Adipocyte reconstitution of Npy4r gene in Npy4r silenced mice promotes diet-induced obesity
Received date: 2022-10-13
Revised date: 2023-01-30
Online published: 2023-02-03
Supported by
the National Natural Science Foundation of China(81900776)
Neural regulation of adipose tissue is crucial in the homeostasis of energy metabolism. Adipose tissue neuropeptide Y (NPY) and its receptors contribute to the development of diet-induced obesity. NPY1R and NPY2R are major receptors for NPY in peripheral tissues including the adipose tissue. NPY receptor 4 (Npy4r) gene is expressed in adipose tissue. However, it is unknown whether Npy4r is involved in the development of diet-induced obesity. Here, we established an immunofluorescence microscopy technique and generated an adipocyte-reconstituted Npy4r gene knockout mouse. Among six adipose depots, we found that NPY is highly expressed around the vasculature in a dot-like fashion in interscapular brown fat and subcutaneous fat, and NPY receptors are expressed in a depot-specific manner. NPY1R is highly expressed in epidydimal fat, interscapular and peri-aortic brown fat, NPY2R in both interscapular and peri-aortic brown fat, and NPY4R in both brown fat and epidydimal fat. Next, we showed that adipocyte-reconstituted expression of Npy4r promoted diet-induced obesity in mice (P < 0.0001). Overall, this study defines the abundance and distribution of NPY and its receptors 1, 2, and 4 in mouse adipose depots, and demonstrates in an adipocyte-reconstituted gene knockout model that adipocyte Npy4r is sufficient to promote diet-induced obesity.
Lan Wang, Fan Zeng, Rongfeng Huang, Shu Lin, Zhihui Zhang, Min-Dian Li . Adipocyte reconstitution of Npy4r gene in Npy4r silenced mice promotes diet-induced obesity[J]. Hereditas(Beijing), 2023 , 45(2) : 144 -155 . DOI: 10.16288/j.yczz.22-302
| [1] | Cypess AM. Reassessing human adipose tissue. N Engl J Med, 2022, 386(8): 768-779. |
| [2] | Zeng F, Wang L, Wan XQ, Huang RF, Zhang ZH, Li MD. Targeting leptin-positive adipocytes by expressing the Cre recombinase transgene under the endogenous leptin gene. Hereditas(Beijing), 2022, 44(10): 950-957. |
| [2] | 曾帆, 王澜, 万小勤, 黄荣凤, 张志辉, 李旻典. 瘦素基因启动的新型脂肪细胞表达Cre工具小鼠的构建. 遗传, 2022, 44(10): 950-957. |
| [3] | Duerrschmid C, He YL, Wang CM, Li C, Bournat JC, Romere C, Saha PK, Lee ME, Phillips KJ, Jain M, Jia P, Zhao ZM, Farias M, Wu Q, Milewicz DM, Sutton VR, Moore DD, Butte NF, Krashes MJ, Xu Y, Chopra AR. Asprosin is a centrally acting orexigenic hormone. Nat Med, 2017, 23(12): 1444-1453. |
| [4] | Li MD, Vera NB, Yang YF, Zhang BC, Ni WM, Ziso- Qejvanaj E, Ding S, Zhang KS, Yin RN, Wang SM, Zhou X, Fang EX, Xu T, Erion DM, Yang XY. Adipocyte OGT governs diet-induced hyperphagia and obesity. Nat Commun, 2018, 9(1): 5103. |
| [5] | Zeng WW, Pirzgalska RM, Pereira MMA, Kubasova N, Barateiro A, Seixas E, Lu YH, Kozlova A, Voss H, Martins GG, Friedman JM, Domingos AI. Sympathetic neuro- adipose connections mediate leptin-driven lipolysis. Cell, 2015, 163(1): 84-94. |
