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Articles by Philipp E. Scherer
The perineurium integrates leptin with its sympathetic outflow to protect against obesity
Abstract The regulatory mechanism of leptin’s afferent action in the brain is contingent upon the efferent sympathetic innervation of white and brown adipose tissues. Nonetheless, the peripheral regulation governing the afferent–efferent balance remains ambiguous.
Publisher Correction: GLP-1R–GIPR–PPARα/γ/δ quintuple agonism corrects obesity and diabetes in mice
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Correction to: Nature https://doi.org/10.1038/s41586-026-10427-5 Published online 29 April 2026 In the version of this article initially published, there were errors in the Fig. 4d colour key labels, where the label now reading “GLP-1-GIP–Lani” alongside the red filled circle originally indicated “GLP-1”, while the label now reading “GLP-1–Lani” alongside the white open circle was originally written “GLP-1-GIP–Lani”. The figure is now amended in the HTML and PDF versions of the article.
By Daniela Liskiewicz, Aaron Novikoff, Seun Akindehin, Jonathan Campbell, Pietra Candela, Russell L. Castelino, Callum Coupland, Maxime Culot, W. Scott Dodson, Jonathan D. Douros, Hannes Embring, Annette Feuchtinger, Brian Finan, Cristina García-Cáceres, Xiao-Bing Gao, Fabien Gosselet, Gerald Grandl, Robert M. Gutgesell, Daniel Haas, Martin Jastroch, Ezgi Karaoglu, Pamela A. Kakimoto, Anna Kaltenbach, Michaela Keuper, Christine M. Kusminski, Danielle C. Leander, Arkadiusz Liskiewicz, Xue Liu, Gandhari Maity-Kumar, Sara Martinez, Sara Martínez, Stephanie A. Mowery, Rubén Nogueiras, Marshall Paisley, Diego Perez-Tilve, Patricia Petersen, Paul T. Pfluger, Sneha Prakash, Sabine Steffens, Alberto Cebrian-Serrano, Monica Tost, Jordan Wean, Christian Weber, Junichi Yoshida, Zachary Gerhart-Hines, Tamas L. Horvath, Tamás Horváth, Philipp E. Scherer, Randy J. Seeley, Richard D. DiMarchi, Matthias H. Tschöp, Natalie Krahmer, Patrick J. Knerr, Timo Müller
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Nature
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GLP-1R–GIPR–PPARα/γ/δ quintuple agonism corrects obesity and diabetes in mice
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Abstract There are increasing numbers of effective drugs to improve obesity-linked metabolic dysfunction; GLP-1R–GIPR co-agonism is effective in the management of obesity and type 2 diabetes1,2, and lanifibranor—a nuclear-acting small-molecule triple agonist of PPARα, PPARγ and PPARδ—is in clinical phase 3 trials for the treatment of metabolic dysfunction-associated steatohepatitis3.
By Daniela Liskiewicz, Aaron Novikoff, Ahmed ' Khalil, Seun Akindehin, Jonathan Campbell, Pietra Candela, Russell L. Castelino, Callum Coupland, Maxime Culot, W. Scott Dodson, Jonathan D. Douros, Hannes Embring, Annette Feuchtinger, Brian Finan, Cristina García-Cáceres, Xiao-Bing Gao, Fabien Gosselet, Gerald Grandl, Robert M. Gutgesell, Daniel Haas, Martin Jastroch, Ezgi Karaoglu, Pamela A. Kakimoto, Anna Kaltenbach, Michaela Keuper, Christine M. Kusminski, Danielle C. Leander, Arkadiusz Liskiewicz, Xue Liu, Gandhari Maity-Kumar, Sara Martinez, Sara Martínez, Stephanie A. Mowery, Rubén Nogueiras, Marshall Paisley, Diego Perez-Tilve, Patricia Petersen, Paul T. Pfluger, Sneha Prakash, Sabine Steffens, Alberto Cebrian-Serrano, Monica Tost, Jordan Wean, Junichi Yoshida, Zachary Gerhart-Hines, Tamas L. Horvath, Tamás Horváth, Philipp E. Scherer, Randy J. Seeley, Richard D. DiMarchi, Matthias H. Tschöp, Natalie Krahmer, Patrick J. Knerr, Timo Müller, Christian Weber
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Nature
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Exoproteome of calorie-restricted humans identifies complement deactivation as an immunometabolic checkpoint reducing inflammaging
Abstract Caloric restriction (CR) extends lifespan across diverse organisms, but the effects of CR on human aging and on healthspan are only beginning to be uncovered. In this study, we applied proteomics to plasma samples collected longitudinally from participants achieving, on average, 14% CR over 2 years as part of the CALERIE trial. We identified that inhibition of the complement pathway is linked to lower inflammaging.
