dwarf mice that are consistent with increased thermogenesis and insulin sensitivity, such as increased cardiolipin and decreased ceramide concentrations. Moreover, we identified 5-hydroxyeicosapentaenoic acid (5-HEPE), an ω-3 fatty acid metabolite, to be increased in Ames dwarf brown adipose tissue (BAT), as well as in circulation. Importantly, 5-HEPE is increased in other models of BAT activation and is negatively correlated with body weight, insulin resistance, and circulating triglyceride concentrations in humans. Together, these data represent a novel lipid signature of adipose tissue in a mouse model of extreme longevity.
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http://dx.doi.org/10.1007/s11357-020-00221-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732932PMC
December 2020

Commentary on: "The Presence of Active Brown Adipose Tissue Determines Cold-Induced Energy Expenditure and Oxylipin Profiles in Humans".

J Clin Endocrinol Metab 2020 08;105(8)

Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts.

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http://dx.doi.org/10.1210/clinem/dgaa339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304926PMC
August 2020

The Perlman syndrome DIS3L2 exoribonuclease safeguards endoplasmic reticulum-targeted mRNA translation and calcium ion homeostasis.

Nat Commun 2020 05 26;11(1):2619. Epub 2020 May 26.

Stem Cell Program, Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, 02115, USA.

DIS3L2-mediated decay (DMD) is a surveillance pathway for certain non-coding RNAs (ncRNAs) including ribosomal RNAs (rRNAs), transfer RNAs (tRNAs), small nuclear RNAs (snRNAs), and RMRP. While mutations in DIS3L2 are associated with Perlman syndrome, the biological significance of impaired DMD is obscure and pathological RNAs have not been identified. Here, by ribosome profiling (Ribo-seq) we find specific dysregulation of endoplasmic reticulum (ER)-targeted mRNA translation in DIS3L2-deficient cells. Mechanistically, DMD functions in the quality control of the 7SL ncRNA component of the signal recognition particle (SRP) required for ER-targeted translation. Upon DIS3L2 loss, sustained 3'-end uridylation of aberrant 7SL RNA impacts ER-targeted translation and causes ER calcium leakage. Consequently, elevated intracellular calcium in DIS3L2-deficient cells activates calcium signaling response genes and perturbs ESC differentiation. Thus, DMD is required to safeguard ER-targeted mRNA translation, intracellular calcium homeostasis, and stem cell differentiation.
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http://dx.doi.org/10.1038/s41467-020-16418-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250864PMC
May 2020

Single-cell transcriptional networks in differentiating preadipocytes suggest drivers associated with tissue heterogeneity.

Nat Commun 2020 04 30;11(1):2117. Epub 2020 Apr 30.

Department of Biomedical Engineering, Boston University, Boston, MA, 02215, USA.

White adipose tissue plays an important role in physiological homeostasis and metabolic disease. Different fat depots have distinct metabolic and inflammatory profiles and are differentially associated with disease risk. It is unclear whether these differences are intrinsic to the pre-differentiated stage. Using single-cell RNA sequencing, a unique network methodology and a data integration technique, we predict metabolic phenotypes in differentiating cells. Single-cell RNA-seq profiles of human preadipocytes during adipogenesis in vitro identifies at least two distinct classes of subcutaneous white adipocytes. These differences in gene expression are separate from the process of browning and beiging. Using a systems biology approach, we identify a new network of zinc-finger proteins that are expressed in one class of preadipocytes and is potentially involved in regulating adipogenesis. Our findings gain a deeper understanding of both the heterogeneity of white adipocytes and their link to normal metabolism and disease.
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http://dx.doi.org/10.1038/s41467-020-16019-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7192917PMC
April 2020

Parental metabolic syndrome epigenetically reprograms offspring hepatic lipid metabolism in mice.

J Clin Invest 2020 05;130(5):2391-2407

Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, Massachusetts, USA.

