Myeloid cell-specific disruption of Period1 and Period2 exacerbates diet-induced inflammation and insulin resistance.
The circadian clockworks gate macrophage inflammatory responses. Given the association between clock dysregulation and metabolic disorders, we conducted experiments to determine the extent to which over-nutrition modulates macrophage clock function and whether macrophage circadian dysregulation is a key factor linking over-nutrition to macrophage proinflammatory activation, adipose tissue inflammation, and systemic insulin resistance. Our results demonstrate that 1) macrophages from high fat diet-fed mice are marked by dysregulation of the molecular clockworks in conjunction with increased proinflammatory activation, 2) global disruption of the clock genes Period1 (Per1) and Per2 recapitulates this amplified macrophage proinflammatory activation, 3) adoptive transfer of Per1/2-disrupted bone marrow cells into wild-type mice potentiates high fat diet-induced adipose and liver tissue inflammation and systemic insulin resistance, and 4) Per1/2-disrupted macrophages similarly exacerbate inflammatory responses and decrease insulin sensitivity in co-cultured adipocytes in vitro. Furthermore, PPARγ levels are decreased in Per1/2-disrupted macrophages and PPARγ2 overexpression ameliorates Per1/2 disruption-associated macrophage proinflammatory activation, suggesting that this transcription factor may link the molecular clockworks to signaling pathways regulating macrophage polarization. Thus, macrophage circadian clock dysregulation is a key process in the physiological cascade by which diet-induced obesity triggers macrophage proinflammatory activation, adipose tissue inflammation, and insulin resistance.
From the Department of Nutrition and Food Science, Texas A&M University, College Station, Texas 77843.
Hang
H
Xu
From the Department of Nutrition and Food Science, Texas A&M University, College Station, Texas 77843.
Honggui
H
Li
From the Department of Nutrition and Food Science, Texas A&M University, College Station, Texas 77843.
Shih-Lung
SL
Woo
Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M Health Science Center, Bryan, Texas 77807.
Sam-Moon
SM
Kim
Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M Health Science Center, Bryan, Texas 77807.
Vikram R
VR
Shende
Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M Health Science Center, Bryan, Texas 77807.
Nichole
N
Neuendorff
From the Department of Nutrition and Food Science, Texas A&M University, College Station, Texas 77843.
Xin
X
Guo
From the Department of Nutrition and Food Science, Texas A&M University, College Station, Texas 77843.
Ting
T
Guo
From the Department of Nutrition and Food Science, Texas A&M University, College Station, Texas 77843.
Ting
T
Qi
From the Department of Nutrition and Food Science, Texas A&M University, College Station, Texas 77843.
Ya
Y
Pei
From the Department of Nutrition and Food Science, Texas A&M University, College Station, Texas 77843.
Yan
Y
Zhao
From the Department of Nutrition and Food Science, Texas A&M University, College Station, Texas 77843, Department of Endocrinology and.
Xiang
X
Hu
From the Department of Nutrition and Food Science, Texas A&M University, College Station, Texas 77843, Department of Stomatology, Union Hospital, Tongji College of Medicine, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China, and.
Jiajia
J
Zhao
Department of Stomatology, Union Hospital, Tongji College of Medicine, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China, and.
Lili
L
Chen
Department of Endocrinology and.
Lulu
L
Chen
Department of Molecular and Cellular Medicine and.
Jun-Yuan
JY
Ji
Department of Microbial and Molecular Pathogenesis, College of Medicine, Texas A&M Health Science Center, College Station, Texas 77843.
Robert C
RC
Alaniz
Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M Health Science Center, Bryan, Texas 77807, DEARNEST@medicine.tamhsc.edu.
David J
DJ
Earnest
From the Department of Nutrition and Food Science, Texas A&M University, College Station, Texas 77843, cdwu@tamu.edu.
Chaodong
C
Wu
D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism*; D018920:Coculture Techniques; D059305:Diet, High-Fat; D007249:Inflammation / Q000378:metabolism*; D007333:Insulin Resistance; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000378:metabolism; D056950:Period Circadian Proteins / Q000378:metabolism*
D047495:PPAR gamma; C539023:Per1 protein, mouse; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins
Adipose Tissue; Circadian Clock; Inflammation; Insulin Resistance; Macrophage