Publications by authors named "Patrick Seale"

74 Publications

Neonatal IL-4 exposure decreases adipogenesis of male rats into adulthood.

Am J Physiol Endocrinol Metab 2021 Apr 19. Epub 2021 Apr 19.

Pediatrics, Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania, United States.

The cytokine interleukin 4 (IL-4) can increase beige adipogenesis in adult rodents. However, neonatal animals use a distinct adipocyte precursor compartment for adipogenesis compared to adults. In this study, we address whether IL-4 can induce persistent effects on adipose tissue when administered subcutaneously in the interscapular region during the neonatal period in Sprague Dawley rats. We injected IL-4 into neonatal male rats during postnatal days 1-6, followed by analysis of adipose tissue and adipocyte precursors at 2 weeks and 10 weeks of age. Adipocyte precursors were cultured and subjected to differentiation in vitro. We found that a short and transient IL-4 exposure in neonates upregulated uncoupling protein 1 (Ucp1) mRNA expression and decreased fat cell size in subcutaneous white adipose tissue (WAT). Adipocyte precursors from mature rats that had been treated with IL-4 as neonates displayed a decrease in adiponectin (Adipoq) but no change in Ucp1 expression, as compared to controls. Thus, neonatal IL-4 induces acute beige adipogenesis and decreases adipogenic differentiation capacity long term. Overall, these findings indicate that the neonatal period is critical for adipocyte development and may influence the later onset of obesity.
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http://dx.doi.org/10.1152/ajpendo.00600.2020DOI 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

Marrow adipogenic lineage precursor: A new cellular component of marrow adipose tissue.

Best Pract Res Clin Endocrinol Metab 2021 Mar 15:101518. Epub 2021 Mar 15.

Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. Electronic address:

Bone marrow mesenchymal stromal cells are a highly heterogenic cell population containing mesenchymal stem cells as well as other cell types. With the advance of single cell transcriptome analysis, several recent reports identified a prominent subpopulation of mesenchymal stromal cells that specifically express adipocyte markers but do not contain lipid droplets. We name this cell type marrow adipogenic lineage precursor, MALP, and consider it as a major cellular component of marrow adipose tissue. Here, we review the discovery of MALPs and summarize their unique features and regulatory roles in bone. We further discuss how these findings advance our understanding of bone remodeling, mesenchymal niche regulation of hematopoiesis, and marrow vasculature maintenance.
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http://dx.doi.org/10.1016/j.beem.2021.101518DOI Listing
March 2021

Prdm16 Deficiency Leads to Age-Dependent Cardiac Hypertrophy, Adverse Remodeling, Mitochondrial Dysfunction, and Heart Failure.

Cell Rep 2020 10;33(3):108288

Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore 169857; National Heart Research Institute Singapore, National Heart Center Singapore, Singapore 169609. Electronic address:

Hypertrophic cardiomyopathy (HCM) is a well-established risk factor for cardiovascular mortality worldwide. Although hypertrophy is traditionally regarded as an adaptive response to physiological or pathological stress, prolonged hypertrophy can lead to heart failure. Here we demonstrate that Prdm16 is dispensable for cardiac development. However, it is required in the adult heart to preserve mitochondrial function and inhibit hypertrophy with advanced age. Cardiac-specific deletion of Prdm16 results in cardiac hypertrophy, excessive ventricular fibrosis, mitochondrial dysfunction, and impaired metabolic flexibility, leading to heart failure. We demonstrate that Prdm16 and euchromatic histone-lysine N-methyltransferase factors (Ehmts) act together to reduce expression of fetal genes reactivated in pathological hypertrophy by inhibiting the functions of the pro-hypertrophic transcription factor Myc. Although young Prdm16 knockout mice show normal cardiac function, they are predisposed to develop heart failure in response to metabolic stress. Our study demonstrates that Prdm16 protects the heart against age-dependent cardiac hypertrophy and heart failure.
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http://dx.doi.org/10.1016/j.celrep.2020.108288DOI Listing
October 2020

Deficiency of bone morphogenetic protein-3b induces metabolic syndrome and increases adipogenesis.

Am J Physiol Endocrinol Metab 2020 08 30;319(2):E363-E375. Epub 2020 Jun 30.

Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.

