Catecholamines stimulate the mobilization of stored triglycerides in adipocytes to provide fatty acids (FAs) for other tissues. However, a large proportion is taken back up and either oxidized or re-esterified. What controls the disposition of these FAs in adipocytes remains unknown. Here, we report that catecholamines redirect FAs for oxidation through the phosphorylation of signal transducer and activator of transcription 3 (STAT3). Adipocyte STAT3 is phosphorylated upon activation of β-adrenergic receptors, and in turn suppresses FA re-esterification to promote FA oxidation. Adipocyte-specific Stat3 KO mice exhibit normal rates of lipolysis, but exhibit defective lipolysis-driven oxidative metabolism, resulting in reduced energy expenditure and increased adiposity when they are on a high-fat diet. This previously unappreciated, non-genomic role of STAT3 explains how sympathetic activation can increase both lipolysis and FA oxidation in adipocytes, revealing a new regulatory axis in metabolism.
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The RNA-sequencing data reported in this paper have been deposited in the National Center for Biotechnology Information (NCBI) Sequence Read Archive (SRA) database under accession code PRJNA557252. All additional data that support the findings of this study are available within the manuscript or supplement and from the corresponding author upon request.
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We thank members of the Saltiel laboratory for helpful discussions. We thank M. R. Mackey and D. Boassa at the NCMIR Core Facility for performing electron microscopy, and B. Vanderfeesten for blinded analysis of lipid droplet volume. This work was supported by US National Institutes of Health grants 1K01DK105075-01A1 and R03DK118195 to S.M.R., R01NS087611 to A.N.M, R01DK117551 and R01DK076906 to A.R.S., K99HL143277 to P.Z., P30DK063491 to A.R.S., S.M.R., P30 2P30CA023100-28 to the Microscopy core at UCSD Moores Cancer Center, P30NS047101 to the UCSD School of Medicine Microscopy Core, and P41 GM103412 to the NCMIR Core Facility. This work was also supported by American Diabetes Association grant 1-19-JDF-012 to S.M.R. and 1-18-PDF-094 to C.W.H. Finally, the authors dedicate this work to the memory of our inspirational friend and colleague Maryam Ahmadian.
The authors declare no competing interests.
Peer review information Primary Handling Editor: Christoph Schmitt.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Extended Data Fig. 1 Catecholamine signaling in white and brown adipose tissue.
Western blot analysis of WT and SAKO mice fed a HFD for 12 weeks, then treated with 1 mg/kg CL-316,243 or vehicle control for indicated time before sacrifice and tissue collection. a, Epididymal white adipose tissue. b, Inguinal white adipose tissue. Outlier detected with Grubs outlier test removed. c, Brown adipose tissue. Blots are representative of results from three independent experiments.
Extended Data Fig. 2 Fractionation of 3T3-L1 differentiated adipocytes.
Relative levels of β-tubulin (cytosol marker), H3 (nuclear marker), Calnexin (ER/membrane marker), TOM20 (mitochondrial marker) and Perilipin1 (lipid droplet marker) in fractionated samples from time course analysis in Fig. 2a. Cytosol, nucleus, membrane and mitochondria run on the same gel. These experiments were repeated independently four times with similar results.
Extended Data Fig. 3 Metabolic phenotype of SAKO mice on a normal diet (ND).
a, Left panel: Western blot of mature adipocytes isolated from 12-week old WT and SAKO mice. Right panel: Quantification of STAT3 protein relative to RalA loading control. Individual data points plotted ± SEM (n = 3 iWAT, 2 eWAT). b, Body weight of 12-week old ND fed WT and SAKO mice. Individual data points plotted ± SEM (n = 6 per genotype). c, Oxygen consumption rate in ND fed WT and SAKO mice at 16-weeks of age. Data are represented as mean ± SEM (n = 16). d, Adipocyte size distribution from ND-fed 12-week old WT and SAKO eWAT (n = 2 WT and 3 SAKO). e, Adipocyte size distribution from ND-fed 12-week old WT and SAKO iWAT (n = 2 WT and 3 SAKO). f, Body composition of ND fed WT and SAKO mice at 12 weeks of age. Individual data points plotted ± SEM (n = 6 WT and 4 SAKO).
Extended Data Fig. 4 Histology from HFD-fed WT and SAKO mice.