The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide. Although gene-environment interactions have been implicated in the etiology of several disorders, the impact of paternal and/or maternal metabolic syndrome on the clinical phenotypes of offspring and the underlying genetic and epigenetic contributors of NAFLD have not been fully explored. To this end, we used the liver-specific insulin receptor knockout (LIRKO) mouse, a unique nondietary model manifesting 3 hallmarks that confer high risk for the development of NAFLD: hyperglycemia, insulin resistance, and dyslipidemia. We report that parental metabolic syndrome epigenetically reprograms members of the TGF-β family, including neuronal regeneration-related protein (NREP) and growth differentiation factor 15 (GDF15). NREP and GDF15 modulate the expression of several genes involved in the regulation of hepatic lipid metabolism. In particular, NREP downregulation increases the protein abundance of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and ATP-citrate lyase (ACLY) in a TGF-β receptor/PI3K/protein kinase B-dependent manner, to regulate hepatic acetyl-CoA and cholesterol synthesis. Reduced hepatic expression of NREP in patients with NAFLD and substantial correlations between low serum NREP levels and the presence of steatosis and nonalcoholic steatohepatitis highlight the clinical translational relevance of our findings in the context of recent preclinical trials implicating ACLY in NAFLD progression.
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http://dx.doi.org/10.1172/JCI127502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190992PMC
May 2020

Analyzing Mitochondrial Function in Brown Adipocytes with a Bioenergetic Analyzer.

Methods Mol Biol 2020 ;2138:289-296

Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA.

Brown adipocytes are a cell type with high mitochondrial content and bioenergetic capacity. A critical means to measure mitochondrial function, macromolecule fuel usage, and other important phenotypes is with a bioenergetic analyzer. Here, we describe how to isolate, culture, and differentiate brown preadipocytes into mature adipocytes. We also explain how to perform a mitochondrial (mito) stress test, using the bioenergetic analyzer. The mito stress test is able to give researchers a plethora of insights into mitochondrial function, including basal respiration, proton leak, ATP production, maximal respiration, and reserve capacity, making it a powerful tool for analyzing brown adipocytes.
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http://dx.doi.org/10.1007/978-1-0716-0471-7_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075131PMC
March 2021

FGF6 and FGF9 regulate UCP1 expression independent of brown adipogenesis.

Nat Commun 2020 03 17;11(1):1421. Epub 2020 Mar 17.

Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA, 02215, USA.

Uncoupling protein-1 (UCP1) plays a central role in energy dissipation in brown adipose tissue (BAT). Using high-throughput library screening of secreted peptides, we identify two fibroblast growth factors (FGF), FGF6 and FGF9, as potent inducers of UCP1 expression in adipocytes and preadipocytes. Surprisingly, this occurs through a mechanism independent of adipogenesis and involves FGF receptor-3 (FGFR3), prostaglandin-E2 and interaction between estrogen receptor-related alpha, flightless-1 (FLII) and leucine-rich-repeat-(in FLII)-interacting-protein-1 as a regulatory complex for UCP1 transcription. Physiologically, FGF6/9 expression in adipose is upregulated by exercise and cold in mice, and FGF9/FGFR3 expression in human neck fat is significantly associated with UCP1 expression. Loss of FGF9 impairs BAT thermogenesis. In vivo administration of FGF9 increases UCP1 expression and thermogenic capacity. Thus, FGF6 and FGF9 are adipokines that can regulate UCP1 through a transcriptional network that is dissociated from brown adipogenesis, and act to modulate systemic energy metabolism.
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http://dx.doi.org/10.1038/s41467-020-15055-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078224PMC
March 2020

Cell-autonomous light sensitivity via Opsin3 regulates fuel utilization in brown adipocytes.

PLoS Biol 2020 02 10;18(2):e3000630. Epub 2020 Feb 10.

Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, United States of America.