Bone morphogenetic protein (BMP) receptor signaling is critical for the regulation of the endocrine system and cardiovascular structure and function. The objective of this study was to investigate whether Bmp3b, a glycoprotein synthetized and secreted by adipose tissue, is necessary to regulate glucose and lipid metabolism, adipogenesis, and cardiovascular remodeling. Over the course of 4 mo, -knockout () mice gained more weight than wild-type (WT) mice. The plasma levels of cholesterol and triglycerides were higher in mice than in WT mice. mice developed insulin resistance and glucose intolerance. The basal heart rate was higher in mice than in WT mice, and echocardiography revealed eccentric remodeling in mice. The expression of adipogenesis-related genes in white adipose tissue was higher in mice than in WT control mice. In vitro studies showed that Bmp3b modulates the activity of the promoter, an effect mediated by Smad2/3. The results of this study suggest that Bmp3b is necessary for the maintenance of homeostasis in terms of age-related weight gain, glucose metabolism, and left ventricular (LV) remodeling and function. Interventions that increase the level or function of BMP3b may decrease cardiovascular risk and pathological cardiac remodeling.
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http://dx.doi.org/10.1152/ajpendo.00362.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473912PMC
August 2020

Skinny Fat Cells Stimulate Wound Healing.

Cell Stem Cell 2020 06;26(6):801-803

Institute for Diabetes, Obesity & Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

In this issue of Cell Stem Cell, Shook et al. (2020) reveal that dermal adipocytes regulate skin wound repair via release of fatty acids that promote macrophage recruitment and accelerated revascularization. Furthermore, mature dermal adipocytes dedifferentiate into migratory extracellularmatrix-producing myofibroblasts.
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http://dx.doi.org/10.1016/j.stem.2020.04.021DOI Listing
June 2020

Single cell transcriptomics identifies a unique adipose lineage cell population that regulates bone marrow environment.

Elife 2020 04 14;9. Epub 2020 Apr 14.

Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.

Bone marrow mesenchymal lineage cells are a heterogeneous cell population involved in bone homeostasis and diseases such as osteoporosis. While it is long postulated that they originate from mesenchymal stem cells, the true identity of progenitors and their in vivo bifurcated differentiation routes into osteoblasts and adipocytes remain poorly understood. Here, by employing large scale single cell transcriptome analysis, we computationally defined mesenchymal progenitors at different stages and delineated their bi-lineage differentiation paths in young, adult and aging mice. One identified subpopulation is a unique cell type that expresses adipocyte markers but contains no lipid droplets. As non-proliferative precursors for adipocytes, they exist abundantly as pericytes and stromal cells that form a ubiquitous 3D network inside the marrow cavity. Functionally they play critical roles in maintaining marrow vasculature and suppressing bone formation. Therefore, we name them marrow adipogenic lineage precursors (MALPs) and conclude that they are a newly identified component of marrow adipose tissue.
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http://dx.doi.org/10.7554/eLife.54695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220380PMC
April 2020

Shared PPARα/γ Target Genes Regulate Brown Adipocyte Thermogenic Function.

Cell Rep 2020 03;30(9):3079-3091.e5

Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

Brown adipose tissue (BAT) generates heat to maintain body temperature and suppress obesity. Agonists for nuclear receptors PPARα and PPARγ both affect brown adipocyte function, yet the interplay between these factors in BAT is uncertain. Here, we report that PPARα shares most genomic binding sites with PPARγ, and these common binding sites are more related to BAT function than PPARγ-selective sites without PPARα. Integrating PPARα and PPARγ genomic occupancy with cold-responsive BAT transcriptomes identifies a subset of 16 genes with potential relevance to BAT function. Among these, we focused on the lysosomal protease cathepsin Z (CTSZ) and showed it is necessary for mitochondrial respiration in both mouse and human brown adipocytes. Thus, CTSZ is a shared PPARα/γ target gene in BAT and a regulator of brown adipocyte thermogenic function.
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http://dx.doi.org/10.1016/j.celrep.2020.02.032DOI Listing
March 2020

Early B Cell Factor Activity Controls Developmental and Adaptive Thermogenic Gene Programming in Adipocytes.

Cell Rep 2020 03;30(9):2869-2878.e4

Institute for Diabetes, Obesity & Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. Electronic address:

Brown adipose tissue (BAT) activity protects animals against hypothermia and represents a potential therapeutic target to combat obesity. The transcription factor early B cell factor-2 (EBF2) promotes brown adipocyte differentiation, but its roles in maintaining brown adipocyte fate and in stimulating BAT recruitment during cold exposure were unknown. We find that the deletion of Ebf2 in adipocytes of mice ablates BAT character and function, resulting in cold intolerance. Unexpectedly, prolonged exposure to cold restores the thermogenic profile and function of Ebf2 mutant BAT. Enhancer profiling and genetic assays identified EBF1 as a candidate regulator of the cold response in BAT. Adipocyte-specific deletion of both Ebf1 and Ebf2 abolishes BAT recruitment during chronic cold exposure. Mechanistically, EBF1 and EBF2 promote thermogenic gene transcription through increasing the expression and activity of ERRα and PGC1α. Together, these studies demonstrate that EBF proteins specify the developmental fate and control the adaptive cold response of brown adipocytes.
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http://dx.doi.org/10.1016/j.celrep.2020.02.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7079313PMC
March 2020

PRDM16 Maintains Homeostasis of the Intestinal Epithelium by Controlling Region-Specific Metabolism.