Adipocytes signal to recruit specific mRNAs from surrounding cells to restore expression deficits
Abstract Extracellular vesicles (EVs) are nano-sized, membrane-delimited, particles released by cells that carry signaling macromolecules. A major pathway of EV production is potentiated by neutral sphingomyelinase 2 (SMPD3/nSMAse2), an enzyme that generates ceramide from sphingomyelin.
Carnitine biosynthesis governs fuel switching - Cell Research
You have full access to this article via your institution. In a recent Science study, Auger and colleagues identified SLC25A45 as a previously unrecognized mitochondrial trimethyllysine (TML) transporter that enables l-carnitine biosynthesis. By regulating mitochondrial TML availability, SLC25A45 links environmental stressors such as cold exposure and fasting to adaptive fuel switching toward fatty acid oxidation, thereby optimizing mitochondrial energetics and metabolic resilience.
Much ado about NAA-thing - Nature Metabolism
A recent study in Nature Metabolism by Felix et al. reveals that the breakdown of N-acetylaspartate (NAA) by the enzyme aspartoacylase (encoded by Aspa) in adipocytes has a crucial role in regulating circulating NAA levels, maintaining systemic glucose homeostasis and controlling postprandial body temperature.
CYBER-DEFENCE FELLOWSHIPS: Philipp Scherer
To promote research and education in cyber-defence, EPFL and the Cyber-Defence (CYD) Campus launched a rolling call for Master Thesis Fellowships – A Talent Program for Cyber-Defence Research. This month we introduce you to Philipp Scherer, a CYD Master Thesis Fellowship recipient, who is finishing up his Master Thesis in the Secure & Trustworthy Systems Group at ETH Zurich. How did you find out about the CYD Fellowships and what motivated you to apply? . What was your CYD Fellowship project about? .
Regulation of the terminal complement cascade in adipose tissue for control of its volume, cellularity, and fibrosis
INTRODUCTION Enormous progress in the understanding of physiological and pathological processes in white adipose tissue (WAT) gradually transformed this tissue from a passive storage compartment for triglycerides and the main energy reservoir in mammals into an active organ expressing different pro- and anti-inflammatory adipokines and demonstrating paracrine and endocrine effects on other tissues.
Enhanced paracrine action of FGF21 in stromal cells delays thymic aging - Nature Aging
Abstract Age-related thymic involution precedes aging of all other organs in vertebrates and initiates the process of declining T cell diversity, which leads to eventual immune dysfunction. Whether FGF21, a liver-derived pro-longevity hormone that is also produced in thymic stroma, including by adipocytes, controls the mechanism of thymic demise is incompletely understood.
The GIP receptor activates futile calcium cycling in white adipose tissue to increase energy expenditure and drive weight loss in mice
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Keywords GIP receptor adipose tissue obesity weight loss energy expenditure SERCA pathway Introduction The prevalence of obesity has substantially increased.
By Xinxin Yu, Shiuhwei Chen, Jan-Bernd Funcke, Leon G. Straub, Valentina Pirro, Margo P. Emont, Brian A. Droz, Kyla AI. Collins, Chanmin Joung, Mackenzie J. Pearson, Corey James, Gopal J. Babu, Vissarion Efthymiou, Ashley Vernon, Mary Elizabeth Patti, Yu An, Evan Rosen, Matthew Coghlan, Ricardo J. Samms, Philipp E. Scherer, Christine M. Kusminski
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Cell Metabolism
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Adiponectin
Adiponectin (APN) – also referred to as ACRP30, AdipoQ, GBP28, and APM1 – is one of the most important adipokines. It is secreted from adipocytes in multimeric forms and binds to its receptors, which are widely expressed in many tissues. Cellular APN expression can be regulated by peroxisome proliferator-activated receptor γ (PPARγ) activity and insulin levels, while its circulating level is affected by sex, body mass index (BMI), age, and many other factors.
