Adipocytes undergo considerable volumetric expansion in the setting of obesity. It has been proposed that such marked increases in adipocyte size may be sensed via adipocyte-autonomous mechanisms to mediate size-dependent intracellular signalling. Here, we show that SWELL1 (LRRC8a), a member of the Leucine-Rich Repeat Containing protein family, is an essential component of a volume-sensitive ion channel (VRAC) in adipocytes. We find that SWELL1-mediated VRAC is augmented in hypertrophic murine and human adipocytes in the setting of obesity. SWELL1 regulates adipocyte insulin–PI3K–AKT2–GLUT4 signalling, glucose uptake and lipid content via SWELL1 C-terminal leucine-rich repeat domain interactions with GRB2/Cav1. Silencing GRB2 in SWELL1 KO adipocytes rescues insulin-pAKT2 signalling. In vivo, shRNA-mediated SWELL1 knockdown and adipose-targeted SWELL1 knockout reduce adiposity and adipocyte size in obese mice while impairing systemic glycaemia and insulin sensitivity. These studies identify SWELL1 as a cell-autonomous sensor of adipocyte size that regulates adipocyte growth, insulin sensitivity and glucose tolerance.
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We thank T. J. Jentsch (FM/MDC, Berlin) for kindly sharing SWELL1/LRRC8a antibody and A. Patapoutian for sharing Flag-SWELL1 and SWELL1Δ91/+35. RNA-Seq data presented herein were obtained at the Genomics Division of the Iowa Institute of Human Genetics. We thank R. Sigmund, J. Galbraith and M. Knudson of the University of Iowa Tissue Procurement Core facility (TPC) for services provided related to acquisition of study specimens (NCI award number P30CA086862) and Susan Walsh of the Small Animal Imaging Core, University of Iowa. We thank the University of Utah Mutation Generation and Detection Core, DNA Sequencing Core, DNA/Peptide Synthesis Core, and Transgenic Gene Targeting Mouse Facility for reagents and services. We thank M. Anderson, F. Abboud, P. Snyder, C. Benson and J. Robertson for their thoughtful review of the manuscript. We thank M. Elliot-Hudson and P. Lüken for assistance with data analysis. This work was supported by grants from the NIH NIDDK 1R01DK106009 (R.S.), the Roy J. Carver Trust (R.S.), the American Heart Association Fellow-to-Faculty Award (R.S.), an American Heart Association Postdoctoral Award (Y.Z.) and an American Cancer Society Pilot Grant (R.S.).
The authors declare no competing financial interests.
Integrated supplementary information
(a) qRT-PCR assessment of SWELL1/LRRC8a, and LRRC8b-e mRNA in human adipocyte cell line transduced with Ad-shSWELL1-mCherry (red) compared to Ad-shSCR-mCherry (black; n = 3 culture dishes of adipocytes for each condition). (b) SWELL1 Western blot in human adipocyte cell line transduced with Ad-shSWELL1-mCherry (red) compared to Ad-shSCR-mCherry (black). β-actin serves as loading control. Representative blot from 4 independent experiments. (c) VRAC over time ± hypotonic swelling (210 mOsm) in 3T3-F442A adipocytes transduced with Ad-shSCR-mCherry (black) and Ad-shSWELL1-mCherry (red). (d) Mean peak outward (+100 mV) and peak inward (−100 mV) VRAC current density from (c) in Ad-shSCR (black, n = 5) and Ad-shSWELL1 (red, n = 4) transduced 3T3-F442A adipocytes. (e) VRAC current-voltage relationship after hypotonic swelling (210 mOsm) in human adipocytes transduced with Ad-shSCR-mCherry (black) and Ad-shSWELL1-mCherry (red). (f) Mean peak outward (+100 mV) and peak inward (−100 mV) VRAC current density from (e) in Ad-shSCR (black, n = 10) and Ad-shSWELL1 (red, n = 10) transduced human adipocytes. Uncropped blots for b are shown in Supplementary Fig. 9a–c. Significance between the indicated groups in a,d and f was calculated using a two-tailed Student’s t-test. Exact P-values are listed in Supplementary Table 6. Error bars represent mean ± s.e.m.∗(P < 0.05), ∗∗(P < 0.01).