Cell Stem Cell 2019 12 26;25(6):830-845.e8. Epub 2019 Sep 26.

Institute for Diabetes, Obesity & Metabolism, Smilow Center for Translational Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, Smilow Center for Translational Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

Metabolic pathways dynamically regulate tissue development and maintenance. However, the mechanisms that govern the metabolic adaptation of stem or progenitor cells to their local niche are poorly understood. Here, we define the transcription factor PRDM16 as a region-specific regulator of intestinal metabolism and epithelial renewal. PRDM16 is selectively expressed in the upper intestine, with enrichment in crypt-resident progenitor cells. Acute Prdm16 deletion in mice triggered progenitor apoptosis, leading to diminished epithelial differentiation and severe intestinal atrophy. Genomic and metabolic analyses showed that PRDM16 transcriptionally controls fatty acid oxidation (FAO) in crypts. Expression of this PRDM16-driven FAO program was highest in the upper small intestine and declined distally. Accordingly, deletion of Prdm16 or inhibition of FAO selectively impaired the development and maintenance of upper intestinal enteroids, and these effects were rescued by acetate treatment. Collectively, these data reveal that regionally specified metabolic programs regulate intestinal maintenance.
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http://dx.doi.org/10.1016/j.stem.2019.08.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6898778PMC
December 2019

Microphysiological Engineering of Self-Assembled and Perfusable Microvascular Beds for the Production of Vascularized Three-Dimensional Human Microtissues.

ACS Nano 2019 07 18;13(7):7627-7643. Epub 2019 Jun 18.

The vasculature is an essential component of the circulatory system that plays a vital role in the development, homeostasis, and disease of various organs in the human body. The ability to emulate the architecture and transport function of blood vessels in the integrated context of their associated organs represents an important requirement for studying a wide range of physiological processes. Traditional models of the vasculature, however, largely fail to offer such capabilities. Here we combine microfluidic three-dimensional (3D) cell culture with the principle of vasculogenic self-assembly to engineer perfusable 3D microvascular beds . Our system is created in a micropatterned hydrogel construct housed in an elastomeric microdevice that enables coculture of primary human vascular endothelial cells and fibroblasts to achieve formation, anastomosis, and controlled perfusion of 3D vascular networks. An open-top chamber design adopted in this hybrid platform also makes it possible to integrate the microengineered 3D vasculature with other cell types to recapitulate organ-specific cellular heterogeneity and structural organization of vascularized human tissues. Using these capabilities, we developed stem cell-derived microphysiological models of vascularized human adipose tissue and the blood-retinal barrier. Our approach was also leveraged to construct a 3D organotypic model of vascularized human lung adenocarcinoma as a high-content drug screening platform to simulate intravascular delivery, tumor-killing effects, and vascular toxicity of a clinical chemotherapeutic agent. Furthermore, we demonstrated the potential of our platform for applications in nanomedicine by creating microengineered models of vascular inflammation to evaluate a nanoengineered drug delivery system based on active targeting liposomal nanocarriers. These results represent a significant improvement in our ability to model the complexity of native human tissues and may provide a basis for developing predictive preclinical models for biopharmaceutical applications.
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http://dx.doi.org/10.1021/acsnano.9b00686DOI Listing
July 2019

A PRDM16-Driven Metabolic Signal from Adipocytes Regulates Precursor Cell Fate.

Cell Metab 2019 07 30;30(1):174-189.e5. Epub 2019 May 30.

Institute for Diabetes, Obesity & Metabolism, University of Pennsylvania, Philadelphia, PA, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA. Electronic address:

The precursor cells for metabolically beneficial beige adipocytes can alternatively become fibrogenic and contribute to adipose fibrosis. We found that cold exposure or β3-adrenergic agonist treatment of mice decreased the fibrogenic profile of precursor cells and stimulated beige adipocyte differentiation. This fibrogenic-to-adipogenic transition was impaired in aged animals, correlating with reduced adipocyte expression of the transcription factor PRDM16. Genetic loss of Prdm16 mimicked the effect of aging in promoting fibrosis, whereas increasing PRDM16 in aged mice decreased fibrosis and restored beige adipose development. PRDM16-expressing adipose cells secreted the metabolite β-hydroxybutyrate (BHB), which blocked precursor fibrogenesis and facilitated beige adipogenesis. BHB catabolism in precursor cells, mediated by BDH1, was required for beige fat differentiation in vivo. Finally, dietary BHB supplementation in aged animals reduced adipose fibrosis and promoted beige fat formation. Together, our results demonstrate that adipocytes secrete a metabolite signal that controls beige fat remodeling.
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http://dx.doi.org/10.1016/j.cmet.2019.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6836679PMC
July 2019

Identification of a mesenchymal progenitor cell hierarchy in adipose tissue.