Opsin3 (Opn3) is a transmembrane heptahelical G protein-coupled receptor (GPCR) with the potential to produce a nonvisual photoreceptive effect. Interestingly, anatomical profiling of GPCRs reveals that Opn3 mRNA is highly expressed in adipose tissue. The photosensitive functions of Opn3 in mammals are poorly understood, and whether Opn3 has a role in fat is entirely unknown. In this study, we found that Opn3-knockout (Opn3-KO) mice were prone to diet-induced obesity and insulin resistance. At the cellular level, Opn3-KO brown adipocytes cultured in darkness had decreased glucose uptake and lower nutrient-induced mitochondrial respiration than wild-type (WT) cells. Light exposure promoted mitochondrial activity and glucose uptake in WT adipocytes but not in Opn3-KO cells. Brown adipocytes carrying a defective mutation in Opn3's putative G protein-binding domain also exhibited a reduction in glucose uptake and mitochondrial respiration in darkness. Using RNA-sequencing, we identified several novel light-sensitive and Opn3-dependent molecular signatures in brown adipocytes. Importantly, direct exposure of brown adipose tissue (BAT) to light in living mice significantly enhanced thermogenic capacity of BAT, and this effect was diminished in Opn3-KO animals. These results uncover a previously unrecognized cell-autonomous, light-sensing mechanism in brown adipocytes via Opn3-GPCR signaling that can regulate fuel metabolism and mitochondrial respiration. Our work also provides a molecular basis for developing light-based treatments for obesity and its related metabolic disorders.
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http://dx.doi.org/10.1371/journal.pbio.3000630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7034924PMC
February 2020

Lipokines and Thermogenesis.

Endocrinology 2019 10;160(10):2314-2325

Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts.

Adaptive thermogenesis is a catabolic process that consumes energy-storing molecules and expends that energy as heat in response to environmental changes. This process occurs primarily in brown and beige adipose tissue. Thermogenesis is regulated by many factors, including lipid derived paracrine and endocrine hormones called lipokines. Recently, technologic advances for identifying new lipid biomarkers of thermogenic activity have shed light on a diverse set of lipokines that act through different pathways to regulate energy expenditure. In this review, we highlight a few examples of lipokines that regulate thermogenesis. The biosynthesis, regulation, and effects of the thermogenic lipokines in several families are reviewed, including oloeylethanolamine, endocannabinoids, prostaglandin E2, and 12,13-diHOME. These thermogenic lipokines present potential therapeutic targets to combat states of excess energy storage, such as obesity and related metabolic disorders.
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http://dx.doi.org/10.1210/en.2019-00337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760332PMC
October 2019

12-Lipoxygenase Regulates Cold Adaptation and Glucose Metabolism by Producing the Omega-3 Lipid 12-HEPE from Brown Fat.

Cell Metab 2019 10 25;30(4):768-783.e7. Epub 2019 Jul 25.

Joslin Diabetes Center, Section on Integrative Physiology and Metabolism, Harvard Medical School, Boston, MA, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA. Electronic address:

Distinct oxygenases and their oxylipin products have been shown to participate in thermogenesis by mediating physiological adaptations required to sustain body temperature. Since the role of the lipoxygenase (LOX) family in cold adaptation remains elusive, we aimed to investigate whether, and how, LOX activity is required for cold adaptation and to identify LOX-derived lipid mediators that could serve as putative cold mimetics with therapeutic potential to combat diabetes. By utilizing mass-spectrometry-based lipidomics in mice and humans, we demonstrated that cold and β3-adrenergic stimulation could promote the biosynthesis and release of 12-LOX metabolites from brown adipose tissue (BAT). Moreover, 12-LOX ablation in mouse brown adipocytes impaired glucose uptake and metabolism, resulting in blunted adaptation to the cold in vivo. The cold-induced 12-LOX product 12-HEPE was found to be a batokine that improves glucose metabolism by promoting glucose uptake into adipocytes and skeletal muscle through activation of an insulin-like intracellular signaling pathway.
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http://dx.doi.org/10.1016/j.cmet.2019.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774888PMC
October 2019

Afadin is a scaffold protein repressing insulin action via HDAC6 in adipose tissue.

EMBO Rep 2019 08 2;20(8):e48216. Epub 2019 Jul 2.

Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.

