43 posts

Hepatic IRF3 fuels dysglycemia in obesity through direct regulation of Ppp2r1b

Suraj J. Patel, Nan Lui, Anton Gulko, Maynara L. Andrade, Frankie D. Heyward, Tyler Sermersheim, Nufar Edingar, Harini Srinivasan, Margo Emont, Gregory P. Wescott, Jay Luther, Raymond T. Chung, Shuai Yan, Manju Kumari, Reeby Thomas, Yann Deleye, André Tchernof, Phillip J. White, Guido A. Baselli, Marica Meroni, Dario F. De Jesus, Rasheed Ahmad, Rohit N. Kulkarni, Luca Valenti, Linus Tsai and Evan D. Rosen

Inflammation has profound but poorly understood effects on metabolism, especially in the context of obesity and nonalcoholic fatty liver disease (NAFLD). Here, we report that hepatic interferon regulatory factor 3 (IRF3) is a direct transcriptional regulator of glucose homeostasis through induction of Ppp2r1b, a component of serine/threonine phosphatase PP2A, and subsequent suppression of glucose production. Global ablation of IRF3 in mice on a high-fat diet protected against both steatosis and dysglycemia, whereas hepatocyte-specific loss of IRF3 affects only dysglycemia. Integration of the IRF3-dependent transcriptome and cistrome in mouse hepatocytes identifies Ppp2r1b as a direct IRF3 target responsible for mediating its metabolic actions on glucose homeostasis. IRF3-mediated induction of Ppp2r1b amplified PP2A activity, with subsequent dephosphorylation of AMPKα and AKT. Furthermore, suppression of hepatic Irf3 expression with antisense oligonucleotides reversed obesity-induced insulin resistance and restored glucose homeostasis in obese mice. Obese humans with NAFLD displayed enhanced activation of liver IRF3, with reversion after bariatric surgery. Hepatic PPP2R1B expression correlated with HgbA1C and was elevated in obese humans with impaired fasting glucose. We therefore identify the hepatic IRF3-PPP2R1B axis as a causal link between obesity-induced inflammation and dysglycemia and suggest an approach for limiting the metabolic dysfunction accompanying obesity-associated NAFLD.

Science Translational Medicine (2022).


A single cell atlas of human and mouse white adipose tissue

Margo P. EmontChristopher JacobsAdam L. EsseneDeepti PantDanielle TenenGeorgia ColleluoriAngelica Di VincenzoAnja M. JørgensenHesam DashtiAdam StefekElizabeth McGonagleSophie StrobelSamantha LaberSaaket AgrawalGregory P. WestcottAmrita KarMolly L. VereggeAnton GulkoHarini SrinivasanZachary KramerEleanna De FilippisErin MerkelJennifer DucieChristopher G. BoydWilliam GourashAnita CourcoulasSamuel J. LinBernard T. LeeDonald MorrisAdam TobiasAmit V. KheraMelina ClaussnitzerTune H. PersAntonio GiordanoOrr AshenbergAviv RegevLinus T. TsaiEvan D. Rosen

White adipose tissue, once regarded as morphologically and functionally bland, is now recognized to be dynamic, plastic and heterogenous, and is involved in a wide array of biological processes including energy homeostasis, glucose and lipid handling, blood pressure control and host defence1. High-fat feeding and other metabolic stressors cause marked changes in adipose morphology, physiology and cellular composition1, and alterations in adiposity are associated with insulin resistance, dyslipidemia and type 2 diabetes2. Here we provide detailed cellular atlases of human and mouse subcutaneous and visceral white fat at single-cell resolution across a range of body weight. We identify subpopulations of adipocytes, adipose stem and progenitor cells, vascular and immune cells and demonstrate commonalities and differences across species and dietary conditions. We link specific cell types to increased risk of metabolic disease and provide an initial blueprint for a comprehensive set of interactions between individual cell types in the adipose niche in leanness and obesity. These data comprise an extensive resource for the exploration of genes, traits and cell types in the function of white adipose tissue across species, depots and nutritional conditions.

Nature (2022).


Integrated genomic analysis of AgRP neurons reveals that IRF3 regulates leptin’s hunger-suppressing effects

Frankie D. HeywardNan LiuChristopher JacobsRachael IvisonNatalia MachadoAykut UnerHarini SrinivasanSuraj J. PatelAnton GulkoTyler SermersheimStuart H. OrkinLinus TsaiEvan D. Rosen

AgRP neurons in the arcuate nucleus of the hypothalamus (ARC) coordinate homeostatic changes in appetite associated with fluctuations in food availability and leptin signaling. Identifying the relevant transcriptional regulatory pathways in these neurons has been a priority, yet such attempts have been stymied due to their low abundance and the rich cellular diversity of the ARC. Here we generated AgRP neuron-specific transcriptomic and chromatin accessibility profiles during opposing states of fasting-induced hunger and leptin-induced hunger suppression. Cis-regulatory analysis of these integrated datasets enabled the identification of 28 putative hunger-promoting and 29 putative hunger-suppressing transcriptional regulators in AgRP neurons, 16 of which were predicted to be transcriptional effectors of leptin. Within our dataset, Interferon regulatory factor 3 (IRF3) emerged as a leading candidate mediator of leptin-induced hunger-suppression. Gain- and loss-of-function experiments in vivo confirm the role of IRF3 in mediating the acute satiety-evoking effects of leptin in AgRP neurons, while live-cell imaging in vitro indicate that leptin can activate neuronal IRF3 in a cell autonomous manner. Finally, we employ CUT&RUN to uncover direct transcriptional targets of IRF3 in AgRP neurons in vivo. Thus, our findings identify AgRP neuron-expressed IRF3 as a key transcriptional effector of the hunger-suppressing effects of leptin.