Science 2019 04;364(6438)

Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.

Metabolic health depends on the capacity of adipose tissue progenitor cells to undergo de novo adipogenesis. The cellular hierarchy and mechanisms governing adipocyte progenitor differentiation are incompletely understood. Through single-cell RNA sequence analyses, we show that the lineage hierarchy of adipocyte progenitors consists of distinct mesenchymal cell types that are present in both mouse and human adipose tissues. Cells marked by dipeptidyl peptidase-4 (DPP4)/CD26 expression are highly proliferative, multipotent progenitors. During the development of subcutaneous adipose tissue in mice, these progenitor cells give rise to intercellular adhesion molecule-1 (ICAM1)/CD54-expressing (CD54+) committed preadipocytes and a related adipogenic cell population marked by and /CD142 expression. Transforming growth factor-β maintains DPP4+ cell identity and inhibits adipogenic commitment of DPP4+ and CD142+ cells. Notably, DPP4+ progenitors reside in the reticular interstitium, a recently appreciated fluid-filled space within and between tissues, including adipose depots.
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http://dx.doi.org/10.1126/science.aav2501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6816238PMC
April 2019

Transcriptional Control of Brown and Beige Fat Development and Function.

Obesity (Silver Spring) 2019 01;27(1):13-21

Institute for Diabetes, Obesity, and Metabolism, Smilow Center for Translational Research, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Adipose tissue, once viewed as an inert organ of energy storage, is now appreciated to be a central node for the dynamic regulation of systemic metabolism. There are three general types of adipose tissue: white, brown, and brown-in-white or "beige" fat. All three types of adipose tissue communicate extensively with other organs in the body, including skin, liver, pancreas, muscle, and brain, to maintain energy homeostasis. When energy intake chronically exceeds energy expenditure, obesity and its comorbidities can develop. Thus, understanding the molecular mechanisms by which different types of adipose tissues develop and function could uncover new therapies for combating disorders of energy imbalance. In this review, the recent findings on the transcriptional and chromatin-mediated regulation of brown and beige adipose tissue activity are highlighted.
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http://dx.doi.org/10.1002/oby.22334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309799PMC
January 2019

Stepping Up Human Beige Fat Cell Production.

Cell Rep 2018 12;25(11):2935-2936

Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address:

Beige fat cells hold significant promise for reducing obesity and metabolic disease. Su et al. (2018) present a robust method to produce human beige adipocytes from pluripotent stem cells via the generation of an expandable intermediary population of mesenchymal progenitor cells.
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http://dx.doi.org/10.1016/j.celrep.2018.11.091DOI Listing
December 2018

Interrogation of nonconserved human adipose lincRNAs identifies a regulatory role of in adipocyte metabolism.

Sci Transl Med 2018 06;10(446)

Division of Cardiology, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA.

Long intergenic noncoding RNAs (lincRNAs) have emerged as important modulators of cellular functions. Most lincRNAs are not conserved among mammals, raising the fundamental question of whether nonconserved adipose-expressed lincRNAs are functional. To address this, we performed deep RNA sequencing of gluteal subcutaneous adipose tissue from 25 healthy humans. We identified 1001 putative lincRNAs expressed in all samples through de novo reconstruction of noncoding transcriptomes and integration with existing lincRNA annotations. One hundred twenty lincRNAs had adipose-enriched expression, and 54 of these exhibited peroxisome proliferator-activated receptor γ (PPARγ) or CCAAT/enhancer binding protein α (C/EBPα) binding at their loci. Most of these adipose-enriched lincRNAs (~85%) were not conserved in mice, yet on average, they showed degrees of expression and binding of PPARγ and C/EBPα similar to those displayed by conserved lincRNAs. Most adipose lincRNAs differentially expressed ( = 53) in patients after bariatric surgery were nonconserved. The most abundant adipose-enriched lincRNA in our subcutaneous adipose data set, , was nonconserved, up-regulated in adipose depots of obese individuals, and markedly induced during in vitro human adipocyte differentiation. We demonstrated that interacts with heterogeneous nuclear ribonucleoprotein U (hnRNPU) and insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) at distinct subcellular locations to regulate adipocyte differentiation and lipogenesis.
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http://dx.doi.org/10.1126/scitranslmed.aar5987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6620026PMC
June 2018

Enhancing brown fat with NFIA.

