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Selective targeting of visceral adiposity by polycation nanomedicine

Nature Nanotechnology volume 17, pages 1311–1321 (2022)Cite this article

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Abstract

Obesity is a pandemic health problem with poor solutions, especially for targeted treatment. Here we develop a polycation-based nanomedicine polyamidoamine generation 3 (P-G3) that—when delivered intraperitoneally—selectively targets visceral fat due to its high charge density. Moreover, P-G3 treatment of obese mice inhibits visceral adiposity, increases energy expenditure, prevents obesity and alleviates the associated metabolic dysfunctions. In vitro adipogenesis models and single-cell RNA sequencing revealed that P-G3 uncouples adipocyte lipid synthesis and storage from adipocyte development to create adipocytes that possess normal functions but are deficient in hypertrophic growth, at least through synergistically modulating nutrient-sensing signalling pathways. The visceral fat distribution of P-G3 is enhanced by modifying P-G3 with cholesterol to form lipophilic nanoparticles, which is effective in treating obesity. Our study highlights a strategy to target visceral adiposity and suggests that cationic nanomaterials could be exploited for treating metabolic diseases.

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Fig. 1: P-G3 is selectively distributed to visceral fat.
Fig. 2: P-G3 prevents DIO and improves metabolic health.
Fig. 3: P-G3 uncouples lipid synthesis from adipocyte formation.
Fig. 4: scRNA-seq analyses reveal the bifurcate regulation of adipocyte development by P-G3.
Fig. 5: P-G3 represses mTOR signalling pathway and decreases NAD+ levels in adipocyte development.
Fig. 6: Engineering P-G3 to improve visceral fat distribution and treat obesity.

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Data availability

The single-cell RNA-seq data are available in the Gene Expression Omnibus (GEO) database under accession number GSE209819. Sample information and sequencing statistics are described in Supplementary Tables 1 and 2. All the remaining data are available from the corresponding authors upon reasonable request. Source data are provided with this paper.

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Acknowledgements

We thank S. K. Fried for kindly providing the human primary adipocytes, L. Yang for scientific discussion and help with designing the schematic and C. H. Quek for all the technical support and scientific suggestions. The studies used the resources of the Diabetes and Endocrinology Research Center Flow Core Facility funded in part through Center Grant 5P30DK063608 and the Maurice Hurd and the Weill Cornell Biorepository Core. The in vivo and in vitro imaging and processing used resources at the Oncology Precision Therapeutics and Imaging Core (OPTIC) (HICCC). This work was supported by the Russell Berrie Foundation (L.Q. and Q.W.), Blavatnik SIRS funding (L.Q. and K.W.L.), National Institutes of Health grant RO1AR073935 and USAMR grant W81XWH1910463 (K.W.L.), and The Manoogian Simone Foundation (M.D.G.).

Author information

Author notes

  1. These authors contributed equally: Qianfen Wan, Baoding Huang.

Authors and Affiliations

  1. Naomi Berrie Diabetes Center and Department of Pathology and Cell Biology, Columbia University, New York, NY, USA

    Qianfen Wan, Ying He, Branden Z. Wang & Li Qiang

  2. Department of Orthopaedic Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University and Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, Guangzhou, China

    Baoding Huang

  3. Department of Biomedical Engineering, Columbia University, New York, NY, USA

    Baoding Huang, Tianyu Li, Yang Xiao & Kam W. Leong

  4. Department of Medicine, Columbia University, New York, NY, USA

    Wen Du & Michael Rosenbaum

  5. Department of Surgery, Weill Cornell Medicine, New York, NY, USA

    Gregory F. Dakin & Shuibing Chen

  6. Department of Pediatrics, Columbia University, New York, NY, USA

    Michael Rosenbaum

  7. Department of Medicine, Weill Cornell Medicine, New York, NY, USA

    Marcus D. Goncalves

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Contributions

Q.W., B.H. and L.Q. designed and performed the research. Y.X. performed the scRNA analyses. T.L. prepared the cationic materials. Y.H. performed the NAD quantification in cells. W.D. performed the confocal imaging. Q.W., B.H., T.L., Y.X., Y.H., W.D. and B.Z.W. provided the experimental data. M.D.G., G.F.D. and S.C. contributed to the human fat biopsy studies and M.R. participated in the discussion and manuscript editing. Q.W., B.H., Y.X., K.W.L. and L.Q. wrote and revised the paper.

Corresponding authors

Correspondence to Kam W. Leong or Li Qiang.

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Competing interests

A patent application (inventors: L.Q., K.W.L., Q.W., B.H., T.L.) was filed in the U.S.A. (Application number: 63309325). The remaining authors declare no competing interests.