Is the endotoxin-complement cascade the major driver in lipedema?
Lipedema: an inherited condition. Am. J. Med. Genet. A. 2010; 152: 970-976 Is subcutaneous adipose tissue expansion in people living with lipedema healthier and reflected by circulating parameters?. Front. Endocrinol. 2022; 13100009 The MMP14–caveolin axis and its potential relevance for lipedema. Nat. Rev. Endocrinol. 2020; 16: 669-674 Adipose tissue remodeling in lipedema: adipocyte death and concurrent regeneration. J. Cutan. Pathol.
Adipose tissue fibrosis: the unwanted houseguest invited by obesity
Figure 1 Obesity-induced alterations in adipose tissue ECM composition. Summary of obesity-stimulated alterations in adipose tissue ECM composition and level of ECM remodelers compared to lean counterparts. Obesity increased ECM deposition as well as the presence of thicker and more aligned collagen fibers and ECM stiffness (Divoux et al. 2010, Mariman & Wang 2010). The levels of several MMPs and their inhibitors (TIMPs) are regulated in response to obesity (Lin et al. 2016).
Circular, Local, Open: A Recipe for Sustainable Building Construction
1. Introduction The construction sector accounts for a large share of the climate crisis and social inequality. Conventional building practices follow linear production models, which depend on global value chains and the extensive use of unsustainable materials. The most crucial environmental consequences of dominant practices are significant carbon emissions, natural resource exploitation, high energy demands, and waste production [1].
Control of adipose tissue cellularity by the terminal complement cascade - Nature Reviews Endocrinology
Adipocytes have high levels of many components of the complement system. These components are involved in antimicrobial activities, but also have the potential to regulate the maintenance and turn-over of adipocytes under normal and pathophysiological conditions through positive and negative regulation of the membrane attack complex. It is widely accepted that members of the complement pathway are expressed at high levels in white adipose tissue (WAT).
Update on Adipose Tissue and Cancer
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Proteolytic rewiring of mitochondria by LONP1 directs cell identity switching of adipocytes - Nature Cell Biology
Abstract Mitochondrial proteases are emerging as key regulators of mitochondrial plasticity and acting as both protein quality surveillance and regulatory enzymes by performing highly regulated proteolytic reactions. However, it remains unclear whether the regulated mitochondrial proteolysis is mechanistically linked to cell identity switching.
Extracellular Matrix (ECM) and Fibrosis in Adipose Tissue: Overview and Perspectives
Abstract Fibrosis in adipose tissue is a major driver of obesity-related metabolic dysregulation. It is characterized by an overaccumulation of extracellular matrix (ECM) during unhealthy expansion of adipose tissue in response to over nutrition.
Insulin sensitive human adipocytes for in vitro studies - Nature Reviews Endocrinology
Adipocyte insulin resistance is a driving force for systemic insulin resistance. Advances in human stem cell culture have established conditions for human adipocytes that give rise to a reproducible population of adipocytes that retain a high level of insulin sensitivity, paving the way for high throughput screening approaches. Refers to Friesen, M. et al. Development of a physiological insulin resistance model in human stem cell–derived adipocytes. Science Advances 8, eabn7298 (2022).
Tumor Suppressor Par-4 Regulates Complement Factor C3 and Obesity
Impact Factor 6.244 | CiteScore 3.9 More on impact › TABLE OF CONTENTS Nathalia Araujo1†, James Sledziona1†, Sunil K. Noothi2†, Ravshan Burikhanov3†, Nikhil Hebbar1, Saptadwipa Ganguly1, Tripti Shrestha-Bhattarai4, Beibei Zhu5,6, Wendy S. Katz6,7, Yi Zhang8, Barry S. Taylor4, Jinze Liu8, Li Chen5,9, Heidi L. Weiss5,9, Daheng He10, Chi Wang9,11, Andrew J. Morris5,9, Lisa A. Cassis6,7, Mariana Nikolova-Karakashian9,12, Prabhakar R. Nagareddy13, Olle Melander14,15, B. Mark Evers9,16, Philip A.