From top to bottom, eWAT (scale bar = 100 μm), iWAT (scale bar = 100 μm), BAT (scale bar = 50 μm), and liver (scale bar = 100 μm). Results are representative of results from three independent experiments.
Extended Data Fig. 5 Effect of CL-316,243 on metabolism.
a, Oxygen consumption and b, RER before and after intraperitoneal injection with 1 mg/kg CL-316,243. Individual data points plotted ± SEM (n = 6 per treatment). * p value = 0.002 (VO2) and <0.0001 (RER) CL versus baseline (two-tailed paired t-test).
Extended Data Fig. 6 Mitochondria bioenergetics profiles.
a-e, Isolated mitochondria. Vertical lines indicate addition of oligomycin (2 μM), and FCCP (two sequential additions of 3 μM). a, 4 mM ADP + 5 mM pyruvate + 1 mM malate, b, 40 μM palmitoyl-carnitine + 1 mM malate, c, 5 mM succinate + 2 μM rotenone, d, 5 mM glycerol 3-phosphate + 2 μM rotenone 700 nM CaCl2, e, 20 mM ascorb-ate + 200 μM Tetramethyl-p-Phenylenediamine. f-j, Permeabilized PPDIVs. Vertical lines indicate addition of oligomycin (2 μM), and FCCP (two sequential additions of 2 μM). f, 40 μM palmitoylcarnitine + 1 mM malate, g, 4 mM ADP + 5 mM pyruvate + 1 mM malate, h, 5 mM succinate + 2 μM rotenone, i, 5 mM glycerol 3 phosphate + 2 μM rotenone 700 nM CaCl2, j, 20 mM ascorbate + 200 μM Tetramethyl-p-Phenylenediamine. Data are represented as mean ± SEM (n = 8 per genotype).
Extended Data Fig. 7 STAT3/GPAT3 interaction.
a, Western blot analysis of fractionated 3T3-L1 adipocytes treated with 10 μM CL-316,243 or vehicle control for 60 min. b-d and f, Western blot analysis of input, flow through and immunoprecipitation using Myc-antibody coated beads (b, c) or Flag-antibody coated beads (d, f) of HEK293T cell lysates overexpressing Flag-tagged STAT3 and/or Myc-tagged GPAT3/GPAT4. Blots are representative of three independent replicates. Dark exposure (D.E.). e, Western blot analysis of input and immunoprecipitation using GPAT3 antibody in 3T3-L1 differentiated adipocytes treated with 10 μM CL-316,243 or vehicle control for 15 min. f, Western blot analysis of input, flow through and immunoprecipitation using Flag antibody coated beads of HEK293T cell lysates overexpressing Flag-tagged STAT3 (WT/S727A/S727D) and/or Myc-tagged GPAT3. Blots are representative of three independent replicates. Arrow indicates expected size of Ser727 phosphorylated STAT3; the band observed in the IP samples is a larger non-specific band. g, Western blot analysis of input, flow through, and immunoprecipitation using Flag antibody coated beads from 3T3-L1 differentiated adipocytes with lentiviral overexpression of flag-tagged STAT3 (WT/Y705F/S727A) and/or Myc-tagged GPAT3, cells treated with 10 μM CL-316,243 or vehicle control for 60 min before harvest and IP. These experiments were repeated independently twice with similar results.
Supplementary Table 1
MS data from STAT3 and IgG co-immunoprecipitation in 3T3-L1 adipocytes
Time course of lipid droplet depletion (visualized by BODIPY staining) in WT and SAKO PPDIVs treated with CL-316,243.
Source Data Fig. 2
Unprocessed western blots
Source Data Fig. 4
Unprocessed western blots
Source Data Fig. 5
Unprocessed western blots. Phosphorylated HSL and p38 from the same membrane, while total HSL and p38 from a second membrane
Source Data Fig. 8
Unprocessed western blots. GPAT3 and STAT3 blots from the same membrane. Two GPAT3 exposures from the same membrane.
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Reilly, S.M., Hung, CW., Ahmadian, M. et al. Catecholamines suppress fatty acid re-esterification and increase oxidation in white adipocytes via STAT3. Nat Metab 2, 620–634 (2020). https://doi.org/10.1038/s42255-020-0217-6
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