Insulin orchestrates metabolic homeostasis through a complex signaling network for which the precise mechanisms controlling its fine-tuning are not completely understood. Here, we report that Afadin, a scaffold protein, is phosphorylated on S1795 (S1718 in humans) in response to insulin in adipocytes, and this phosphorylation is impaired with obesity and insulin resistance. In turn, loss of Afadin enhances the response to insulin in adipose tissues via upregulation of the insulin receptor protein levels. This happens in a cell-autonomous and phosphorylation-dependent manner. Insulin-stimulated Afadin-S1795 phosphorylation modulates Afadin binding with interaction partners in adipocytes, among which HDAC6 preferentially interacts with phosphorylated Afadin and acts as a key intermediate to suppress insulin receptor protein levels. Adipose tissue-specific Afadin depletion protects against insulin resistance and improves glucose homeostasis in diet-induced obese mice, independently of adiposity. Altogether, we uncover a novel insulin-induced cellular feedback mechanism governed by the interaction of Afadin with HDAC6 to negatively control insulin action in adipocytes, which may offer new strategies to alleviate insulin resistance.
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http://dx.doi.org/10.15252/embr.201948216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6680131PMC
August 2019

ComBATing aging-does increased brown adipose tissue activity confer longevity?

Geroscience 2019 06 22;41(3):285-296. Epub 2019 Jun 22.

Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA, 02215, USA.

Brown and its related beige adipose tissue (BAT) play a definitive role in maintaining body temperature by producing heat through uncoupling protein 1 (UCP1), which acts by dissociating oxidative phosphorylation from ATP production, resulting in the release of heat. Therefore, in order to maintain high thermogenic capacity, BAT must act as a metabolic sink by taking up vast amounts of circulating glucose and lipids for oxidation. This, along with the rediscovery of BAT in adult humans, has fueled the study of BAT as a putative therapeutic approach to manage the growing rates of obesity and metabolic syndromes. Notably, many of the beneficial consequences of BAT activity overlap with metabolic biomarkers of extended lifespan and healthspan. In this review, we provide background about BAT including the thermogenic program, BAT's role as a secretory organ, and differences between BAT in mice and humans. We also provide details on BAT during aging, and perspectives on the potential of targeting BAT to promote lifespan and healthspan.
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http://dx.doi.org/10.1007/s11357-019-00076-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702504PMC
June 2019

TGF-β2 is an exercise-induced adipokine that regulates glucose and fatty acid metabolism.

Nat Metab 2019 02 11;1(2):291-303. Epub 2019 Feb 11.

Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.

Exercise improves health and well-being across diverse organ systems, and elucidating mechanisms underlying the beneficial effects of exercise can lead to new therapies. Here, we show that transforming growth factor-β2 (TGF-β2) is secreted from adipose tissue in response to exercise and improves glucose tolerance in mice. We identify TGF-β2 as an exercise-induced adipokine in a gene expression analysis of human subcutaneous adipose tissue biopsies after exercise training. In mice, exercise training increases TGF-β2 in scWAT, serum, and its secretion from fat explants. Transplanting scWAT from exercise-trained wild type mice, but not from adipose tissue-specific Tgfb2-/- mice, into sedentary mice improves glucose tolerance. TGF-β2 treatment reverses the detrimental metabolic effects of high fat feeding in mice. Lactate, a metabolite released from muscle during exercise, stimulates TGF-β2 expression in human adipocytes. Administration of the lactate-lowering agent dichloroacetate during exercise training in mice decreases circulating TGF-β2 levels and reduces exercise-stimulated improvements in glucose tolerance. Thus, exercise training improves systemic metabolism through inter-organ communication with fat via a lactate-TGF-β2-signaling cycle.
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http://dx.doi.org/10.1038/s42255-018-0030-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481955PMC
February 2019

Insulin receptor-mediated signaling regulates pluripotency markers and lineage differentiation.

Mol Metab 2018 12 19;18:153-163. Epub 2018 Sep 19.

Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02215, USA. Electronic address:

Objectives: Insulin receptor (IR)-mediated signaling is involved in the regulation of pluripotent stem cells; however, its direct effects on regulating the maintenance of pluripotency and lineage development are not fully understood. The main objective of this study is to understand the role of IR signaling in pluripotency and lineage development.

