We are a team of eight scientists and physicians from the United Kingdom, United States, Canada, Spain, and Turkey with distinct and complementary expertise. The goal of our highly interdisciplinary work is to determine the basis for the metabolic and cardiovascular benefits of brown fat.
Rockefeller University (USA)
The Cohen Lab investigates the biology and genetics of brown fat to understand how it mediates these pleiotropic effects. Centered on human biology and employing unique patient cohorts and novel imaging and biochemical methods, the lab takes a systems-based approach focusing on three interconnected themes: (1) Mechanistic Studies of Brown Fat Guided by Human Genetics; (2) Comprehensive Analysis of Humoral Factors Secreted by Brown Fat to Maintain Metabolic Health; (3) Understanding How Brown Fat Contributes to Cardiovascular Protection.
The Cohen Lab has benefited greatly from collaborations established in the funded Leducq Network. Ongoing projects include: Identification and functional analysis of candidate genetic variants associated with brown fat function (in collaboration with Farooqi, Itan, and Ozcelik Labs). Mechanistic studies dissecting the effects of brown fat on vascular function and blood pressure regulation (in collaboration with Graupera and Touyz Labs). Profiling of cold-regulated secreted factors in humans (in collaboration with Gerszten and Wang labs).
Led by Paul Cohen, MD, PhD
University of Cambridge (UK)
Our goal is to develop new treatments for people living with severe obesity by delivering a step-change in our understanding of the control of human energy balance. Previously, we have demonstrated that mutations disrupting the hormone leptin and its downstream neural targets cause severe childhood obesity. In clinical studies, we have demonstrated the critical role of this pathway in food intake, food reward and fat preference.
We are currently interested in understanding how and why some people remain thin in an obesogenic environment. Thinness (BMI<19kg/m2) is as heritable as severe obesity. We have recruited a UK cohort of >3000 thin people (STILTS cohort; www.stilts.org.uk) in whom we are undertaking genetic and physiological studies. As part of the Network, we are working with colleagues to characterize the function of these genes in cells, zebrafish and mice.
Led by: I. Sadaf Farooqi, MB, ChB, PhD
Beth Israel Deaconess Medical Center (USA)
The Gerszten Lab is a nationally recognized research program that focuses on personal genomics and cardiometabolic disease. The lab closely examines molecular signs of heart disease to uncover early disease risk factors and is a leader in metabolomics and proteomics technologies.
The lab uses extensive biochemical profiling techniques and is actively collaborating with others in the Leducq Network. Metabolite or protein biomarkers identified in the context of brown adipose tissue (BAT) are being assessed for associations with cardiometabolic traits in large population based cohorts that have been or are being profiled using the same technologies (Framingham Heart Study, Jackson Heart Study, Dallas Heart Study, etc.). Triaged lists of candidate molecules (or their “upstream” genes) will be further studied in the model systems.
Led by: Robert Gerszten, MD
Josep Carreras Leukemia Research Institute (Spain)
The main aim of the Graupera Lab is to understand the physiology of blood vessels and their role in disease towards the development of therapeutic strategies to target the vascular compartment. Specifically, the Graupera Lab has a strong interest in the fundamental understanding of physiological vessel growth and function, and the pathological contexts in which the vasculature plays a critical role either intrinsically or extrinsically, as a key component of the stromal compartment, and in obesity, where the vasculature has a main role in the regulation of systemic metabolism.
The lab applies a holistic approach utilizing state-of-the-art techniques as high-throughput analysis, next-generation sequencing, single cell RNA sequencing, phospho/proteomics, and high-resolution imaging. The team is closely collaborating on mechanistic studies dissecting the effects of brown fat on vascular function and blood pressure regulation (in collaboration with Cohen and Touyz Labs).
Led by Mariona Graupera, PhD
Icahn School of Medicine at Mount Sinai (USA)
The Itan Lab is developing computational methods to predict the functional impact of human genetic variants. In particular, machine learning classifiers predict gain and loss-of-function variants and disease-specific pathogenic variant predictions. Additionally, the Itan Lab performs phenome-wide and gene associations (utilizing our method tailored for small cohorts) to detect novel variants, genes, and phenotypes associated with candidate variants.