Post-acute sequelae of COVID-19: A metabolic perspective
Abstract The SARS-CoV-2 pandemic continues to rage around the world. At the same time, despite strong public health measures and high vaccination rates in some countries, a post-COVID-19 syndrome has emerged which lacks a clear definition, prevalence, or etiology. However, fatigue, dyspnea, brain fog, and lack of smell and/or taste are often characteristic of patients with this syndrome.
Highlights • Adult pancreatic islet endocrine cells arise as embryonic hormone-expressing cells • No detectable islet cell differentiation from putative precursor cells after birth • Some embryonic hormone-producing cells display a switch in hormone gene expression Summary The precise developmental dynamics of the pancreatic islet endocrine cell types, and their interrelation, are unknown.
Mitochondrial regulation and white adipose tissue homeostasis
Ehrlund A. et al. The cell-type specific transcriptome in human adipose tissue and influence of obesity on adipocyte progenitors. Sci. Data. 2017; 4: 1-11 Vijay J. et al. Single-cell analysis of human adipose tissue identifies depot- and disease-specific cell types. Nat. Metab. 2020; 2: 97-109 Lee Y.S. et al. Inflammation is necessary for long-term but not short-term high-fat diet-induced insulin resistance. Diabetes. 2011; 60: 2474-2483 Jeffery E. et al.
A Novel Serum Protein Similar to C1q, Produced Exclusively in Adipocytes
Philipp E. Scherer(1)(§), Suzanne Williams(2), Michael Fogliano(2), Giulia Baldini(1)(¶) and Harvey F. Lodish(1),(3)(**) From the (1) Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142-1479 (2) Pfizer Central Research, Groton, Connecticut 06340, and the (3) Department of Biology, Massachusetts Institute of Technology, Cambridge Massachusetts 02139 ↵** To whom correspondence should be addressed. Tel.: 617-258-5216; Fax: 617-258-9872; lodish{at}wi.mit.edu.
PHOSPHO1 puts the breaks on thermogenesis in brown adipocytes
The nonshivering heat production in mitochondria-rich brown or beige adipocytes allows rodents and humans to adapt to cold stress (1). The best-characterized thermogenic effector is uncoupling protein 1 (UCP1), which dissipates energy as heat by proton transport across the mitochondrial inner membrane. Of note, there are also important UCP1-independent pathways mediating brown adipose tissue (BAT) thermogenesis (2).
Tissue-specific disruption of Kbtbd2 uncovers adipocyte-intrinsic and -extrinsic features of the teeny lipodystrophy syndrome
Significance To examine the function of KBTBD2 in different cell types, we knocked the gene out in adipocytes, liver, and muscle cells. None of these conditional knockouts could reproduce the growth retardation observed in mice with a global knockout. An adipose tissue-specific knockout was similar to a global knockout in most respects; however, hyperglycemia was less severe and hyperinsulinemia was more sustained.
The role of adipocytes and adipocyte‐like cells in the severity of COVID‐19 infections
PERSPECTIVES Philipp E.
Leptin: Less Is More
Perspectives in Diabetes Abstract The successful use of leptin for the treatment of individuals with lipodystrophy and leptin deficiency is well established. However, pharmacological approaches of leptin therapy for the treatment of diet-induced obesity have been ineffective. There is ample room for a better understanding of the much famed “leptin resistance” phenomenon. Our recent data in this area prompt us to call for a conceptual shift.
Lowering ceramides to overcome diabetes
PerspectiveMetabolism Christine M. Kusminski, Philipp E. Scherer Touchstone Diabetes Center, The University of Texas Southwestern Medical Center, Dallas, TX, USA. Email: philipp.scherer{at}utsouthwestern.edu See allHide authors and affiliations Science 26 Jul 2019: Vol. 365, Issue 6451, pp. 319-320 DOI: 10.1126/science.aax6594 Summary Excess nutrient intake leads to a disruption in metabolic homeostasis.
Obesity, Diabetes, and Cardiovascular Diseases: A Compendium
Excess body weight, a burgeoning problem worldwide, is a major risk factor for cardiovascular disease.