Methods: To explore the role of IR signaling, we generated IR knock-out (IRKO) mouse induced pluripotent stem cells (miPSCs) from E14.5 mouse embryonic fibroblasts (MEFs) of global IRKO mice using a cocktail of four reprogramming factors: Oct4, Sox2, Klf4, cMyc. We performed pluripotency characterization and directed the differentiation of control and IRKO iPSCs into neural progenitors (ectoderm), adipocyte progenitors (mesoderm), and pancreatic beta-like cells (endoderm). We mechanistically confirmed these findings via phosphoproteomics analyses of control and IRKO iPSCs.

Results: Interestingly, expression of pluripotency markers including Klf4, Lin28a, Tbx3, and cMyc were upregulated, while abundance of Oct4 and Nanog were enhanced by 4-fold and 3-fold, respectively, in IRKO iPSCs. Analyses of signaling pathways demonstrated downregulation of phospho-STAT3, p-mTor and p-Erk and an increase in the total mTor and Erk proteins in IRKO iPSCs in the basal unstimulated state. Stimulation with leukemia inhibitory factor (LIF) showed a ∼33% decrease of phospho-ERK in IRKO iPSCs. On the contrary, Erk phosphorylation was increased during in vitro spontaneous differentiation of iPSCs lacking IRs. Lineage-specific directed differentiation of the iPSCs revealed that cells lacking IR showed enhanced expression of neuronal lineage markers (Pax6, Tubb3, Ascl1 and Oligo2) while exhibiting a decrease in adipocyte (Fas, Acc, Pparγ, Fabp4, C/ebpα, and Fsp27) and pancreatic beta cell markers (Ngn3, Isl1, and Sox9). Further molecular characterization by phosphoproteomics confirmed the novel IR-mediated regulation of the global pluripotency network including several key proteins involved in diverse aspects of growth and embryonic development.

Conclusion: We report, for the first time to our knowledge, the phosphoproteome of insulin, IGF1, and LIF stimulation in mouse iPSCs to reveal the importance of insulin receptor signaling for the maintenance of pluripotency and lineage determination.
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http://dx.doi.org/10.1016/j.molmet.2018.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6308035PMC
December 2018

Cold-Activated Lipid Dynamics in Adipose Tissue Highlights a Role for Cardiolipin in Thermogenic Metabolism.

Cell Rep 2018 07;24(3):781-790

Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA. Electronic address:

Thermogenic fat expends energy during cold for temperature homeostasis, and its activity regulates nutrient metabolism and insulin sensitivity. We measured cold-activated lipid landscapes in circulation and in adipose tissue by MS/MS shotgun lipidomics. We created an interactive online viewer to visualize the changes of specific lipid species in response to cold. In adipose tissue, among the approximately 1,600 lipid species profiled, we identified the biosynthetic pathway of the mitochondrial phospholipid cardiolipin as coordinately activated in brown and beige fat by cold in wild-type and transgenic mice with enhanced browning of white fat. Together, these data provide a comprehensive lipid bio-signature of thermogenic fat activation in circulation and tissue and suggest pathways regulated by cold exposure.
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http://dx.doi.org/10.1016/j.celrep.2018.06.073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117118PMC
July 2018

RGB-Color Intensiometric Indicators to Visualize Spatiotemporal Dynamics of ATP in Single Cells.

Angew Chem Int Ed Engl 2018 08 18;57(34):10873-10878. Epub 2018 Jul 18.

Cell Signaling Group, Waseda Bioscience Research Institute in Singapore (WABIOS), Singapore, 138667, Republic of Singapore.

Adenosine triphosphate (ATP) provides energy for the regulation of multiple cellular processes in living organisms. Capturing the spatiotemporal dynamics of ATP in single cells is fundamental to our understanding of the mechanisms underlying cellular energy metabolism. However, it has remained challenging to visualize the dynamics of ATP in and between distinct intracellular organelles and its interplay with other signaling molecules. Using single fluorescent proteins, multicolor ATP indicators were developed, enabling the simultaneous visualization of subcellular ATP dynamics in the cytoplasm and mitochondria of cells derived from mammals, plants, and worms. Furthermore, in combination with additional fluorescent indicators, the dynamic interplay of ATP, cAMP, and Ca could be visualized in activated brown adipocyte. This set of indicator tools will facilitate future research into energy metabolism.
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http://dx.doi.org/10.1002/anie.201804304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456769PMC
August 2018