The Itan Lab is actively collaborating with most labs in the Leducq networks (Cohen, Gerszten, Ozcelik, Touyz, Farooqi, and Graupera) in PheWAS and gene associations, as well as in novel candidate variant and gene predictions. Additional future collaborations will continue this ongoing work with a focus on population-specific analyses (particularly of under-represented populations such as African American and Hispanic) and further analyses of new projects such as machine learning feature importance and classification of candidate variants with the Graupera Lab.
Led by: Yuval Itan, PhD
Bilkent University (Turkey)
The primary objective of the Ozcelik Lab is the molecular characterization of inherited disorders through genetic mapping. The lab identified the genes for several monogenic and complex disorders including Prader-Willi syndrome, Charcot-Marie-Tooth disease type 1A, hereditary leukemia, Üner Tan syndrome, Parkinson's disease, essential tremors, delayed sleep phase disorder, and attention deficit hyperactivity disorder.
However, there remains a large body of diseases for which the causal genes are not known. Especially complex diseases such as obesity, metabolic disorders and diabetes. One major reason that many diseases remain unsolved at the genetic level is that the inheritance patterns of human diseases are not fully understood and analysis of human genome is not straightforward. We need to undertake innovative approaches to establish robust genotype/phenotype correlations. To this end, the lab initiated the Turkish Obesity Study to discover new genes and therapeutic targets to investigate the connection between obesity and associated cardiovascular and metabolic diseases. The group is also actively collaborating with most labs in the Leducq Network (Cohen, Gerszten, Itan, Touyz, Farooqi, and Graupera) in novel candidate variant and gene predictions.
Led by: Tayfun Ozcelik, MD
Research Institute of the McGill University Health Centre (Canada)
The Touyz Lab studies the mechanisms of hypertension and target organ damage and how this impacts cardiometabolic disorders. The lab examines molecular and vascular mechanisms of hypertension and small vessel disease with a particular interest in vascular signaling and redox biology, vascular biology of cations and TRPM channels, and cardiovascular and metabolic toxicity of anti-cancer drugs. In addition, using a systems-based approach, the lab studies processes linking hypertension and obesity with a focus on the interplay between adipose tissue and the vascular system. The work spans molecular biology to clinical studies and the team uses a combination of proteomics, cellular and molecular biology, transgenic models, molecular imaging technologies and human physiological assessment.
The Touyz Lab has developed the concept of the adipose:vascular interactome and how it influences cardiometabolic disorders including obesity, diabetes and hypertension, which are common co-morbidities clinically. There studies explore the differential roles of white, beige and brown adipose tissue and the molecular processes in adipocytes that define adipose function and the impact on endothelial and vascular function. The lab has a particular interest in unravelling the vasoprotective effects of brown adipose tissue by studying novel signaling pathways including c-Src, Notch3, VEGF and Nox/ROS. Working with the Cohen and Graupera laboratories they explore the vascular mechanisms and role of the adipose secretome underlying cardiometabolic benefits of brown adipose tissue. They are also interested in identifying novel biomarkers of the adipose:vascular interactome in cardiometabolic disorders through liquid biopsies and by deep phenotyping of vascular and adipose microvesicles. These studies, in association with those of the Gerszten lab, will define molecular adipose and vascular signatures linked to specific clinical phenotypes.
Led by: Rhian Touyz, MD, PhD
UT Southwestern Medical Center (USA)
A major areas of interest to the Wang Lab is the interaction between metabolism and cardiovascular disease. The lab focuses on hormones that the heart makes called natriuretic peptides, and how these hormones operate in healthy people as well as in people with diseases. The lab also studies how cardiovascular risk can be assessed in people who don’t have disease yet, using a variety of tools such as biomarkers and genetics.
The Wang Lab is collaborating with others in the network to identify BAT-derived mediators responsible for its unique cardiometabolic effects through the use of extensive biochemical profiling.
Led by: Thomas Wang, MD