Deletion of Endothelial Leptin Receptors in Mice Promotes Diet-induced Obesity

Overview

Journal Sci Rep

Specialty Science

Date 2023 May 22

PMID 37217565

Authors

Rajinikanth Gogiraju

Claudius Witzler

Fatemeh Shahneh

Astrid Hubert

Luisa Renner

Magdalena L Bochenek

Konstantinos Zifkos

Christian Becker

Madhusudhan Thati

Katrin Schafer

Affiliations

Soon will be listed here.

Abstract

Obesity promotes endothelial dysfunction. Endothelial cells not only respond, but possibly actively promote the development of obesity and metabolic dysfunction. Our aim was to characterize the role of endothelial leptin receptors (LepR) for endothelial and whole body metabolism and diet-induced obesity. Mice with tamoxifen-inducible, Tie2.Cre-ER-mediated deletion of LepR in endothelial cells (End.LepR knockout, KO) were fed high-fat diet (HFD) for 16 weeks. Body weight gain, serum leptin levels, visceral adiposity and adipose tissue inflammation were more pronounced in obese End.LepR-KO mice, whereas fasting serum glucose and insulin levels or the extent of hepatic steatosis did not differ. Reduced brain endothelial transcytosis of exogenous leptin, increased food intake and total energy balance were observed in End.LepR-KO mice and accompanied by brain perivascular macrophage accumulation, whereas physical activity, energy expenditure and respiratory exchange rates did not differ. Metabolic flux analysis revealed no changes in the bioenergetic profile of endothelial cells from brain or visceral adipose tissue, but higher glycolysis and mitochondrial respiration rates in those isolated from lungs. Our findings support a role for endothelial LepRs in the transport of leptin into the brain and neuronal control of food intake, and also suggest organ-specific changes in endothelial cell, but not whole-body metabolism.

Citing Articles

Endothelial autophagy-related gene 7 contributes to high fat diet-induced obesity.

Ren G, Bhatnagar S, Young M, Lee T, Kim J Mol Metab. 2025; 93:102099.

PMID: 39832563 PMC: 11802379. DOI: 10.1016/j.molmet.2025.102099.

Regulation of energy balance by leptin as an adiposity signal and modulator of the reward system.

Asgari R, Caceres-Valdiviezo M, Wu S, Hamel L, Humber B, Agarwal S Mol Metab. 2024; 91():102078.

PMID: 39615837 PMC: 11696864. DOI: 10.1016/j.molmet.2024.102078.

Expression of mRNA for molecules that regulate angiogenesis, endothelial cell survival, and vascular permeability is altered in endothelial cells isolated from db/db mouse hearts.

Bartkowiak K, Bartkowiak M, Jankowska-Steifer E, Ratajska A, Czarnowska E, Kujawa M Histochem Cell Biol. 2024; 162(6):523-539.

PMID: 39317805 PMC: 11455669. DOI: 10.1007/s00418-024-02327-4.

Generation of LEPR Knockout Rabbits with CRISPR/CAS9 System.

Silaeva Y, Safonova P, Popov D, Filatov M, Okulova Y, Shafei R Dokl Biol Sci. 2024; 518(1):248-255.

PMID: 39212886 DOI: 10.1134/S0012496624600234.

Bone-derived PDGF-BB enhances hippocampal non-specific transcytosis through microglia-endothelial crosstalk in HFD-induced metabolic syndrome.

Liu G, Shu W, Chen Y, Fu Y, Fang S, Zheng H J Neuroinflammation. 2024; 21(1):111.

PMID: 38685040 PMC: 11057146. DOI: 10.1186/s12974-024-03097-5.

References

Tu H, Kastin A, Hsuchou H, Pan W . Soluble receptor inhibits leptin transport. J Cell Physiol. 2007; 214(2):301-5. DOI: 10.1002/jcp.21195. View

Bennett P, Lindell K, Karlsson C, Robinson I, Carlsson L, Carlsson B . Differential expression and regulation of leptin receptor isoforms in the rat brain: effects of fasting and oestrogen. Neuroendocrinology. 1998; 67(1):29-36. DOI: 10.1159/000054295. View

Gogiraju R, Hubert A, Fahrer J, Straub B, Brandt M, Wenzel P . Endothelial Leptin Receptor Deletion Promotes Cardiac Autophagy and Angiogenesis Following Pressure Overload by Suppressing Akt/mTOR Signaling. Circ Heart Fail. 2019; 12(1):e005622. DOI: 10.1161/CIRCHEARTFAILURE.118.005622. View

Liao Z, Ran L, Qi X, Wang Y, Wang Y, Yang J . Adipose endothelial cells mastering adipose tissues metabolic fate. Adipocyte. 2022; 11(1):108-119. PMC: 8786343. DOI: 10.1080/21623945.2022.2028372. View