Nat Cell Biol 2017 Aug;19(9):1006-1007

Institute for Diabetes, Obesity, and Metabolism, Department of Cell and Developmental Biology, Smilow Center for Translational Research, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

Brown adipose tissue is a key metabolic organ that oxidizes fatty acids and glucose to generate heat. Through epigenomic analyses of multiple adipose depots, the transcription factor nuclear factor I-A (NFIA) is now shown to drive the brown fat genetic program through binding to lineage-specific cis-regulatory elements.
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http://dx.doi.org/10.1038/ncb3591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5761334PMC
August 2017

Neonatal GLP1R activation limits adult adiposity by durably altering hypothalamic architecture.

Mol Metab 2017 07 15;6(7):748-759. Epub 2017 May 15.

Institute for Diabetes, Obesity and Metabolism and the Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA, 19104, USA.

Objective: Adult obesity risk is influenced by alterations to fetal and neonatal environments. Modifying neonatal gut or neurohormone signaling pathways can have negative metabolic consequences in adulthood. Here we characterize the effect of neonatal activation of glucagon like peptide-1 (GLP-1) receptor (GLP1R) signaling on adult adiposity and metabolism.

Methods: Wild type C57BL/6 mice were injected with 1 nmol/kg Exendin-4 (Ex-4), a GLP1R agonist, for 6 consecutive days after birth. Growth, body composition, serum analysis, energy expenditure, food intake, and brain and fat pad histology and gene expression were assessed at multiple time points through 42 weeks. Similar analyses were conducted in a conditional allele crossed with a Sim1Cre deleter strain to produce Sim1Cre;Glp1r mice and control littermates.

Results: Neonatal administration of Ex-4 reduced adult body weight and fat mass, increased energy expenditure, and conferred protection from diet-induced obesity in female mice. This was associated with induction of brown adipose genes and increased noradrenergic fiber density in parametrial white adipose tissue (WAT). We further observed durable alterations in orexigenic and anorexigenic projections to the paraventricular hypothalamic nucleus (PVH). Genetic deletion of Glp1r in the PVH by Sim1-Cre abrogated the impact of neonatal Ex-4 on adult body weight, WAT browning, and hypothalamic architecture.

Conclusion: These observations suggest that the acute activation of GLP1R in neonates durably alters hypothalamic architecture to limit adult weight gain and adiposity, identifying GLP1R as a therapeutic target for obesity prevention.
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http://dx.doi.org/10.1016/j.molmet.2017.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5485307PMC
July 2017

Histone deacetylase 3 prepares brown adipose tissue for acute thermogenic challenge.

Nature 2017 06 14;546(7659):544-548. Epub 2017 Jun 14.

Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

Brown adipose tissue is a thermogenic organ that dissipates chemical energy as heat to protect animals against hypothermia and to counteract metabolic disease. However, the transcriptional mechanisms that determine the thermogenic capacity of brown adipose tissue before environmental cold are unknown. Here we show that histone deacetylase 3 (HDAC3) is required to activate brown adipose tissue enhancers to ensure thermogenic aptitude. Mice with brown adipose tissue-specific genetic ablation of HDAC3 become severely hypothermic and succumb to acute cold exposure. Uncoupling protein 1 (UCP1) is nearly absent in brown adipose tissue lacking HDAC3, and there is also marked downregulation of mitochondrial oxidative phosphorylation genes resulting in diminished mitochondrial respiration. Remarkably, although HDAC3 acts canonically as a transcriptional corepressor, it functions as a coactivator of oestrogen-related receptor α (ERRα) in brown adipose tissue. HDAC3 coactivation of ERRα is mediated by deacetylation of PGC-1α and is required for the transcription of Ucp1, Ppargc1a (encoding PGC-1α), and oxidative phosphorylation genes. Importantly, HDAC3 promotes the basal transcription of these genes independently of adrenergic stimulation. Thus, HDAC3 uniquely primes Ucp1 and the thermogenic transcriptional program to maintain a critical capacity for thermogenesis in brown adipose tissue that can be rapidly engaged upon exposure to dangerously cold temperature.
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http://dx.doi.org/10.1038/nature22819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5826652PMC
June 2017

EBF2 transcriptionally regulates brown adipogenesis via the histone reader DPF3 and the BAF chromatin remodeling complex.

Genes Dev 2017 04 20;31(7):660-673. Epub 2017 Apr 20.

Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

The transcription factor early B-cell factor 2 (EBF2) is an essential mediator of brown adipocyte commitment and terminal differentiation. However, the mechanisms by which EBF2 regulates chromatin to activate brown fat-specific genes in adipocytes were unknown. ChIP-seq (chromatin immunoprecipitation [ChIP] followed by deep sequencing) analyses in brown adipose tissue showed that EBF2 binds and regulates the activity of lineage-specific enhancers. Mechanistically, EBF2 physically interacts with the chromatin remodeler BRG1 and the BAF chromatin remodeling complex in brown adipocytes. We identified the histone reader protein DPF3 as a brown fat-selective component of the BAF complex that was required for brown fat gene programming and mitochondrial function. Loss of DPF3 in brown adipocytes reduced chromatin accessibility at EBF2-bound enhancers and led to a decrease in basal and catecholamine-stimulated expression of brown fat-selective genes. Notably, is a direct transcriptional target of EBF2 in brown adipocytes, thereby establishing a regulatory module through which EBF2 activates and also recruits DPF3-anchored BAF complexes to chromatin. Together, these results reveal a novel mechanism by which EBF2 cooperates with a tissue-specific chromatin remodeling complex to activate brown fat identity genes.
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http://dx.doi.org/10.1101/gad.294405.116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5411707PMC
April 2017

PRDM16 represses the type I interferon response in adipocytes to promote mitochondrial and thermogenic programing.

EMBO J 2017 06 13;36(11):1528-1542. Epub 2017 Apr 13.

Institute for Diabetes, Obesity & Metabolism, Smilow Center for Translational Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

Brown adipose has the potential to counteract obesity, and thus, identifying signaling pathways that regulate the activity of this tissue is of great clinical interest. PRDM16 is a transcription factor that activates brown fat-specific genes while repressing white fat and muscle-specific genes in adipocytes. Whether PRDM16 also controls other gene programs to regulate adipocyte function was unclear. Here, we identify a novel role for PRDM16 in suppressing type I interferon (IFN)-stimulated genes (ISGs), including , in adipocytes and Ectopic activation of type I IFN signaling in brown adipocytes induces mitochondrial dysfunction and reduces uncoupling protein 1 (UCP1) expression. -deficient adipose displays an exaggerated response to type I IFN, including higher STAT1 levels and reduced mitochondrial gene expression. Mechanistically, PRDM16 represses ISGs through binding to promoter regions of these genes and blocking the activating function of IFN regulatory factor 1 (IRF1). Together, these data indicate that PRDM16 diminishes responsiveness to type I IFN in adipose cells to promote thermogenic and mitochondrial function.
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http://dx.doi.org/10.15252/embj.201695588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5452012PMC
June 2017

Targeting PPARγ in the epigenome rescues genetic metabolic defects in mice.

J Clin Invest 2017 Apr 27;127(4):1451-1462. Epub 2017 Feb 27.

Obesity causes insulin resistance, and PPARγ ligands such as rosiglitazone are insulin sensitizing, yet the mechanisms remain unclear. In C57BL/6 (B6) mice, obesity induced by a high-fat diet (HFD) has major effects on visceral epididymal adipose tissue (eWAT). Here, we report that HFD-induced obesity in B6 mice also altered the activity of gene regulatory elements and genome-wide occupancy of PPARγ. Rosiglitazone treatment restored insulin sensitivity in obese B6 mice, yet, surprisingly, had little effect on gene expression in eWAT. However, in subcutaneous inguinal fat (iWAT), rosiglitazone markedly induced molecular signatures of brown fat, including the key thermogenic gene Ucp1. Obesity-resistant 129S1/SvImJ mice (129 mice) displayed iWAT browning, even in the absence of rosiglitazone. The 129 Ucp1 locus had increased PPARγ binding and gene expression that were preserved in the iWAT of B6x129 F1-intercrossed mice, with an imbalance favoring the 129-derived alleles, demonstrating a cis-acting genetic difference. Thus, B6 mice have genetically defective Ucp1 expression in iWAT. However, when Ucp1 was activated by rosiglitazone, or by iWAT browning in cold-exposed or young mice, expression of the B6 version of Ucp1 was no longer defective relative to the 129 version, indicating epigenomic rescue. These results provide a framework for understanding how environmental influences like drugs can affect the epigenome and potentially rescue genetically determined disease phenotypes.
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http://dx.doi.org/10.1172/JCI91211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5373865PMC
April 2017

Regeneration of fat cells from myofibroblasts during wound healing.

Science 2017 02 5;355(6326):748-752. Epub 2017 Jan 5.

The Saban Research Institute of Children's Hospital Los Angeles and Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA.

Although regeneration through the reprogramming of one cell lineage to another occurs in fish and amphibians, it has not been observed in mammals. We discovered in the mouse that during wound healing, adipocytes regenerate from myofibroblasts, a cell type thought to be differentiated and nonadipogenic. Myofibroblast reprogramming required neogenic hair follicles, which triggered bone morphogenetic protein (BMP) signaling and then activation of adipocyte transcription factors expressed during development. Overexpression of the BMP antagonist Noggin in hair follicles or deletion of the BMP receptor in myofibroblasts prevented adipocyte formation. Adipocytes formed from human keloid fibroblasts either when treated with BMP or when placed with human hair follicles in vitro Thus, we identify the myofibroblast as a plastic cell type that may be manipulated to treat scars in humans.
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http://dx.doi.org/10.1126/science.aai8792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5464786PMC
February 2017

The tumor suppressor FLCN mediates an alternate mTOR pathway to regulate browning of adipose tissue.

