Lipid-overloaded enlarged adipocytes provoke insulin resistance independent of inflammation.
In obesity, adipocyte hypertrophy and proinflammatory responses are closely associated with the development of insulin resistance in adipose tissue. However, it is largely unknown whether adipocyte hypertrophy per se might be sufficient to provoke insulin resistance in obese adipose tissue. Here, we demonstrate that lipid-overloaded hypertrophic adipocytes are insulin resistant independent of adipocyte inflammation. Treatment with saturated or monounsaturated fatty acids resulted in adipocyte hypertrophy, but proinflammatory responses were observed only in adipocytes treated with saturated fatty acids. Regardless of adipocyte inflammation, hypertrophic adipocytes with large and unilocular lipid droplets exhibited impaired insulin-dependent glucose uptake, associated with defects in GLUT4 trafficking to the plasma membrane. Moreover, Toll-like receptor 4 mutant mice (C3H/HeJ) with high-fat-diet-induced obesity were not protected against insulin resistance, although they were resistant to adipose tissue inflammation. Together, our in vitro and in vivo data suggest that adipocyte hypertrophy alone may be crucial in causing insulin resistance in obesity.
National Creative Research Initiatives Center for Adipose Tissue Remodeling, Department of Biological Sciences, Institute of Molecular Biology and Genetics, Seoul National University, Seoul, South Korea.
Jong In
JI
Kim
National Creative Research Initiatives Center for Adipose Tissue Remodeling, Department of Biological Sciences, Institute of Molecular Biology and Genetics, Seoul National University, Seoul, South Korea.
Jin Young
JY
Huh
National Creative Research Initiatives Center for Adipose Tissue Remodeling, Department of Biological Sciences, Institute of Molecular Biology and Genetics, Seoul National University, Seoul, South Korea.
Jee Hyung
JH
Sohn
National Creative Research Initiatives Center for Adipose Tissue Remodeling, Department of Biological Sciences, Institute of Molecular Biology and Genetics, Seoul National University, Seoul, South Korea.
Sung Sik
SS
Choe
Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California, USA Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.
Yun Sok
YS
Lee
Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
Chun Yan
CY
Lim
Department of Chemistry, Seoul National University, Seoul, South Korea.
Ala
A
Jo
Department of Chemistry, Seoul National University, Seoul, South Korea.
Seung Bum
SB
Park
Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
Weiping
W
Han
National Creative Research Initiatives Center for Adipose Tissue Remodeling, Department of Biological Sciences, Institute of Molecular Biology and Genetics, Seoul National University, Seoul, South Korea jaebkim@snu.ac.kr.
Jae Bum
JB
Kim
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000276:immunology; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology*; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D066298:In Vitro Techniques; D007333:Insulin Resistance; D066292:Lipid Droplets / Q000378:metabolism; D008297:Male; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D009765:Obesity / Q000139:chemically induced / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism
D016207:Cytokines; D004041:Dietary Fats; D005229:Fatty Acids, Monounsaturated; D005230:Fatty Acids, Nonesterified; D051275:Glucose Transporter Type 4; C495693:Slc2a4 protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4