(a) Sequences of mutant alleles showing deletions generated by CRISPR–cas9 single-guide RNA (gRNA) mediated approach (KO1). (b) CRISPR–cas9 double-gRNA mediated SWELL1 knockout (KO2) resulting in excision of the DNA fragment (240 bp) between the two cut sites. (c) PCR of the double-gRNA mediated knockout gene yields a ∼639 bp amplicon, reflecting the expected 240 bp deletion. (d) Schematic representation of CRISPR–cas9 mediated loxP knockin around Exon 3 to generate SWELL1fl allele. SWELL1null allele is generated by Cre-Lox mediated excision of Exon 3. (e) Cre-mediated Exon 3 deletion yields the expected PCR amplicons 426 and 196 bp from two individual primer pairs flanking loxP sites around Exon 3. The ∼5 Kb region between loxP sites in the SWELL1fl allele could not be amplified. Uncropped blots for c are shown in Supplementary Fig. 9a–d, and e in Supplementary Fig. 9a–e. Representative gel image from 2 independent experiments (c,e). (f) Experimental approach for generating WT and SWELL1 KO primary SVF used for differentiation into cultured primary adipocytes. (g) Bright-field image (left) of SWELL1fl primary cultured adipocytes from SVF and mCherry fluorescence image (right) showing nuclear localization of Cre-mCherry. Scale bar: 200 μm. (h) Relative mRNA expression assessed by qPCR (n = 3 each). (i–k) Representative VRAC current over time ± hypotonic swelling (i), VRAC current-voltage plots upon swelling (j), and mean peak outward (+100 mV) and inward (−100 mV) VRAC current density (k) in WT and SWELL1 primary SVF (n = 5–6 each). Significance between the indicated groups in h and k were calculated using a two-tailed Student’s t-test. Exact P-values are listed in Supplementary Table 6. Error bars represent mean ± s.e.m.∗(P < 0.05), ∗∗(P < 0.01).
Supplementary Figure 3 Lean and obese mouse body weight and patient characteristics. Related to Fig. 3.
(a) Body weights of lean and obese mice from which mature adipocytes were isolated for patch-clamp recordings in Fig. 3c–h. (b) Relative mRNA expression of SWELL1/LRRC8A and LRRC8B through E assessed by qPCR in mice raised on normal chow (n = 8) compared to HFD (n = 7). (c) Age, Gender and BMI of patients from which visceral adipocytes were isolated for patch-clamp recordings in Fig. 3i–n. BMI: Body mass index. Significance between the indicated groups in a and b were calculated using a two-tailed Student’s t-test. Exact P-values are listed in Supplementary Table 6. Error bars represent mean ± s.e.m.∗(P < 0.05), ∗∗(P < 0.01), ∗∗∗(P < 0.001).
Supplementary Figure 4 SWELL1 is required for lipogenesis and adipocyte glucose metabolism, Related to Fig. 4.
(a) Heat map displaying 2-way hierarchical clustering and mRNA expression levels of WT (n = 3) and CRISPR–cas9 SWELL1 KO (n = 3) 3T3-F442A adipocytes. Columns WT 1-3 and KO 1-3 represent RNA from individual experiments. (b) Gene Set Enrichment Analysis revealing pathways and processes negatively enriched in SWELL1 KO compared with WT 3T3-F442A adipocytes. Q value is the false discovery rate (FDR)-adjusted p value. Q < 0.10 is considered statistically significant. (c) Representative fluorescence images of AdipoRed stained WT and SWELL1 KO 3T3-F442A adipocytes under low glucose (5.6 mM) and high glucose (25 mM) culture conditions. Mean AdipoRed fluorescence intensity per cell under each condition (nWT,5.6 mM = 444, nWT,25 mM = 422, nKO,5.6 mM = 527, nKO,25 mM = 589). Measurements pooled from 3 separate independent experiments. Scale bar: 200 μm. (d) Transmission Electron Microscopy (TEM) images of glycogen granules in WT and SWELL1 KO adipocytes. Scale bar: 0.5 μm. Significance between the indicated groups in c were calculated using a two-tailed Student’s t-test. Exact P-values are listed in Supplementary Table 6. Error bars represent mean ± s.e.m.∗∗∗(P < 0.001).
(a) GRB2 immunoprecipitation from 3T3-F442A adipocytes and immunoblot with insulin receptor (IR) and GRB2 antibodies. Representative blot of 3 independent experiments. (b) IR immunoprecipitation from HEK293 cells and immunoblot with GRB2 antibody. Representative blot of 3 independent experiments. (c) GRB2 immunoprecipitation from HEK293 cells ± transfection with Myc-HA-tagged insulin receptor substrate 1 (IRS-1-HA-Myc) and immunoblot with HA and GRB2 antibodies. Representative blot of 1 replicate. Uncropped blots for a are shown in Supplementary Fig. 9a, f; for b are shown in Supplementary Fig. 9a, g; for c are shown in Supplementary Fig. 9a, h.