Genes Dev 2016 11 2;30(22):2551-2564. Epub 2016 Dec 2.

Department of Medicine and Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

Noncanonical mechanistic target of rapamycin (mTOR) pathways remain poorly understood. Mutations in the tumor suppressor folliculin (FLCN) cause Birt-Hogg-Dubé syndrome, a hamartomatous disease marked by mitochondria-rich kidney tumors. FLCN functionally interacts with mTOR and is expressed in most tissues, but its role in fat has not been explored. We show here that FLCN regulates adipose tissue browning via mTOR and the transcription factor TFE3. Adipose-specific deletion of FLCN relieves mTOR-dependent cytoplasmic retention of TFE3, leading to direct induction of the PGC-1 transcriptional coactivators, drivers of mitochondrial biogenesis and the browning program. Cytoplasmic retention of TFE3 by mTOR is sensitive to ambient amino acids, is independent of growth factor and tuberous sclerosis complex (TSC) signaling, is driven by RagC/D, and is separable from canonical mTOR signaling to S6K. Codeletion of TFE3 in adipose-specific FLCN knockout animals rescues adipose tissue browning, as does codeletion of PGC-1β. Conversely, inducible expression of PGC-1β in white adipose tissue is sufficient to induce beige fat gene expression in vivo. These data thus unveil a novel FLCN-mTOR-TFE3-PGC-1β pathway-separate from the canonical TSC-mTOR-S6K pathway-that regulates browning of adipose tissue.
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http://dx.doi.org/10.1101/gad.287953.116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5159669PMC
November 2016

Activation of β3-adrenoceptors increases in vivo free fatty acid uptake and utilization in brown but not white fat depots in high-fat-fed rats.

Am J Physiol Endocrinol Metab 2016 12 25;311(6):E901-E910. Epub 2016 Oct 25.

Cardiovascular and Metabolic Diseases Innovative Medicines and Early Development Biotech Unit, AstraZeneca Gothenburg, Sweden;

Activation of brown adipose tissue (BAT) and browning of white adipose tissue (WAT) present potential new therapies for obesity and type 2 diabetes. Here, we examined the effects of β-adrenergic stimulation on tissue-specific uptake and storage of free fatty acids (FFA) and its implications for whole body FFA metabolism in diet-induced obese rats using a multi-radiotracer technique. Male Wistar rats were high fat-fed for 12 wk and administered β3-agonist CL316,243 (CL, 1 mg·kg·day) or saline via osmotic minipumps during the last 3 wk. The rats were then fasted and acutely infused with a tracer mixture ([C]palmitate and the partially metabolized R-[H]bromopalmitate) under anesthesia. CL infusion decreased body weight gain and fasting plasma glucose levels. While core body temperature was unaffected, infrared thermography showed an increase in tail heat dissipation following CL infusion. Interestingly, CL markedly increased both FFA storage and utilization in interscapular and perirenal BAT, whereas the flux of FFA to skeletal muscle was decreased. In this rat model of obesity, only sporadic populations of beige adipocytes were detected in the epididymal WAT depot of CL-infused rats, and there was no change in FFA uptake or utilization in WAT following CL infusion. In summary, β-agonism robustly increased FFA flux to BAT coupled with enhanced utilization. Increased BAT activation most likely drove the increased tail heat dissipation to maintain thermostasis. Our results emphasize the quantitative role of brown fat as the functional target of β-agonism in obesity.
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http://dx.doi.org/10.1152/ajpendo.00204.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5183882PMC
December 2016

Control of brown and beige fat development.

Nat Rev Mol Cell Biol 2016 11 24;17(11):691-702. Epub 2016 Aug 24.

Institute for Diabetes, Obesity and Metabolism, Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

Brown and beige adipocytes expend chemical energy to produce heat and are therefore important in regulating body temperature and body weight. Brown adipocytes develop in discrete and relatively homogenous depots of brown adipose tissue, whereas beige adipocytes are induced to develop in white adipose tissue in response to certain stimuli - notably, exposure to cold. Fate-mapping analyses have identified progenitor populations that give rise to brown and beige fat cells, and have revealed unanticipated cell-lineage relationships between vascular smooth muscle cells and beige adipocytes, and between skeletal muscle cells and brown fat. In addition, non-adipocyte cells in adipose tissue, including neurons, blood vessel-associated cells and immune cells, have crucial roles in regulating the differentiation and function of brown and beige fat.
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http://dx.doi.org/10.1038/nrm.2016.96DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5627770PMC
November 2016

Lack of AKT in adipocytes causes severe lipodystrophy.