| [6] | Chi JY, Wu ZH, Choi CHJ, Nguyen L, Tegegne S, Ackerman SE, Crane A, Marchildon F, Tessier-Lavigne M, Cohen P. Three-Dimensional adipose tissue imaging reveals regional variation in beige fat biogenesis and PRDM16-dependent sympathetic neurite density. Cell Metab, 2018, 27(1): 226-236.e3. |
| [7] | Jiang HC, Ding XF, Cao Y, Wang HH, Zeng WW. Dense intra-adipose sympathetic arborizations are essential for cold-induced beiging of mouse white adipose tissue. Cell Metab, 2017, 26(4): 686-692.e3. |
| [8] | Zeng X, Ye MC, Resch JM, Jedrychowski MP, Hu B, Lowell BB, Ginty DD, Spiegelman BM. Innervation of thermogenic adipose tissue via a calsyntenin 3beta-S100b axis. Nature, 2019, 569(7755): 229-235. |
| [9] | Wang Y, Leung VH, Zhang YX, Nudell VS, Loud M, Servin-Vences MR, Yang D, Wang K, Moya-Garzon MD, Li VL, Long JZ, Patapoutian A, Ye L. The role of somatosensory innervation of adipose tissues. Nature, 2022, 609(7927): 569-574. |
| [10] | Myers MG Jr, Affinati AH, Richardson N, Schwartz MW. Central nervous system regulation of organismal energy and glucose homeostasis. Nat Metab, 2021, 3(6): 737-750. |
| [11] | Rossi MA, Stuber GD. Overlapping brain circuits for homeostatic and hedonic feeding. Cell Metab, 2018, 27(1): 42-56. |
| [12] | Loh K, Herzog H, Shi YC. Regulation of energy homeostasis by the NPY system. Trends Endocrinol Metab, 2015, 26(3): 125-135. |
| [13] | Yan CX, Zeng TS, Lee KL, Nobis M, Loh K, Gou LN, Xia ZF, Gao ZM, Bensellam M, Hughes W, Lau J, Zhang L, Ip CK, Enriquez R, Gao H, Wang QP, Wu Q, Haigh JJ, Laybutt DR, Timpson P, Herzog H, Shi YC. Peripheral- specific Y1 receptor antagonism increases thermogenesis and protects against diet-induced obesity. Nat Commun, 2021, 12(1): 2622. |
| [14] | Kuo LE, Kitlinska JB, Tilan JU, Li LJ, Baker SB, Johnson MD, Lee EW, Burnett MS, Fricke ST, Kvetnansky R, Herzog H, Zukowska Z. Neuropeptide Y acts directly in the periphery on fat tissue and mediates stress-induced obesity and metabolic syndrome. Nat Med, 2007, 13(7): 803-811. |
| [15] | Shi YC, Lin S, Castillo L, Aljanova A, Enriquez RF, Nguyen AD, Baldock PA, Zhang L, Bijker MS, Macia L, Yulyaningsih E, Zhang H, Lau J, Sainsbury A, Herzog H. Peripheral-specific y 2 receptor knockdown protects mice from high-fat diet-induced obesity. Obesity (Silver Spring), 2011, 19(11): 2137-2148. |
| [16] | Rangwala SM, D'Aquino K, Zhang YM, Bader L, Edwards W, Zheng SM, Eckardt A, Lacombe A, Pick R, Moreno V, Kang LJ, Jian WY, Arnoult E, Case M, Jenkinson C, Chi E, Swanson RV, Kievit P, Grove K, Macielag M, Erion MD, SinhaRoy R, Leonard JN. A long-acting PYY(3-36) analog mediates robust anorectic efficacy with minimal emesis in nonhuman primates. Cell Metab, 2019, 29(4): 837-843.e5. |
| [17] | Sainsbury A, Schwarzer C, Couzens M, Jenkins A, Oakes SR, Ormandy CJ, Herzog H. Y4 receptor knockout rescues fertility in ob/ob mice. Genes Dev, 2002, 16(9): 1077-1088. |