(a) mCherry fluorescence indicative of AAV/Rec2 transduction at different regions of iWAT and eWAT in AAV-shRNA-mCherry injected mouse. (i) indicates the injection site. Scale bar: 200 μm. (b) mCherry fluorescence indicating AAV/Rec2 transduction in skeletal muscle (tibalis anterior) and liver in AAV-shRNA-mCherry injected mouse. Scale bar: 200 μm. mCherry fluorescence indicating AAV/Rec2 transduction at regions in a,b were visualized from 6 independent experiments. (c) Nuclear Magnetic Resonance (NMR) measurements of percent fat in AAV-shSCR-mCherry (n = 6) and AAV-shSWELL1-mCherry (n = 6) transduced mice. (d) NMR measurements of percent lean mass in AAV-shSCR-mCherry (n = 6) and AAV-shSWELL1-mCherry (n = 6) transduced mice. Significance between the indicated groups in c and d were calculated using a two-tailed Student’s t-test. Exact P-values are listed in Supplementary Table 6. Error bars represent mean ± s.e.m.∗(P < 0.05).
Supplementary Figure 7 WT and Adipo KO adipocyte size, expression of adipocyte differentiation genes and indirect calorimetry data in lean, regular chow fed mice, Related to Fig. 7.
(a) Bright field images of mature adipocytes isolated from iWAT of lean littermate WT and Adipo KO mice. Scale bar: 50 μm. (bc) Mean adipocyte area (b) and size distribution (c) of WT (n = 1214) and Adipo KO (n = 982) adipocytes. Measurements pooled from 3 pairs of mice. (d) H&E staining of iWAT adipose tissues in lean littermate WT and Adipo KO mice. Scale bar: 50 μm. (e,f) Mean adipocyte cross-sectional area (e) and size distribution (f) of WT (n = 979) and Adipo KO (n = 1118) adipocytes. Measurements pooled from 3 pairs of mice. (g) Relative mRNA expression of adipocyte differentiation markers assessed by qPCR (nWT = 8, nAdipoKO = 5). (h-n) Metabolic cage studies were performed on WT (n = 9) and Adipo KO (n = 7) mice fed a regular chow diet (13–19 weeks of age). The mice were housed individually in the chambers for 5 days, and data was analyzed from the last 3 days. (h) Heat production; (i) Respiratory exchange ratio (RER); (j) CO2 production; (k) O2 consumption; (l) Physical activity; (m) Food consumption; and (n) Sleep. Significance between the indicated groups were calculated using a two-tailed Student’s t-test. Exact P-values are listed in Supplementary Table 6. Error bars represent mean ± s.e.m.∗(P < 0.05).
Supplementary Figure 8 WT and Adipo KO adipocyte size and indirect calorimetry data in obese, HFD fed mice, Related to Fig. 7.
(a) Bright field images of mature primary adipocytes freshly isolated from iWAT of WT and Adipo KO mice (17 weeks HFD). (b,c) Mean adipocyte area (b) and size distribution (c) of WT (n = 284) and Adipo KO adipocytes (n = 470) in a. Measurements pooled from 3 pairs of mice. (d–j) Metabolic cage studies were performed in WT (n = 7) and Adipo KO (n = 9) mice (HFD for 12–16 weeks). The mice were housed individually in the chambers for 5 days, and data was analyzed from the last 3 days. (d) Heat production; (e) Respiratory exchange ratio (RER); (f) CO2 production; (g) O2 consumption; (h) Physical activity; (i) Food consumption; and (j) Sleep. Significance between the indicated groups in a and b were calculated using a two-tailed Student’s t-test. Exact P-values are listed in Supplementary Table 6. Error bars represent mean ± s.e.m.∗(P < 0.05), ∗∗∗(P < 0.001). Scale bar in a: 50 μm.
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Zhang, Y., Xie, L., Gunasekar, S. et al. SWELL1 is a regulator of adipocyte size, insulin signalling and glucose homeostasis. Nat Cell Biol 19, 504–517 (2017). https://doi.org/10.1038/ncb3514
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