Adipose hypothermia in obesity and its association with period homolog 1, insulin sensitivity, and inflammation in fat

Masaya Yamaoka; Norikazu Maeda; Yasunori Takayama; Ryohei Sekimoto; Yu Tsushima; Keisuke Matsuda; Takuya Mori; Kana Inoue; Hitoshi Nishizawa; Makoto Tominaga; Tohru Funahashi; Iichiro Shimomura

doi:10.1371/journal.pone.0112813

Adipose hypothermia in obesity and its association with period homolog 1, insulin sensitivity, and inflammation in fat

PLoS One. 2014 Nov 14;9(11):e112813. doi: 10.1371/journal.pone.0112813. eCollection 2014.

Affiliations

¹ Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan.
² Division of Cell Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Okazaki, Aichi, 444-8787, Japan.
³ Division of Cell Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Okazaki, Aichi, 444-8787, Japan; Department of Physiological Sciences, The Graduate University for Advanced Studies, Okazaki, Aichi, 444-8585, Japan.
⁴ Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan; Department of Metabolism and Atherosclerosis, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan.

Abstract

Visceral fat adiposity plays an important role in the development of metabolic syndrome. We reported previously the impact of human visceral fat adiposity on gene expression profile of peripheral blood cells. Genes related to circadian rhythm were highly associated with visceral fat area and period homolog 1 (PER1) showed the most significant negative correlation with visceral fat area. However, regulation of adipose Per1 remains poorly understood. The present study was designed to understand the regulation of Per1 in adipose tissues. Adipose Per1 mRNA levels of ob/ob mice were markedly low at 25 and 35 weeks of age. The levels of other core clock genes of white adipose tissues were also low in ob/ob mice at 25 and 35 weeks of age. Per1 mRNA was mainly expressed in the mature adipocyte fraction (MAF) and it was significantly low in MAF of ob/ob mice. To examine the possible mechanisms, 3T3-L1 adipocytes were treated with H2O2, tumor necrosis factor-α (TNF-α), S100A8, and lipopolysaccharide (LPS). However, no significant changes in Per1 mRNA level were observed by these agents. Exposure of cultured 3T3-L1 adipocytes to low temperature (33°C) decreased Per1 and catalase, and increased monocyte chemoattractant protein-1 (Mcp-1) mRNA levels. Hypothermia also worsened insulin-mediated Akt phosphorylation in 3T3-L1 adipocytes. Finally, telemetric analysis showed low temperature of adipose tissues in ob/ob mice. In obesity, adipose hypothermia seems to accelerate adipocyte dysfunction.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3T3-L1 Cells
Adipose Tissue / metabolism*
Animals
Blotting, Western
Body Temperature
Catalase / genetics
Catalase / metabolism
Cell Differentiation / drug effects
Chemokine CCL2 / genetics
Chemokine CCL2 / metabolism
Humans
Hydrogen Peroxide / toxicity
Hypothermia, Induced
Inflammation*
Insulin / pharmacology
Lipopolysaccharides / toxicity
Male
Mice
Mice, Inbred C57BL
Mice, Obese
Motor Activity / drug effects
Obesity / metabolism
Obesity / pathology*
Period Circadian Proteins / genetics
Period Circadian Proteins / metabolism*
Phosphorylation / drug effects
Proto-Oncogene Proteins c-akt / metabolism
RNA, Messenger / metabolism
Real-Time Polymerase Chain Reaction
Tumor Necrosis Factor-alpha / pharmacology

Substances

Ccl2 protein, mouse
Chemokine CCL2
Insulin
Lipopolysaccharides
Per1 protein, mouse
Period Circadian Proteins
RNA, Messenger
Tumor Necrosis Factor-alpha
Hydrogen Peroxide
Catalase
Proto-Oncogene Proteins c-akt

Grants and funding

This work was supported in part by a Grants-in-Aid for Scientific Research (C) no. 22590979 (to NM), a Grants-in-Aid for Scientific Research (B) no. 24390238 (to IS), a Grants-in-Aid for Scientific Research on Innovative Areas no. 22126008 (to TF), Takeda Science Foundation (to NM), Japan Diabetes Foundation (to NM), and Suzuken Memorial Foundation (to NM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.