Pan W, Hsuchou H, Cornelissen-Guillaume G, Jayaram B, Wang Y, Tu H . Endothelial leptin receptor mutation provides partial resistance to diet-induced obesity. J Appl Physiol (1985). 2012; 112(8):1410-8. PMC: 3331584. DOI: 10.1152/japplphysiol.00590.2011. View

Frederich R, Hamann A, Anderson S, Lollmann B, Lowell B, Flier J . Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action. Nat Med. 1995; 1(12):1311-4. DOI: 10.1038/nm1295-1311. View

Bouloumie A, Marumo T, Lafontan M, Busse R . Leptin induces oxidative stress in human endothelial cells. FASEB J. 1999; 13(10):1231-8. View

Hsuchou H, Kastin A, Tu H, Markadakis E, Stone K, Wang Y . Effects of cell-type specific leptin receptor mutation on leptin transport across the BBB. Peptides. 2011; 32(7):1392-9. PMC: 3137692. DOI: 10.1016/j.peptides.2011.05.011. View

Butiaeva L, Slutzki T, Swick H, Bourguignon C, Robins S, Liu X . Leptin receptor-expressing pericytes mediate access of hypothalamic feeding centers to circulating leptin. Cell Metab. 2021; 33(7):1433-1448.e5. DOI: 10.1016/j.cmet.2021.05.017. View

10.

Tschop M, Speakman J, Arch J, Auwerx J, Bruning J, Chan L . A guide to analysis of mouse energy metabolism. Nat Methods. 2011; 9(1):57-63. PMC: 3654855. DOI: 10.1038/nmeth.1806. View

11.

Tartaglia L, Dembski M, Weng X, Deng N, Culpepper J, Devos R . Identification and expression cloning of a leptin receptor, OB-R. Cell. 1995; 83(7):1263-71. DOI: 10.1016/0092-8674(95)90151-5. View

12.

Cattaneo P, Mukherjee D, Spinozzi S, Zhang L, Larcher V, Stallcup W . Parallel Lineage-Tracing Studies Establish Fibroblasts as the Prevailing In Vivo Adipocyte Progenitor. Cell Rep. 2020; 30(2):571-582.e2. DOI: 10.1016/j.celrep.2019.12.046. View

13.

Jais A, Solas M, Backes H, Chaurasia B, Kleinridders A, Theurich S . Myeloid-Cell-Derived VEGF Maintains Brain Glucose Uptake and Limits Cognitive Impairment in Obesity. Cell. 2016; 165(4):882-95. DOI: 10.1016/j.cell.2016.03.033. View

14.

Bagchi D, Nishii A, Li Z, Delproposto J, Corsa C, Mori H . Wnt/β-catenin signaling regulates adipose tissue lipogenesis and adipocyte-specific loss is rigorously defended by neighboring stromal-vascular cells. Mol Metab. 2020; 42:101078. PMC: 7554252. DOI: 10.1016/j.molmet.2020.101078. View

15.

Flak J, Myers Jr M . Minireview: CNS Mechanisms of Leptin Action. Mol Endocrinol. 2015; 30(1):3-12. PMC: 4695630. DOI: 10.1210/me.2015-1232. View

16.

Vijay J, Gauthier M, Biswell R, Louiselle D, Johnston J, Cheung W . Single-cell analysis of human adipose tissue identifies depot and disease specific cell types. Nat Metab. 2020; 2(1):97-109. PMC: 7025882. DOI: 10.1038/s42255-019-0152-6. View

17.

Golden P, Maccagnan T, Pardridge W . Human blood-brain barrier leptin receptor. Binding and endocytosis in isolated human brain microvessels. J Clin Invest. 1997; 99(1):14-8. PMC: 507761. DOI: 10.1172/JCI119125. View

18.

Faouzi M, Leshan R, Bjornholm M, Hennessey T, Jones J, Munzberg H . Differential accessibility of circulating leptin to individual hypothalamic sites. Endocrinology. 2007; 148(11):5414-23. DOI: 10.1210/en.2007-0655. View

19.

Di Spiezio A, Sandin E, Dore R, Muller-Fielitz H, Storck S, Bernau M . The LepR-mediated leptin transport across brain barriers controls food reward. Mol Metab. 2017; 8:13-22. PMC: 5985039. DOI: 10.1016/j.molmet.2017.12.001. View

20.

Tu H, Pan W, Feucht L, Kastin A . Convergent trafficking pattern of leptin after endocytosis mediated by ObRa-ObRd. J Cell Physiol. 2007; 212(1):215-22. DOI: 10.1002/jcp.21020. View