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Extended data

Extended data Fig. 1 Selective biodistribution of P-G3 to visceral fat.

a, Cy5 signal quantification of different tissues in Fig. 1a. b, Tissue distribution quantification of different materials in Fig. 1h–i: vehicle (n = 2), all the treatment groups (n = 2). c–e, 200 μg Cy5-labled P-G3 was i.p. injected into chow-fed mice and fluorescent signals were determined using an IVIS Optical Imager. PBS was used as vehicle control. c, Signal in live animals during the treatment at indicated time; imaging of tissues from mice sacrificed at 56-hr post-injection (d) and quantification of fluorescent signals, vehicle (n = 1), P-G3 group (n = 3). Data were represented as mean ± s.e.m. (e). f, 200 μg Cy5-labled P-G3 was injected into HFD-fed mice comparing different delivery routes, and Cy5 signal in tissues was determined at 24-hr post-injection. The unit of fluorescent scale bar is photons/sec/cm2/sr.

Extended data Fig. 2 The anti-obesity effect of P-G3 is reproduced in diet-induced obese female mice but not in lean animals.

a–d, 17-wk-old female C57BL/6J mice were intraperitoneally treated with P-G3 (10 mg/kg.BW) or vehicle twice weekly for 6 weeks since the beginning of HFD feeding. Data were represented as mean ± s.e.m. (n = 5, 6). Statistical significance was calculated via 2-tailed Student’s t-test. a, Body weight curve. b, c, Changes of fat mass (b) and lean mass (c) during P-G3 treatment determined by Echo-MRI. d, Organ weights at sacrifice. e–g, 6-wk-old male mice were fed on chow diet and received twice weekly P-G3 (10 mg/kg.BW) intraperitoneally for 6 weeks. Data were represented as mean ± s.e.m. (n = 5, 5). Statistical significance was calculated via 2-tailed Student’s t-test. e, Body weight curve. f, Body composition determined by EchoMRI. g, Organ weights at sacrifice.

Extended data Fig. 3 P-G3 treatment improves metabolic health in DIO mice.

a, Western blotting of adipocyte markers and insulin signalling proteins in the eWAT of DIO mice after P-G3 treatment. Representative data were repeated twice independently with similar results. b-e, Mice were treated with P-G3 since the beginning of HFD feeding in Fig. 2. Before sacrifice, mice were fasted overnight and then refed for 4 hours to measure plasma metabolites. Data were represented as mean ± s.e.m. (n = 8, 5). f, g, H&E and PAS staining of glycogen contents (f) and qPCR analysis of gene expression (g) in the liver. Data were represented as mean ± s.e.m. (n = 7, 5). Statistical significance was calculated via 2-tailed Student’s t-test. h, Plasma alanine aminotransferase (ALT) level in another cohort of mice after P-G3 treatment for 6 weeks. Data were represented as mean ± s.e.m. (n = 7, 7). i, j Gene expression of inflammatory and anti-inflammatory markers (i) and F4/80 staining (j) in eWAT from mice with or without P-G3 treatment. Data were represented as mean ± s.e.m. (n = 14, 10). Statistical significance was calculated via 2-tailed Student’s t-test. k-m, Male mice were received 3 dosages of P-G3 (10 mg/kg.BW) or vehicle (intraperitoneally) twice-weekly since the beginning of HFD feeding, then housed singly in metabolic cages for calorimetric analysis. k, Locomotor activity. l, Respiration exchange ratio (RER). m, Food intake within 1 dark/light cycle. Data were represented as mean ± s.e.m. (n = 7, 7). n, Oral fat tolerance test from mice after 6-wk P-G3 treatment. Data were represented as mean ± s.e.m. (n = 7, 7). o, p, Plasma NEFA (o) and glycerol (p) level in mice before and 15 min after the intraperitoneal injection of isoproterenol (10 mg/kg.BW). Data were represented as mean ± s.e.m. (n = 6, 7).

Source data

Extended data Fig. 4 P-G3 inhibits adipocyte hypertrophic growth.

a, BODIPY staining of lipid accumulation in C3H10T1/2 cells during differentiation time course with or without P-G3 treatment. Representative data were repeated three times independently with similar results. b, qPCR analysis of gene expression of adipogenic markers during the time course of 3T3-L1 differentiation with or without P-G3 treatment. Data were represented as mean ± s.e.m. (n = 4, 4). Statistical significance was calculated via 2-tailed Student’s t-test. c, d, Human adipose stromal cells were differentiated into adipocytes with or without P-G3 treatment, and qPCR analyses of gene expression in cells at Day 7 (c) or Day 9 (d) of differentiation. Data were represented as mean ± s.e.m. (n = 4, 4). Statistical significance was calculated via 2-tailed Student’s t-test. e, C3H10T1/2 cells were fully differentiated into mature adipocytes and then treated with 10 μg/ml P-G3 from Day 15 to Day 21. qPCR analysis of gene expression. Data were represented as mean ± s.e.m. (n = 4, 4). Statistical significance was calculated via 2-tailed Student’s t-test. f, qPCR analysis of gene expression in iWAT from mice after 8-wk P-G3 treatment. Data were represented as mean ± s.e.m. (n = 6, 5). Statistical significance was calculated via 2-tailed Student’s t-test. g, h, Mice were fed on HFD diet for 4 weeks, then received vehicle or a single-dose P-G3 (intraperitoneally) and scarified at Day 3 or Day 7 post-injection. qPCR analysis of gene expression of lipogenic (g) and adipogenic (h) markers in the eWAT. Data were represented as mean ± s.e.m. (n = 5, 3, 5). Statistical significance was calculated via 2-tailed Student’s t-test (treatment group vs vehicle group). i, PPARγ2-reconstituted Pparg-KO embryonic fibroblasts (MEFs) cells were differentiated into adipocytes in the presence or absence of P-G3. On Day 7 of differentiation, lipid droplet morphology was assessed by BODIPY staining. j, Mature adipocytes were treated with or without 10 μg/ml P-G3 or B-PEI from differentiation Day 8 to Day 11. Representative data in i and j were repeated twice independently with similar results.