| [18] | Lin S, Shi YC, Yulyaningsih E, Aljanova A, Zhang L, Macia L, Nguyen AD, Lin EJ, During MJ, Herzog H, Sainsbury A. Critical role of arcuate Y4 receptors and the melanocortin system in pancreatic polypeptide-induced reduction in food intake in mice. PLoS One, 2009, 4(12): e8488. |
| [19] | Sainsbury A, Bergen HT, Boey D, Bamming D, Cooney GJ, Lin S, Couzens M, Stroth N, Lee NJ, Lindner D, Singewald N, Karl T, Duffy L, Enriquez R, Slack K, Sperk G, Herzog H. Y2Y 4 receptor double knockout protects against obesity due to a high-fat diet or Y 1 receptor deficiency in mice. Diabetes, 2006, 55(1): 19-26. |
| [20] | Eguchi J, Wang X, Yu ST, Kershaw EE, Chiu PC, Dushay J, Estall JL, Klein U, Maratos-Flier E, Rosen ED.Transcriptional control of adipose lipid handling by IRF4. Cell Metab, 2011, 13(3): 249-259. |
| [21] | Kong XX, Banks A, Liu TM, Kazak L, Rao RR, Cohen P, Wang X, Yu ST, Lo JC, Tseng YH, Cypess AM, Xue RD, Kleiner S, Kang S, Spiegelman BM, Rosen ED. IRF4 is a key thermogenic transcriptional partner of PGC-1alpha. Cell, 2014, 158(1): 69-83. |
| [22] | Virtue S, Vidal-Puig A. GTTs and ITTs in mice: simple tests, complex answers. Nat Metab, 2021, 3(7): 883-886. |
| [23] | Shin H, Ma YY, Chanturiya T, Cao Q, Wang YL, Kadegowda AKG, Jackson R, Rumore D, Xue BZ, Shi H, Gavrilova O, Yu LQ. Lipolysis in brown adipocytes is not essential for cold-induced thermogenesis in mice. Cell Metab, 2017, 26(5): 764-777.e5. |
| [24] | Zhao QW, Pan DN. Progress on the epigenetic regulation of adipose tissue thermogenesis. Hereditas (Beijing), 2022, 44(10): 867-880. |
| [24] | 赵清雯, 潘东宁. 表观遗传修饰对脂肪组织产热的调控进展. 遗传, 2022, 44(10): 867-880. |
| [25] | Tang Y, He Y, Li C, Mu WJ, Zou Y, Liu CH, Qian SW, Zhang FC, Pan JB, Wang YN, Huang HY, Pan DN, Yang PY, Mei J, Zeng R, Tang QQ. RPS3A positively regulates the mitochondrial function of human periaortic adipose tissue and is associated with coronary artery diseases. Cell Discov, 2018, 4: 52. |
| [26] | Koronowski KB, Kinouchi K, Welz PS, Smith JG, Zinna VM, Shi JJ, Samad M, Chen SW, Magnan CN, Kinchen JM, Li W, Baldi P, Benitah SA, Sassone-Corsi P. Defining the independence of the liver circadian clock. Cell, 2019, 177(6): 1448-1462.e14. |
| [27] | Welz PS, Zinna VM, Symeonidi A, Koronowski KB, Kinouchi K, Smith JG, Guillén IM, Castellanos A, Furrow S, Aragón F, Crainiciuc G, Prats N, Caballero JM, Hidalgo A, Sassone-Corsi P, Benitah SA. BMAL1-driven tissue clocks respond independently to light to maintain homeostasis. Cell, 2019, 177(6): 1436-1447.e12. |
| [28] | Tang TT, Tan QX, Han S, Diemar A, L?bner K, Wang HY, Schü? C, Behr V, M?rl K, Wang M, Chu XJ, Yi CY, Keller M, Kofoed J, Reedtz-Runge S, Kaiser A, Beck-Sickinger AG, Zhao Q, Wu B. Receptor-specific recognition of NPY peptides revealed by structures of NPY receptors. Sci Adv, 2022, 8(18): eabm1232. |
| [29] | Wang L, Pydi SP, Zhu L, Barella LF, Cui YH, Gavrilova O, Bence KK, Vernochet C, Wess J. Adipocyte G(i) signaling is essential for maintaining whole-body glucose homeostasis and insulin sensitivity. Nat Commun, 2020, 11(1): 2995. |
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