TY - JOUR
T1 - Vascular Endothelial Growth Factor–D (VEGF-D) Overexpression and Lymphatic Expansion in Murine Adipose Tissue Improves Metabolism in Obesity
AU - Chakraborty, Adri
AU - Barajas, Sheridan
AU - Lammoglia, Gabriela M.
AU - Reyna, Andrea J.
AU - Morley, Thomas S.
AU - Johnson, Joshua A.
AU - Scherer, Philipp E.
AU - Rutkowski, Joseph M.
N1 - Funding Information:
Supported by the American Heart Association grant 17GRNT33671220 (J.M.R.), the Texas A&M University Health Science Center College of Medicine and Department of Medical Physiology (J.M.R.), NIH grants R01-DK55758 (P.E.S.), R01-DK099110 (P.E.S.), and P01-DK088761-01 (P.E.S.), and the Lipedema Foundation (J.M.R., P.E.S., and A.C.). Supported by the American Heart Association grant 17GRNT33671220 (J.M.R.), the Texas A&M University Health Science Center College of Medicine and Department of Medical Physiology (J.M.R.), NIH grants R01-DK55758 (P.E.S.), R01-DK099110 (P.E.S.), and P01-DK088761-01 (P.E.S.), and the Lipedema Foundation (J.M.R., P.E.S., and A.C.). We thank Selene Howe (Texas A&M College of Medicine and Texas A&M Institute for Genome Sciences and Society) and David Threadgill (Texas A&M College of Medicine and Texas A&M Institute for Genome Sciences and Society) for assistance with and use of the metabolic cages, and Michael Dellinger (University of Texas Southwestern Medical Center at Dallas) for performing and capturing the LYVE-1 intestinal imaging. Supported by the American Heart Association grant 17GRNT33671220 (J.M.R.), the Texas A&M University Health Science Center College of Medicine and Department of Medical Physiology (J.M.R.), NIH grants R01-DK55758 (P.E.S.), R01-DK099110 (P.E.S.), and P01-DK088761-01 (P.E.S.), and the Lipedema Foundation (J.M.R., P.E.S., and A.C.).
Publisher Copyright:
© 2019 American Society for Investigative Pathology
PY - 2019/4
Y1 - 2019/4
N2 - Obese adipose tissue expansion is an inflammatory process that results in dysregulated lipolysis, increased circulating lipids, ectopic lipid deposition, and systemic insulin resistance. Lymphatic vessels provide a route of fluid, macromolecule, and immune cell clearance, and lymphangiogenesis increases this capability. Indeed, inflammation-associated lymphangiogenesis is critical in resolving acute and chronic inflammation, but it is largely absent in obese adipose tissue. Enhancing adipose tissue lymphangiogenesis could, therefore, improve metabolism in obesity. To test this hypothesis, transgenic mice with doxycycline-inducible expression of murine vascular endothelial growth factor (VEGF)-D under a tightly controlled Tet-On promoter were crossed with adipocyte-specific adiponectin–reverse tetracycline–dependent transactivator mice (Adipo-VD) to stimulate adipose tissue–specific lymphangiogenesis during 16-week high-fat diet–induced obesity. Adipose VEGF-D overexpression induced de novo lymphangiogenesis in murine adipose tissue, and obese Adipo-VD mice exhibited enhanced glucose clearance, lower insulin levels, and reduced liver triglycerides. On β-3 adrenergic stimulation, Adipo-VD mice exhibited more rapid and increased glycerol flux from adipose tissue, suggesting that the lymphatics are a potential route of glycerol clearance. Resident macrophage crown-like structures were scarce and total F4/80 + macrophages were reduced in obese Adipo-VD s.c. adipose tissue with evidence of increased immune trafficking from the tissue. Augmenting VEGF-D signaling and lymphangiogenesis specifically in adipose tissue, therefore, reduces obesity-associated immune accumulation and improves metabolic responsiveness.
AB - Obese adipose tissue expansion is an inflammatory process that results in dysregulated lipolysis, increased circulating lipids, ectopic lipid deposition, and systemic insulin resistance. Lymphatic vessels provide a route of fluid, macromolecule, and immune cell clearance, and lymphangiogenesis increases this capability. Indeed, inflammation-associated lymphangiogenesis is critical in resolving acute and chronic inflammation, but it is largely absent in obese adipose tissue. Enhancing adipose tissue lymphangiogenesis could, therefore, improve metabolism in obesity. To test this hypothesis, transgenic mice with doxycycline-inducible expression of murine vascular endothelial growth factor (VEGF)-D under a tightly controlled Tet-On promoter were crossed with adipocyte-specific adiponectin–reverse tetracycline–dependent transactivator mice (Adipo-VD) to stimulate adipose tissue–specific lymphangiogenesis during 16-week high-fat diet–induced obesity. Adipose VEGF-D overexpression induced de novo lymphangiogenesis in murine adipose tissue, and obese Adipo-VD mice exhibited enhanced glucose clearance, lower insulin levels, and reduced liver triglycerides. On β-3 adrenergic stimulation, Adipo-VD mice exhibited more rapid and increased glycerol flux from adipose tissue, suggesting that the lymphatics are a potential route of glycerol clearance. Resident macrophage crown-like structures were scarce and total F4/80 + macrophages were reduced in obese Adipo-VD s.c. adipose tissue with evidence of increased immune trafficking from the tissue. Augmenting VEGF-D signaling and lymphangiogenesis specifically in adipose tissue, therefore, reduces obesity-associated immune accumulation and improves metabolic responsiveness.
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U2 - 10.1016/j.ajpath.2018.12.008
DO - 10.1016/j.ajpath.2018.12.008
M3 - Article
C2 - 30878136
AN - SCOPUS:85063088277
SN - 0002-9440
VL - 189
SP - 924
EP - 939
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 4
ER -