Caveolin-1 as a target in prevention and treatment of hypertrophic scarring
Abstract Reduced expression of caveolin-1 (Cav-1) is an important pathogenic factor in hypertrophic scarring (HTS). Such a reduction can be found in connection with the main known risk factors for HTS, including dark skin, female gender, young age, burn site and severity of the injury. The degree of overexpression of Cav-1 associated with different therapeutic options for HTS correlates with clinical improvements in HTS.
Caveolin-1 as a pathophysiological factor and target in psoriasis
Abstract Low expression of caveolin-1 (Cav-1) is typical in psoriatic lesions and overexpression of Cav-1 leads to a reduction of inflammation and suppression of epidermal hyperproliferation, thus ameliorating these two well-known hallmarks of psoriasis. At the same time, the interfacial layers of the white adipose tissue (WAT) adjacent to psoriatic lesions demonstrate much higher stiffness, which also points to a modification of Cav-1 expression in this tissue.
Reduced oxygen consumption by fat cells improves metabolic defects
A major cause of type 2 diabetes is obesity, in which fat cells expand rapidly, in both size and number, and their oxygen demand outstrips supply. This low-oxygen state, known as hypoxia, leads to upregulation of the anti-hypoxic protein HIF-1α, which in turn causes tissue inflammation and prevents fat cells (adipocytes) from responding normally to insulin1,2.
Adipose tissue: The dysfunctional adipocyte — a cancer cell's best friend
The interactions of adipocytes with tumour cells have been extensively scrutinized. The adipocyte's mitogenic influence on tumour cells is attributed to several hormonal, growth factor and adipokine effects. A recent study has expanded our understanding of how adipocytes promote tumour progression by demonstrating that adipocytes actively catabolize the chemotherapeutic agent daunorubicin.
Immunologic and endocrine functions of adipose tissue: implications for kidney disease
Key Points Adipocytes are metabolically active cells; they produce signalling lipids and metabolites and secrete protein factors (adipokines) The relative levels of these lipids, proteins and metabolites change under different nutritional and pathological states, with adipocytes integrating information regarding the metabolic status quo at any given time and adjusting their cellular physiological state to maintain systemic homeostasis Adipocyte-derived factors establish complex paracrine and...
Structural biology: Receptors grease the metabolic wheels
Since its discovery1, 2 in 1995, the fat-derived hormone adiponectin has garnered attention for its roles in regulating glucose and lipid metabolism. Its two membrane-spanning receptors3, adiponectin receptor 1 (AdipoR1) and AdipoR2, transduce adiponectin signals in many target tissues, including the liver, heart, kidney and pancreas4.
Adiponectin
Adiponectin is the most adipocyte-specific of all secretory factors described to date. Despite its exclusive expression at the level of the fat cell, adiponectin concentrations in plasma are generally inversely proportional to fat mass.1,2 More detailed studies reveal that it is not fat mass, but rather fat quality that is the driving force for adiponectin expression.
Obesity, Diabetes, and Cardiovascular Diseases
Excess body weight, a burgeoning problem worldwide, is a major risk factor for cardiovascular disease.
The Multifaceted Roles of Adipose Tissue-Therapeutic Targets for Diabetes and Beyond: The 2015 Banting Lecture
Banting Lecture Abstract The Banting Medal for Scientific Achievement is the highest scientific award of the American Diabetes Association (ADA). Given in memory of Sir Frederick Banting, one of the key investigators in the discovery of insulin, the Banting Medal is awarded annually for scientific excellence, recognizing significant long-term contributions to the understanding, treatment, or prevention of diabetes. Philipp E.
Adiponectin, Leptin, and Fatty Acids in the Maintenance of Metabolic Homeostasis through Adipose Tissue Crosstalk
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A Role of the Inflammasome in the Low Storage Capacity of the Abdominal Subcutaneous Adipose Tissue in Obese Adolescents
The innate immune cell sensor leucine-rich–containing family, pyrin domain containing 3 (NLRP3) inflammasome controls the activation of caspase-1, and the release of proinflammatory cytokines interleukin (IL)-1β and IL-18. The NLRP3 inflammasome is implicated in adipose tissue inflammation and the pathogenesis of insulin resistance.
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