Deletion of hypoxia-inducible factor-1α in adipocytes enhances glucagon-like peptide-1 secretion and reduces adipose tissue inflammation.
It is known that obese adipose tissues are hypoxic and express hypoxia-inducible factor (HIF)-1α. Although some studies have shown that the expression of HIF-1α in adipocytes induces glucose intolerance, the mechanisms are still not clear. In this study, we examined its effects on the development of type 2 diabetes by using adipocyte-specific HIF-1α knockout (ahKO) mice. ahKO mice showed improved glucose tolerance compared with wild type (WT) mice. Macrophage infiltration and mRNA levels of monocyte chemotactic protein-1 (MCP-1) and tumor necrosis factor α (TNFα) were decreased in the epididymal adipose tissues of high fat diet induced obese ahKO mice. The results indicated that the obesity-induced adipose tissue inflammation was suppressed in ahKO mice. In addition, in the ahKO mice, serum insulin levels were increased under the free-feeding but not the fasting condition, indicating that postprandial insulin secretion was enhanced. Serum glucagon-like peptide-1 (GLP-1) levels were also increased in the ahKO mice. Interestingly, adiponectin, whose serum levels were increased in the obese ahKO mice compared with the obese WT mice, stimulated GLP-1 secretion from cultured intestinal L cells. Therefore, insulin secretion may have been enhanced through the adiponectin-GLP-1 pathway in the ahKO mice. Our results suggest that the deletion of HIF-1α in adipocytes improves glucose tolerance by enhancing insulin secretion through the GLP-1 pathway and by reducing macrophage infiltration and inflammation in adipose tissue.
Department of Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
Yoshitaka
Y
Kihira
Department of Medical Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
Mariko
M
Miyake
Department of Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan; Student Laboratory, Faculty of Medicine, The University of Tokushima, Tokushima, Japan.
Manami
M
Hirata
Department of Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan; Student Laboratory, Faculty of Medicine, The University of Tokushima, Tokushima, Japan.
Yoji
Y
Hoshina
Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, Miyagi, Japan.
Kana
K
Kato
Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, Miyagi, Japan.
Hitoshi
H
Shirakawa
Department of Nutrition and Metabolism, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
Hiroshi
H
Sakaue
Department of Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
Noriko
N
Yamano
Department of Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
Yuki
Y
Izawa-Ishizawa
Department of Medical Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
Keisuke
K
Ishizawa
Department of Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
Yasumasa
Y
Ikeda
Department of Medical Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
Koichiro
K
Tsuchiya
Department of Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
Toshiaki
T
Tamaki
Division of Molecular Pharmacology, Faculty of Medicine, Tottori University, Tottori, Japan.
Shuhei
S
Tomita
D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D018932:Chemokine CCL2 / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D017353:Gene Deletion; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D005951:Glucose Tolerance Test; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000172:deficiency* / Q000235:genetics; D007150:Immunohistochemistry; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D051379:Mice; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D017931:DNA Primers; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007328:Insulin; D014409:Tumor Necrosis Factor-alpha; D052216:Glucagon-Like Peptide 1