Extended data Fig. 5 scRNA-seq analyses of adipocyte development.

a, Heterogeneous cell distributions during 3T3-L1 adipogenesis. b, Dot-plot showing bifurcate regulation of key genes in adipogenesis (Pparg, Cebpa, Fabp4, Adipoq, and Cfd) and lipogenesis (Fasn, Scd1, Srebf1, Acaca, and Acacb) in P-G3-treated cells on Day 6 of differentiation. c, Key gene regulatory networks identified in each cell type. d, Expression of key cell type markers. e, Expression of spliced mature mRNA of representative adipocyte genes and their RNA velocity based on unspliced/spliced mRNA ratio.

Extended data Fig. 6 P-G3 enters cells to modulate mTOR and NAD signal pathways in adipocyte development.

a, Schematic experiment design (top) and Oil Red O staining (bottom) of 3T3-L1 cells after the treatments of different localizations of P-G3. 3T3-L1 preadipocytes were differentiated in the presence of naked P-G3, microbead-conjugated P-G3 to prevent entering cells, or P-G3 beads in transwells to prevent the contact with cells. b, qPCR analyses of gene expression of cells in (a). Data were represented as mean ± s.e.m. (n = 4, 4, 4, 4). Statistical significance was calculated via 2-tailed Student’s t-test (treatment group vs vehicle group). c, The internalization of Cy5-labelled P-G3 into early endosome. Confocal images of Cy5-labelled P-G3 with early endosome marker in mature C3H10T1/2 adipocytes after 15 min or 1 hr of Cy5-P-G3 treatment. d, Colocalization of Cy5-P-G3 with lipid droplet, ER, and mitochondria in mature 3T3-L1 adipocytes after 24-hr of Cy5-P-G3 treatment. Representative data in c and d repeated twice with similar results. e, Representative gating strategy used in FACS analysis of lysosomal activity in Fig. 5b. f, Gene expression in C3H10T1/2 cells after indicated treatments from differentiation Day 4 to Day 9. Data were represented as mean ± s.e.m. (n = 4, 4). Statistical significance was calculated via 2-tailed Student’s t-test (treatment group vs vehicle group). g, P-G3 failed to affect NAD+ and NADH levels in mature adipocytes after 14-hr treatment. Data were represented as mean ± s.e.m. (n = 3, 3).

Extended data Fig. 7 Lipophilic P-G3 NPs retains the effects of P-G3.

a, NMR spectrum of P-G3 and P-G3-Chol(5). b, The internalization of Cy5-labelled NPs into early endosome. Confocal images of Cy5-labelled NPs with early endosome marker in mature C3H10T1/2 adipocytes after 15 min or 1 hr of Cy5-NPs treatment. Representative data repeated twice with similar results. c, C3H10T1/2 preadipocytes were treated with 10 μg/ml P-G3 or NPs since the induction of differentiation Day 0, and cells were harvested on Day 4 to measure adipogenic genes by qPCR. Data were represented as mean ± s.e.m. (n = 4, 4). Statistical significance was calculated via 2-tailed Student’s t-test (treatment group vs vehicle group). d, e, 200 μg Cy5-labled NPs or Cy5-labelled P-G3 were i.p. injected into mice in Fig. 6c; d, signal intensity quantification of tissue distribution and at 72-hr post-injection by IVIS (PBS group n = 1, P-G3 group n = 2, NPs group n = 3); e, colocalization of Cy5-labelled NPs with DAPI and Caveolin-1 in frozen sections of eWAT. f, Macrophage-related gene expression in the eWAT after NP treatment. Data were represented as mean ± s.e.m. (n = 8, 8). Statistical significance was calculated via 2-tailed Student’s t-test. g, Body composition change of NPs-treated DIO mice during 24-hr fasting and 24-hr refeeding. Data were represented as mean ± s.e.m. (n = 8, 8). h, WB analysis of mTOR signalling pathway in eWAT after NPs treatment and the quantification. Data were represented as mean ± s.e.m. (n = 4, 5). Statistical significance was calculated via 2-tailed Student’s t-test.

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Wan, Q., Huang, B., Li, T. et al. Selective targeting of visceral adiposity by polycation nanomedicine. Nat. Nanotechnol. 17, 1311–1321 (2022). https://doi.org/10.1038/s41565-022-01249-3

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