Organic Cation Transporter 3 (Oct3) Is a Distinct Catecholamines Clearance Route in Adipocytes Mediating the Beiging of White Adipose Tissue

PLoS Biol. 2019 Jan 17;17(1):e2006571. doi: 10.1371/journal.pbio.2006571. eCollection 2019 Jan.

Abstract

Beiging of white adipose tissue (WAT) is a particularly appealing target for therapeutics in the treatment of metabolic diseases through norepinephrine (NE)-mediated signaling pathways. Although previous studies report NE clearance mechanisms via SLC6A2 on sympathetic neurons or proinflammatory macrophages in adipose tissues (ATs), the low catecholamine clearance capacity of SLC6A2 may limit the cleaning efficiency. Here, we report that mouse organic cation transporter 3 (Oct3; Slc22a3) is highly expressed in WAT and displays the greatest uptake rate of NE as a selective non-neural route of NE clearance in white adipocytes, which differs from other known routes such as adjacent neurons or macrophages. We further show that adipocytes express high levels of NE degradation enzymes Maoa, Maob, and Comt, providing the molecular basis on NE clearance by adipocytes together with its reuptake transporter Oct3. Under NE administration, ablation of Oct3 induces higher body temperature, thermogenesis, and lipolysis compared with littermate controls. After prolonged cold challenge, inguinal WAT (ingWAT) in adipose-specific Oct3-deficient mice shows much stronger browning characteristics and significantly elevated expression of thermogenic and mitochondrial biogenesis genes than in littermate controls, and this response involves enhanced β-adrenergic receptor (β-AR)/protein kinase A (PKA)/cyclic adenosine monophosphate (cAMP)-responsive element binding protein (Creb) pathway activation. Glycolytic genes are reprogrammed to significantly higher levels to compensate for the loss of ATP production in adipose-specific Oct3 knockout (KO) mice, indicating the fundamental role of glucose metabolism during beiging. Inhibition of β-AR largely abolishes the higher lipolytic and thermogenic activities in Oct3-deficient ingWAT, indicating the NE overload in the vicinity of adipocytes in Oct3 KO adipocytes. Of note, reduced functional alleles in human OCT3 are also identified to be associated with increased basal metabolic rate (BMR). Collectively, our results demonstrate that Oct3 governs β-AR activity as a NE recycling transporter in white adipocytes, offering potential therapeutic applications for metabolic disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / metabolism
  • Adipose Tissue / metabolism
  • Adipose Tissue, Beige / metabolism*
  • Adipose Tissue, White / metabolism*
  • Animals
  • Catecholamines / metabolism*
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Energy Metabolism
  • HEK293 Cells
  • Humans
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Norepinephrine / pharmacology
  • Norepinephrine Plasma Membrane Transport Proteins / metabolism
  • Obesity / metabolism
  • Octamer Transcription Factor-3 / biosynthesis
  • Octamer Transcription Factor-3 / genetics
  • Octamer Transcription Factor-3 / metabolism*
  • Organic Cation Transport Proteins / biosynthesis
  • Organic Cation Transport Proteins / genetics
  • Organic Cation Transport Proteins / metabolism*
  • Signal Transduction
  • Thermogenesis / physiology

Substances

  • Catecholamines
  • Cyclic AMP Response Element-Binding Protein
  • Norepinephrine Plasma Membrane Transport Proteins
  • Octamer Transcription Factor-3
  • Organic Cation Transport Proteins
  • POU5F1 protein, human
  • solute carrier family 22 (organic cation transporter), member 3
  • Cyclic AMP-Dependent Protein Kinases
  • Norepinephrine

Grant support

National Key R&D Program of China (grant number No. 2018YFA0506903) received by L.C. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. National Science and Technology Major Projects for Major New Drugs Innovation and Development (grant number No. 2018ZX09711003-004-002) received by L.C. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Tsinghua University Initiative Scientific Research Program (grant number No. 20161080086) received by L.C. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. National Natural Science Foundation of China (grant number No. 81470839) received by L.C. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. National Institutes of Health (grant number GM117163) received by K.M.G. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.