Mol Metab 2016 Jul 13;5(7):472-479. Epub 2016 May 13.

Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. Electronic address:

Objective: Adipose depot mass is tightly regulated to maintain energy homeostasis. AKT is a critical kinase in the insulin-signaling cascade that is required for the process of adipogenesis in vitro. However, the role of AKT in the maintenance and/or function of mature adipocytes in vivo had not been examined.

Methods: To study this, we deleted Akt1 and Akt2 in adipocytes of mice using the AdipoQ-Cre driver.

Results: Strikingly, mice lacking adipocyte AKT were severely lipodystrophic, having dramatically reduced gonadal adipose and no discernible subcutaneous or brown adipose tissue. As a result, these mice developed severe insulin resistance accompanied by fatty liver, hepatomegaly and with enlarged islets of Langerhans.

Conclusions: These data reveal the critical role of adipocyte AKT and insulin signaling for maintaining adipose tissue mass.
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http://dx.doi.org/10.1016/j.molmet.2016.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4921941PMC
July 2016

SnapShot: Brown and Beige Adipose Thermogenesis.

Cell 2016 Jun;166(1):258-258.e1

Department of Cell & Developmental Biology and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.

Brown and beige adipose tissues have been identified as potential therapeutic targets for combating diet-induced obesity and metabolic disease. Here, we present transcriptional and developmental regulation of brown and beige adipose tissue, as well as critical physiological and pharmaceutical activators of thermogenesis in both tissues.
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http://dx.doi.org/10.1016/j.cell.2016.06.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5478388PMC
June 2016

Zfp423 Maintains White Adipocyte Identity through Suppression of the Beige Cell Thermogenic Gene Program.

Cell Metab 2016 Jun 26;23(6):1167-1184. Epub 2016 May 26.

Touchstone Diabetes Center and Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address:

The transcriptional regulators Ebf2 and Prdm16 establish and maintain the brown and/or beige fat cell identity. However, the mechanisms operating in white adipocytes to suppress the thermogenic gene program and maintain an energy-storing phenotype are less understood. Here, we report that the transcriptional regulator Zfp423 is critical for maintaining white adipocyte identity through suppression of the thermogenic gene program. Zfp423 expression is enriched in white versus brown adipocytes and suppressed upon cold exposure. Doxycycline-inducible inactivation of Zfp423 in mature adipocytes, combined with β-adrenergic stimulation, triggers a conversion of differentiated adiponectin-expressing inguinal and gonadal adipocytes into beige-like adipocytes; this reprogramming event is sufficient to prevent and reverse diet-induced obesity and insulin resistance. Mechanistically, Zfp423 acts in adipocytes to inhibit the activity of Ebf2 and suppress Prdm16 activation. These data identify Zfp423 as a molecular brake on adipocyte thermogenesis and suggest a therapeutic strategy to unlock the thermogenic potential of white adipocytes in obesity.
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http://dx.doi.org/10.1016/j.cmet.2016.04.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5091077PMC
June 2016

Rapamycin Blocks Induction of the Thermogenic Program in White Adipose Tissue.

Diabetes 2016 04 8;65(4):927-41. Epub 2016 Feb 8.

Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA

Rapamycin extends life span in mice, yet paradoxically causes lipid dysregulation and glucose intolerance through mechanisms that remain incompletely understood. Whole-body energy balance can be influenced by beige/brite adipocytes, which are inducible by cold and other stimuli via β-adrenergic signaling in white adipose depots. Induction of beige adipocytes is considered a promising strategy to combat obesity because of their ability to metabolize glucose and lipids, dissipating the resulting energy as heat through uncoupling protein 1. Here, we report that rapamycin blocks the ability of β-adrenergic signaling to induce beige adipocytes and expression of thermogenic genes in white adipose depots. Rapamycin enhanced transcriptional negative feedback on the β3-adrenergic receptor. However, thermogenic gene expression remained impaired even when the receptor was bypassed with a cell-permeable cAMP analog, revealing the existence of a second inhibitory mechanism. Accordingly, rapamycin-treated mice are cold intolerant, failing to maintain body temperature and weight when shifted to 4°C. Adipocyte-specific deletion of the mTORC1 subunit Raptor recapitulated the block in β-adrenergic signaling. Our findings demonstrate a positive role for mTORC1 in the recruitment of beige adipocytes and suggest that inhibition of β-adrenergic signaling by rapamycin may contribute to its physiological effects.
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http://dx.doi.org/10.2337/db15-0502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4806661PMC
April 2016