News

Greg Westcott’s oral presentation at the Lymphatics Gordon Research Conference in Lucca, Italy, received an Abstract Award conferred by the European Vascular Biology Organisation. Congratulations Greg!

Congratulations to Greg Westcott on his newly awarded K08! It is titled Lymphatic-adipocyte interactions in obesity and lymphedema. The K08 will focus on specific mechanisms of the bidirectional relationship between adipocytes and lymphatic endothelial cells using metabolic and lymphatic vascular functional testing. It also includes single-nucleus RNA sequencing of adipose tissue hypertrophy associated with lymphatic diseases.

Frankie Heyward has discovered an unexpected transcriptional effector of leptin action in AgRP neurons. His manuscript “Integrated genomic analysis of AgRP neurons reveals that IRF3 regulates leptin’s hunger-suppressing effects” is now available on BioRxiv (https://www.biorxiv.org/content/10.1101/2022.01.03.474708v1). Check it out!

Suraj Patel found that while global knockout of IRF3 reduces both liver insulin resistance and steatosis in obesity, hepatocyte-specific knockout of IRF3 in hepatocytes only affects insulin resistance. He was able to track a key target gene of IRF3 down: it’s Ppp2r1b, a component of the PP2A complex which affects AMPK and AKT signaling. This paper demonstrates that inflammation causes insulin resistance in liver by modulating signaling pathways that regulate gluconeogenesis. Read about it in Science Translational Medicine (Hepatic IRF3 Fuels Dysglycemia in Obesity Through Direct Regulation of Ppp2r1b. Science Translational Medicine, 2022; Mar 23;14(637):eabh3831. doi: 10.1126/scitranslmed.abh3831). Suraj’s paper was chosen for the cover image of the current issue Science Translational Medicine, seen here.

The single cell revolution has been going on for a few years, but adipocytes have lagged, because their large size and fragility make them unamenable to traditional whole cell approaches. Our (long and expensive!) optimization of single nucleus strategies for adipose tissue finally pays off. Read our paper (A single cell atlas of human and mouse white adipose tissue. Nature, 2022) in Nature to learn about the diversity of cell types in mouse and human adipose tissue, the discovery of several unique adipocyte subpopulations, and associations between these cells and metabolic diseases like T2D. Cells are featured across visceral and subcutaneous depots, as well as in leanness and obesity. This work was spearheaded by Margo Emont.

Margo Emont wins Best Poster at the 2021 Broad Institute Retreat in the Genetics and Disease Biology category. The poster presented her recent efforts to create an atlas of cell types in both human and mouse white adipose tissue using single cell and single nucleus RNA sequencing. In addition to presenting a comprehensive dataset of all cell types within the adipose tissue, she specifically focused on the subtypes of adipocytes identified in this study and predict adipocyte subtype functions using gene expression data and correspondence to human phenotype. The open access to the paper with the data she presented can be found here (https://rdcu.be/cJXHi). Congratulations Margo!

Congratulations to Frankie Heyward, who founded the Harvard Black Postdoc Association (https://www.hbpa.hms.harvard.edu/), which provides advice and support for this critically underrepresented group in the life sciences. Congratulations, Frankie!

Farewell to two excellent technicians: Sam Piaker is headed to Dallas to manage Suraj Patel’s lab, and Molly Veregge is off to get her Ph.D at the University of Minnesota in the Department of Plant Pathology. Plants!

Suraj Patel is moving to Dallas to start his own lab! Suraj is an Assistant Professor of Internal Medicine at UT Southwestern Medical Center, and is a member of the Center for Human Nutrition and the Division of Digestive and Liver Diseases. Congrats to Suraj!

Greg Westcott had a great review article about connections between lymphatics and adipose tissue in Endocrinology (Cross-talk between adipose and lymphatics in health and disease. Endocrinology. 2022; 163(1):1-12.) Check it out!

There is an interesting and unexplained bidirectional relationship between the lymphatic system and adiposity, but no clear mechanisms have been defined. Jin Li and Erwei Li show that lymphatic endothelial cells make a hormone called neurotensin (NTS), which has powerful anti-thermogenic properties. Their paper (Neurotensin is an anti-thermogenic peptide produced by lymphatic endothelial cells) is out in Cell Metabolism.

Others had reported that mesothelial cells could become visceral adipocytes in mice, but Greg Westcott and Margo Emont noted that the marker used to make that conclusion (WT1) is not exclusive to the mesothelium. Their new paper in Cell Reports uses a more specific marker gene to demonstrate that mesothelial cells are not, in fact, a source of adipocytes in mice (Cell Reports, 2021;13;36(2):109388.doi:10.1016/j.celrep. 2021.109388. PMCID: PMC8317472).

How does inflammation decrease adipose thermogenesis? Shuai Yan’s paper ( IRF3 Reduces Adipose Thermogenesis via ISG15-mediated Reprogramming of Glycolysis) in the Journal of Clinical Investigation demonstrates one critical mechanism. Shuai showed that IRF3 in adipocytes drives a transcriptional program that includes ISG15, a ubiquitin-like molecule. ISG15 binds covalently to glycolytic enzymes, reducing lactate production, which is critical for thermogenesis.

Congratulations to Suraj Patel on his newly awarded K08! The K08 will support Suraj’s research about the immunoregulation of hepatic metabolism.

This is a research career development award that provides funding for 3 years. Suraj has previously found that Interferon Regulatory Factor 3 (IRF3) plays an essential role in obesity-induced non-alcoholic fatty liver disease (NAFLD). Mice deficient in IRF3 (IRF3KO) are protected against steatosis and hepatic insulin resistance induced by high fat diet. Genome-wide transcriptional profiling of IRF3KO and wild-type mice on HFD revealed two candidate IRF3 target genes, Isg15 and Srebf1, mediating IRF3-induced hepatic steatosis and insulin resistance. The aims of this project are to identify the hepatic cell type(s) responsible for IRF3-mediated steatosis and IR in NAFLD, and define the role of ISG15 and SREBP1 in promoting IRF3-induced metabolic dysfunction. 

Congratulations on the grant Suraj!

This collaboration with Amit Majithia’s group at the Broad (now at UC San Diego) shows that high content image morphometric analysis can be used to predict molecular pathways in adipogenesis. Read more about it here!