Papers

Erwei Li, Luhong Wang, Daqing Wang, Jingyi Chi, Gordon I. Smith, Samuel Klein, Paul Cohen, Evan D. Rosen

Oxytocin (OXT), a nine amino acid peptide produced in the hypothalamus and released by the posterior pituitary, has well-known actions in parturition, lactation, and social behavior¹, and has become an intriguing therapeutic target for diseases like autism and schizophrenia². Exogenous OXT has also been shown to promote weight loss, among other beneficial metabolic effects^1,3, suggesting that its therapeutic potential may extend to diabetes and obesity^1,4. It is unclear, however, whether endogenous OXT participates in metabolic homeostasis. Here we show that OXT is a critical regulator of adipose tissue lipolysis in both mice and humans. In addition, OXT serves to license the ability of β- adrenergic agonists to fully promote lipolysis. Most surprisingly, the relevant source of OXT in these metabolic actions is a previously unidentified subpopulation of tyrosine hydroxylase (TH)-positive sympathetic neurons. Our data reveal that OXT from the peripheral nervous system is an endogenous regulator of adipose and systemic metabolism.

bioRxiv 2022.09.27.509745; doi: https://doi.org/10.1101/2022.09.27.509745

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). https://www.science.org/doi/10.1126/scitranslmed.abh3831

PubMed

Margo P. Emont, Christopher Jacobs, Adam L. Essene, Deepti Pant, Danielle Tenen, Georgia Colleluori, Angelica Di Vincenzo, Anja M. Jørgensen, Hesam Dashti, Adam Stefek, Elizabeth McGonagle, Sophie Strobel, Samantha Laber, Saaket Agrawal, Gregory P. Westcott, Amrita Kar, Molly L. Veregge, Anton Gulko, Harini Srinivasan, Zachary Kramer, Eleanna De Filippis, Erin Merkel, Jennifer Ducie, Christopher G. Boyd, William Gourash, Anita Courcoulas, Samuel J. Lin, Bernard T. Lee, Donald Morris, Adam Tobias, Amit V. Khera, Melina Claussnitzer, Tune H. Pers, Antonio Giordano, Orr Ashenberg, Aviv Regev, Linus T. Tsai, Evan 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). https://doi.org/10.1038/s41586-022-04518-2

PubMed